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  1. Prolonged ethanol administration depletes mitochondrial DNA in MnSOD-overexpressing transgenic mice, but not in their wild type littermates

    International Nuclear Information System (INIS)

    Alcohol consumption increases reactive oxygen species formation and lipid peroxidation, whose products can damage mitochondrial DNA (mtDNA) and alter mitochondrial function. A possible role of manganese superoxide dismutase (MnSOD) on these effects has not been investigated. To test whether MnSOD overexpression modulates alcohol-induced mitochondrial alterations, we added ethanol to the drinking water of transgenic MnSOD-overexpressing (TgMnSOD) mice and their wild type (WT) littermates for 7 weeks. In TgMnSOD mice, alcohol administration further increased the activity of MnSOD, but decreased cytosolic glutathione as well as cytosolic glutathione peroxidase activity and peroxisomal catalase activity. Whereas ethanol increased cytochrome P-450 2E1 and mitochondrial ROS generation in both WT and TgMnSOD mice, hepatic iron, lipid peroxidation products and respiratory complex I protein carbonyls were only increased in ethanol-treated TgMnSOD mice but not in WT mice. In ethanol-fed TgMnSOD mice, but not ethanol-fed WT mice, mtDNA was depleted, and mtDNA lesions blocked the progress of polymerases. The iron chelator, DFO prevented hepatic iron accumulation, lipid peroxidation, protein carbonyl formation and mtDNA depletion in alcohol-treated TgMnSOD mice. Alcohol markedly decreased the activities of complexes I, IV and V of the respiratory chain in TgMnSOD, with absent or lesser effects in WT mice. There was no inflammation, apoptosis or necrosis, and steatosis was similar in ethanol-treated WT and TgMnSOD mice. In conclusion, prolonged alcohol administration selectively triggers iron accumulation, lipid peroxidation, respiratory complex I protein carbonylation, mtDNA lesions blocking the progress of polymerases, mtDNA depletion and respiratory complex dysfunction in TgMnSOD mice but not in WT mice

  2. Mitochondrial Toxicity of Depleted Uranium: Protection by Beta-Glucan

    OpenAIRE

    Shaki, Fatemeh; Pourahmad, Jalal

    2013-01-01

    Considerable evidence suggests that mitochondrial dysfunction contributes to the toxicity of uranyl acetate (UA), a soluble salt of depleted uranium (DU). We examined the ability of the two antioxidants, beta-glucan and butylated hydroxyl toluene (BHT), to prevent UA-induced mitochondrial dysfunction using rat-isolated kidney mitochondria. Beta-glucan (150 nM) and BHT (20 nM) attenuated UA-induced mitochondrial reactive oxygen species (ROS) formation, lipid peroxidation and glutathione oxidat...

  3. "Stiff neonate" with mitochondrial DNA depletion and secondary neurotransmitter defects.

    LENUS (Irish Health Repository)

    Moran, Margaret M

    2011-12-01

    Mitochondrial disorders comprise a heterogenous group. A neonate who presented with episodes of severe truncal hypertonia and apnea progressed to a hypokinetic rigid syndrome characterized by hypokinesia, tremulousness, profound head lag, absent suck and gag reflexes, brisk deep tendon reflexes, ankle and jaw clonus, and evidence of autonomic dysfunction. Analysis of cerebrospinal fluid neurotransmitters from age 7 weeks demonstrated low levels of amine metabolites (homovanillic acid and 5-hydroxyindoleacetic acid), tetrahydrobiopterin, and pyridoxal phosphate. Mitochondrial DNA quantitative studies on muscle homogenate demonstrated a mitochondrial DNA depletion disorder. Respiratory chain enzymology demonstrated decreased complex IV activity. Screening for mitochondrial DNA rearrangement disorders and sequencing relevant mitochondrial genes produced negative results. No clinical or biochemical response to treatment with pyridoxal phosphate, tetrahydrobiopterin, or l-dopa occurred. The clinical course was progressive, and the patient died at age 19 months. Mitochondrial disorders causing secondary neurotransmitter diseases are usually severe, but are rarely reported. This diagnosis should be considered in neonates or infants who present with hypertonia, hypokinesia rigidity, and progressive neurodegeneration.

  4. Mitochondrial toxicity of depleted uranium: protection by Beta-glucan.

    Science.gov (United States)

    Shaki, Fatemeh; Pourahmad, Jalal

    2013-01-01

    Considerable evidence suggests that mitochondrial dysfunction contributes to the toxicity of uranyl acetate (UA), a soluble salt of depleted uranium (DU). We examined the ability of the two antioxidants, beta-glucan and butylated hydroxyl toluene (BHT), to prevent UA-induced mitochondrial dysfunction using rat-isolated kidney mitochondria. Beta-glucan (150 nM) and BHT (20 nM) attenuated UA-induced mitochondrial reactive oxygen species (ROS) formation, lipid peroxidation and glutathione oxidation. Beta-glucan and BHT also prevented the loss of mitochondrial membrane potential (MMP) and mitochondrial swelling following the UA treatment in isolated mitochondria. Our results show that beta-glucan and BHT prevented UA-induced mitochondrial outer membrane damage as well as release of cytochrome c from mitochondria. UA also decreased the ATP production in isolated mitochondria significantly inhibited with beta-glucan and BHT pre-treatment. Our results showed that beta-glucan may be mitochondria-targeted antioxidant and suggested this compound as a possible drug candidate for prophylaxis and treatment against DU-induced nephrotoxicity. PMID:24250581

  5. Adult mitochondrial DNA depletion syndrome with mild manifestations

    Directory of Open Access Journals (Sweden)

    Josef Finsterer

    2013-06-01

    Full Text Available Mitochondrial DNA depletion syndrome (MDS is usually a severe disorder of infancy or childhood, due to a reduced copy number of mtDNA molecules. MDS with only mild, non-specific clinical manifestations and onset in adulthood has not been reported. A 47-year-old Caucasian female with short stature and a history of migraine, endometriosis, Crohn’s disease, C-cell carcinoma of the thyroid gland, and a family history positive for mitochondrial disorder (2 sisters, aunt, niece, developed day-time sleepiness, exercise intolerance, and myalgias in the lower-limb muscles since age 46y. She slept 9-10 hours during the night and 2 hours after lunch daily. Clinical exam revealed sore neck muscles, bilateral ptosis, and reduced Achilles tendon reflexes exclusively. Blood tests revealed hyperlipidemia exclusively. Nerve conduction studies, needle electromyography, and cerebral and spinal magnetic resonance imaging were non-informative. Muscle biopsy revealed detached lobulated fibers with subsarcolemmal accentuation of the NADH and SDH staining. Real-time polymerase chain reaction revealed depletion of the mtDNA down to 9% of normal. MDS may be associated with a mild phenotype in adults and may not significantly progress during the first year after onset. In an adult with hypersomnia, severe tiredness, exercise intolerance, and a family history positive for mitochondrial disorder, a MDS should be considered.

  6. Cellular aging of mitochondrial DNA-depleted cells

    International Nuclear Information System (INIS)

    We have reported that mitochondrial DNA-depleted ρ0 cells are resistant to cell death. Because aged cells have frequent mitochondrial DNA mutations, the resistance of ρ0 cells against cell death might be related to the apoptosis resistance of aged cells and frequent development of cancers in aged individuals. We studied if ρ0 cells have features simulating aged cells. SK-Hep1 hepatoma ρ0 cells showed typical morphology associated with aging such as increased size and elongated appearance. They had increased senescence-associated β-Gal activity, lipofuscin pigment, and plasminogen activator inhibitor-1 expression. Consistent with their decreased proliferation, the expression of mitotic cyclins was decreased and that of cdk inhibitors was increased. Rb hypophosphorylation and decreased telomerase activity were also noted. Features simulating aged cells were also observed in MDA-MB-435 ρ0 cells. These results support the mitochondrial theory of aging, and suggest that ρ0 cells could serve as an in vitro model for aged cells

  7. The interplay between SUCLA2, SUCLG2, and mitochondrial DNA depletion

    DEFF Research Database (Denmark)

    Miller, Chaya; Wang, Liya; Ostergaard, Elsebet;

    2011-01-01

    SUCLA2-related mitochondrial DNA (mtDNA) depletion syndrome is a result of mutations in the β subunit of the ADP-dependent isoform of the Krebs cycle succinyl-CoA synthase (SCS). The mechanism of tissue specificity and mtDNA depletion is elusive but complementation by the GDP-dependent isoform...

  8. Age-related mitochondrial DNA depletion and the impact on pancreatic Beta cell function.

    Directory of Open Access Journals (Sweden)

    Donna L Nile

    Full Text Available Type 2 diabetes is characterised by an age-related decline in insulin secretion. We previously identified a 50% age-related decline in mitochondrial DNA (mtDNA copy number in isolated human islets. The purpose of this study was to mimic this degree of mtDNA depletion in MIN6 cells to determine whether there is a direct impact on insulin secretion. Transcriptional silencing of mitochondrial transcription factor A, TFAM, decreased mtDNA levels by 40% in MIN6 cells. This level of mtDNA depletion significantly decreased mtDNA gene transcription and translation, resulting in reduced mitochondrial respiratory capacity and ATP production. Glucose-stimulated insulin secretion was impaired following partial mtDNA depletion, but was normalised following treatment with glibenclamide. This confirms that the deficit in the insulin secretory pathway precedes K+ channel closure, indicating that the impact of mtDNA depletion is at the level of mitochondrial respiration. In conclusion, partial mtDNA depletion to a degree comparable to that seen in aged human islets impaired mitochondrial function and directly decreased insulin secretion. Using our model of partial mtDNA depletion following targeted gene silencing of TFAM, we have managed to mimic the degree of mtDNA depletion observed in aged human islets, and have shown how this correlates with impaired insulin secretion. We therefore predict that the age-related mtDNA depletion in human islets is not simply a biomarker of the aging process, but will contribute to the age-related risk of type 2 diabetes.

  9. In EXOG-depleted cardiomyocytes cell death is marked by a decreased mitochondrial reserve capacity of the electron transport chain.

    Science.gov (United States)

    Tigchelaar, Wardit; De Jong, Anne Margreet; van Gilst, Wiek H; De Boer, Rudolf A; Silljé, Herman H W

    2016-07-01

    Depletion of mitochondrial endo/exonuclease G-like (EXOG) in cultured neonatal cardiomyocytes stimulates mitochondrial oxygen consumption rate (OCR) and induces hypertrophy via reactive oxygen species (ROS). Here, we show that neurohormonal stress triggers cell death in endo/exonuclease G-like-depleted cells, and this is marked by a decrease in mitochondrial reserve capacity. Neurohormonal stimulation with phenylephrine (PE) did not have an additive effect on the hypertrophic response induced by endo/exonuclease G-like depletion. Interestingly, PE-induced atrial natriuretic peptide (ANP) gene expression was completely abolished in endo/exonuclease G-like-depleted cells, suggesting a reverse signaling function of endo/exonuclease G-like. Endo/exonuclease G-like depletion initially resulted in increased mitochondrial OCR, but this declined upon PE stimulation. In particular, the reserve capacity of the mitochondrial respiratory chain and maximal respiration were the first indicators of perturbations in mitochondrial respiration, and these marked the subsequent decline in mitochondrial function. Although pathological stimulation accelerated these processes, prolonged EXOG depletion also resulted in a decline in mitochondrial function. At early stages of endo/exonuclease G-like depletion, mitochondrial ROS production was increased, but this did not affect mitochondrial DNA (mtDNA) integrity. After prolonged depletion, ROS levels returned to control values, despite hyperpolarization of the mitochondrial membrane. The mitochondrial dysfunction finally resulted in cell death, which appears to be mainly a form of necrosis. In conclusion, endo/exonuclease G-like plays an essential role in cardiomyocyte physiology. Loss of endo/exonuclease G-like results in diminished adaptation to pathological stress. The decline in maximal respiration and reserve capacity is the first sign of mitochondrial dysfunction that determines subsequent cell death. PMID:27417117

  10. Palmitate induces ER calcium depletion and apoptosis in mouse podocytes subsequent to mitochondrial oxidative stress.

    Science.gov (United States)

    Xu, S; Nam, S M; Kim, J-H; Das, R; Choi, S-K; Nguyen, T T; Quan, X; Choi, S J; Chung, C H; Lee, E Y; Lee, I-K; Wiederkehr, A; Wollheim, C B; Cha, S-K; Park, K-S

    2015-01-01

    Pathologic alterations in podocytes lead to failure of an essential component of the glomerular filtration barrier and proteinuria in chronic kidney diseases. Elevated levels of saturated free fatty acid (FFA) are harmful to various tissues, implemented in the progression of diabetes and its complications such as proteinuria in diabetic nephropathy. Here, we investigated the molecular mechanism of palmitate cytotoxicity in cultured mouse podocytes. Incubation with palmitate dose-dependently increased cytosolic and mitochondrial reactive oxygen species, depolarized the mitochondrial membrane potential, impaired ATP synthesis and elicited apoptotic cell death. Palmitate not only evoked mitochondrial fragmentation but also caused marked dilation of the endoplasmic reticulum (ER). Consistently, palmitate upregulated ER stress proteins, oligomerized stromal interaction molecule 1 (STIM1) in the subplasmalemmal ER membrane, abolished the cyclopiazonic acid-induced cytosolic Ca(2+) increase due to depletion of luminal ER Ca(2+). Palmitate-induced ER Ca(2+) depletion and cytotoxicity were blocked by a selective inhibitor of the fatty-acid transporter FAT/CD36. Loss of the ER Ca(2+) pool induced by palmitate was reverted by the phospholipase C (PLC) inhibitor edelfosine. Palmitate-dependent activation of PLC was further demonstrated by following cytosolic translocation of the pleckstrin homology domain of PLC in palmitate-treated podocytes. An inhibitor of diacylglycerol (DAG) kinase, which elevates cytosolic DAG, strongly promoted ER Ca(2+) depletion by low-dose palmitate. GF109203X, a PKC inhibitor, partially prevented palmitate-induced ER Ca(2+) loss. Remarkably, the mitochondrial antioxidant mitoTEMPO inhibited palmitate-induced PLC activation, ER Ca(2+) depletion and cytotoxicity. Palmitate elicited cytoskeletal changes in podocytes and increased albumin permeability, which was also blocked by mitoTEMPO. These data suggest that oxidative stress caused by saturated FFA

  11. Residue depletion of colistin in swine after intramuscular administration

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    S.S. Tang

    2009-05-01

    Full Text Available A newly formulated colistin sulphate solution was prepared in a previous study as a potential agent for intramuscular injection and its effectiveness, toxicity and pharmacokinetics were investigated. In order to provide more information to establish scientific guidance for safe use of this preparation, its residue depletion in swine tissues following intramuscular administration was investigated in this experiment. Fifty healthy cross-bred piglets (13.3 ± 0.9 kg were used in this study. Five animals were kept as untreated controls and the other 45 animals were intramuscularly injected with the colistin preparation at a dose of 2.5 mg / kg of body weight. From the treated piglets, 5 animals were randomly selected and sacrificed at different withdrawal times. Liver, kidney and muscle tissues were sampled to examine the colistin residue levels by microbiological assay. The results showed that the colistin residue in liver and muscle decreased quickly and could not be detected at 1 day after the final dosing. However, the residue depletion in the kidneys was much slower than that in other tissues and even a small quantity of drug could be detected at 14 days after withdrawal. Using the method recommended by the Committee for Veterinary Medical Products (CVMP, a withdrawal time of 10 days was established for the safe use of the newly formulated colistin sulphate solution.

  12. Mitochondrial ATP transporter Ant2 depletion impairs erythropoiesis and B lymphopoiesis.

    Science.gov (United States)

    Cho, J; Seo, J; Lim, C H; Yang, L; Shiratsuchi, T; Lee, M-H; Chowdhury, R R; Kasahara, H; Kim, J-S; Oh, S P; Lee, Y J; Terada, N

    2015-09-01

    Adenine nucleotide translocases (ANTs) transport ADP and ATP through mitochondrial inner membrane, thus playing an essential role for energy metabolism of eukaryotic cells. Mice have three ANT paralogs, Ant1 (Slc25a4), Ant2 (Slc25a5) and Ant4 (Slc25a31), which are expressed in a tissue-dependent manner. While knockout mice have been characterized with Ant1 and Ant4 genes, which resulted in exercise intolerance and male infertility, respectively, the role of the ubiquitously expressed Ant2 gene in animal development has not been fully demonstrated. Here, we generated Ant2 hypomorphic mice by targeted disruption of the gene, in which Ant2 expression is largely depleted. The mice showed apparently normal embryonic development except pale phenotype along with a reduced birth rate. However, postnatal growth was severely retarded with macrocytic anemia, B lymphocytopenia, lactic acidosis and bloated stomach, and died within 4 weeks. Ant2 depletion caused anemia in a cell-autonomous manner by maturation arrest of erythroid precursors with increased reactive oxygen species and premature deaths. B-lymphocyte development was similarly affected by Ant2 depletion, and splenocytes showed a reduction in maximal respiration capacity and cellular ATP levels as well as an increase in cell death accompanying mitochondrial permeability transition pore opening. In contrast, myeloid, megakaryocyte and T-lymphocyte lineages remained apparently intact. Erythroid and B-cell development may be particularly vulnerable to Ant2 depletion-mediated mitochondrial dysfunction and oxidative stress. PMID:25613378

  13. Targeted impairment of thymidine kinase 2 expression in cells induces mitochondrial DNA depletion and reveals molecular mechanisms of compensation of mitochondrial respiratory activity

    International Nuclear Information System (INIS)

    Highlights: → We impaired TK2 expression in Ost TK1- cells via siRNA-mediated interference (TK2-). → TK2 impairment caused severe mitochondrial DNA (mtDNA) depletion in quiescent cells. → Despite mtDNA depletion, TK2- cells show high cytochrome oxidase activity. → Depletion of mtDNA occurs without imbalance in the mitochondrial dNTP pool. → Nuclear-encoded ENT1, DNA-pol γ, TFAM and TP gene expression is lowered in TK2- cells. -- Abstract: The mitochondrial DNA (mtDNA) depletion syndrome comprises a clinically heterogeneous group of diseases characterized by reductions of the mtDNA abundance, without associated point mutations or rearrangements. We have developed the first in vitro model to study of mtDNA depletion due to reduced mitochondrial thymidine kinase 2 gene (TK2) expression in order to understand the molecular mechanisms involved in mtDNA depletion syndrome due to TK2 mutations. Small interfering RNA targeting TK2 mRNA was used to decrease TK2 expression in Ost TK1- cells, a cell line devoid of endogenous thymidine kinase 1 (TK1). Stable TK2-deficient cell lines showed a reduction of TK2 levels close to 80%. In quiescent conditions, TK2-deficient cells showed severe mtDNA depletion, also close to 80% the control levels. However, TK2-deficient clones showed increased cytochrome c oxidase activity, higher cytochrome c oxidase subunit I transcript levels and higher subunit II protein expression respect to control cells. No alterations of the deoxynucleotide pools were found, whereas a reduction in the expression of genes involved in nucleoside/nucleotide homeostasis (human equilibrative nucleoside transporter 1, thymidine phosphorylase) and mtDNA maintenance (DNA-polymerase γ, mitochondrial transcription factor A) was observed. Our findings highlight the importance of cellular compensatory mechanisms that enhance the expression of respiratory components to ensure respiratory activity despite profound depletion in mtDNA levels.

  14. Clinical variability in neurohepatic syndrome due to combined mitochondrial DNA depletion and Gaucher disease

    Directory of Open Access Journals (Sweden)

    Julie Harvengt

    2014-01-01

    Full Text Available A 1-year-old girl born to consanguineous parents presented with unexplained liver failure, leading to transplantation at 19 months. Subsequent partial splenectomy for persistent cytopenia showed the presence of foamy cells, and Gaucher disease was confirmed by homozygosity for the p.Leu483Pro mutation in the GBA gene. She was treated by enzyme replacement therapy (ERT. Clinical follow-up showed mild developmental delay, strabismus, nystagmus and oculomotor apraxia. Biochemical studies revealed multiple respiratory chain deficiencies and a mosaic pattern of deficient complex IV immunostaining in liver and fibroblast. Molecular analysis identified a mtDNA depletion syndrome due to the homozygous p.Pro98Leu mutation in MPV17. A younger sister unaffected by mtDNA depletion, presented with pancytopenia and hepatosplenomegaly. ERT for Gaucher disease resulted in visceral normalization without any neurological symptom. A third sister, affected by both conditions, had marked developmental delay, strabismus and ophthalmoplegia but no liver cirrhosis. In conclusion, intrafamilal variability occurs in MPV17-related disease. The combined pathological effect of Gaucher and mitochondrial diseases can negatively impact neurological and liver functions and influence the outcome in consanguineous families. The immunocytochemical staining of OXPHOS protein in tissues and cultured cells is a powerful tool revealing mosaic pattern of deficiency pointing to mtDNA-related mitochondrial disorders.

  15. Iron-depletion promotes mitophagy to maintain mitochondrial integrity in pathogenic yeast Candida glabrata

    Science.gov (United States)

    Nagi, Minoru; Tanabe, Koichi; Nakayama, Hironobu; Ueno, Keigo; Yamagoe, Satoshi; Umeyama, Takashi; Ohno, Hideaki; Miyazaki, Yoshitsugu

    2016-01-01

    ABSTRACT Candida glabrata, a haploid budding yeast, is the cause of severe systemic infections in immune-compromised hosts. The amount of free iron supplied to C. glabrata cells during systemic infections is severely limited by iron-chelating proteins such as transferrin. Thus, the iron-deficiency response in C. glabrata cells is thought to play important roles in their survival inside the host's body. In this study, we found that mitophagy was induced under iron-depleted conditions, and that the disruption of a gene homologous to ATG32, which is responsible for mitophagy in Saccharomyces cerevisiae, blocked mitophagy in C. glabrata. The mitophagic activity in C. glabrata cells was not detected on short-period exposure to nitrogen-starved conditions, which is a mitophagy-inducing condition used in S. cerevisiae. The mitophagy-deficient atg32Δ mutant of C. glabrata also exhibited decreased longevity under iron-deficient conditions. The mitochondrial membrane potential in Cgatg32Δ cells was significantly lower than that in wild-type cells under iron-depleted conditions. In a mouse model of disseminated infection, the Cgatg32Δ strain resulted in significantly decreased kidney and spleen fungal burdens compared with the wild-type strain. These results indicate that mitophagy in C. glabrata occurs in an iron-poor host tissue environment, and it may contribute to the longevity of cells, mitochondrial quality control, and pathogenesis. PMID:27347716

  16. Mitochondrial DNA depletion causes decreased ROS production and resistance to apoptosis.

    Science.gov (United States)

    Chen, Hulin; Wang, Junling; Liu, Zhongrong; Yang, Huilan; Zhu, Yingjie; Zhao, Minling; Liu, Yan; Yan, Miaomiao

    2016-10-01

    Mitochondrial DNA (mtDNA) depletion occurs frequently in many diseases including cancer. The present study was designed in order to examine the hypothesis that mtDNA‑depleted cells are resistant to apoptosis and to explore the possible mechanisms responsible for this effect. Parental human osteosarcoma 143B cells and mtDNA‑deficient (Rho˚ or ρ˚) 206 cells (derived from 143B cells) were exposed to different doses of solar-simulated ultraviolet (UV) radiation. The effects of solar irradiation on cell morphology were observed under both light and fluorescence microscopes. Furthermore, apoptosis, mitochondrial membrane potential (MMP) disruption and reactive oxygen species (ROS) production were detected and measured by flow cytometry. In both cell lines, apoptosis and ROS production were clearly increased, whereas MMP was slightly decreased. However, apoptosis and ROS production were reduced in the Rho˚206 cells compared with the 143B cells. We also performed western blot analysis and demonstrated the increased release of cytosolic Cyt c from mitochondria in the 143B cells compared with that in the Rho˚206 cells. Thus, we concluded that Rho˚206 cells exhibit more resistance to solar‑simulated UV radiation‑induced apoptosis at certain doses than 143B cells and this is possibly due to decreased ROS production. PMID:27499009

  17. Norcantharidin induced DU145 cell apoptosis through ROS-mediated mitochondrial dysfunction and energy depletion.

    Science.gov (United States)

    Shen, Bo; He, Pei-Jie; Shao, Chun-Lin

    2013-01-01

    Norcantharidin (NCTD), a demethylated analog of cantharidin derived from blister beetles, has attracted considerable attentions in recent years due to their definitely toxic properties and the noteworthy advantages in stimulating bone marrow and increasing the peripheral leukocytes. Hence, it is worth studying the anti-tumor effect of NCTD on human prostate cancer cells DU145. It was found that after the treatment of NCTD with different concentrations (25-100 μM), the cell proliferation was significantly inhibited, which led to the appearance of micronucleus (MN). Moreover, the cells could be killed in a dose-/time-dependent manner along with the reduction of PCNA (proliferating cell nuclear antigen) expression, destruction of mitochondrial membrane potential (MMP), down-regulation of MnSOD, induction of ROS, depletion of ATP, and activation of AMPK (Adenosine 5'-monophosphate -activated protein kinase) . In addition, a remarkable release of cytochrome c was found in the cells exposed to 100 μM NCTD and exogenous SOD-PEG could eliminate the generation of NCTD-induced MN. In conclusion, our studies indicated that NCTD could induce the collapse of MMP and mitochondria dysfunction. Accumulation of intercellular ROS could eventually switch on the apoptotic pathway by causing DNA damage and depleting ATP. PMID:24367681

  18. Norcantharidin induced DU145 cell apoptosis through ROS-mediated mitochondrial dysfunction and energy depletion.

    Directory of Open Access Journals (Sweden)

    Bo Shen

    Full Text Available Norcantharidin (NCTD, a demethylated analog of cantharidin derived from blister beetles, has attracted considerable attentions in recent years due to their definitely toxic properties and the noteworthy advantages in stimulating bone marrow and increasing the peripheral leukocytes. Hence, it is worth studying the anti-tumor effect of NCTD on human prostate cancer cells DU145. It was found that after the treatment of NCTD with different concentrations (25-100 μM, the cell proliferation was significantly inhibited, which led to the appearance of micronucleus (MN. Moreover, the cells could be killed in a dose-/time-dependent manner along with the reduction of PCNA (proliferating cell nuclear antigen expression, destruction of mitochondrial membrane potential (MMP, down-regulation of MnSOD, induction of ROS, depletion of ATP, and activation of AMPK (Adenosine 5'-monophosphate -activated protein kinase . In addition, a remarkable release of cytochrome c was found in the cells exposed to 100 μM NCTD and exogenous SOD-PEG could eliminate the generation of NCTD-induced MN. In conclusion, our studies indicated that NCTD could induce the collapse of MMP and mitochondria dysfunction. Accumulation of intercellular ROS could eventually switch on the apoptotic pathway by causing DNA damage and depleting ATP.

  19. A novel missense mutation in SUCLG1 associated with mitochondrial DNA depletion, encephalomyopathic form, with methylmalonic aciduria

    DEFF Research Database (Denmark)

    Østergaard, Elsebet; Schwartz, Marianne; Batbayli, Mustafa;

    2010-01-01

    Mitochondrial DNA depletion, encephalomyopathic form, with methylmalonic aciduria is associated with mutations in SUCLA2, the gene encoding a beta subunit of succinate-CoA ligase, where 17 patients have been reported. Mutations in SUCLG1, encoding the alpha subunit of the enzyme, have been reported...

  20. Targeted impairment of thymidine kinase 2 expression in cells induces mitochondrial DNA depletion and reveals molecular mechanisms of compensation of mitochondrial respiratory activity

    Energy Technology Data Exchange (ETDEWEB)

    Villarroya, Joan, E-mail: joanvillarroya@gmail.com [Institut de Recerca, Hospital Universitari de la Vall d' Hebron, Barcelona (Spain); Institut de Recerca l' Hospital de la Santa Creu i Sant Pau, Barcelona (Spain); Lara, Mari-Carmen [Institut de Recerca, Hospital Universitari de la Vall d' Hebron, Barcelona (Spain); Department of Neurology, Columbia University Medical Center, New York, NY (United States); Centro de Investigacion Biomedica en Red de Enfermedades Raras (CIBERER), ISCIII (Spain); Dorado, Beatriz [Department of Neurology, Columbia University Medical Center, New York, NY (United States); Garrido, Marta [Unitat de Biologia Cel.lular i Molecular, IMIM-Hospital del Mar, Barcelona (Spain); Garcia-Arumi, Elena [Institut de Recerca, Hospital Universitari de la Vall d' Hebron, Barcelona (Spain); Centro de Investigacion Biomedica en Red de Enfermedades Raras (CIBERER), ISCIII (Spain); Meseguer, Anna [Institut de Recerca, Hospital Universitari de la Vall d' Hebron, Barcelona (Spain); Hirano, Michio [Department of Neurology, Columbia University Medical Center, New York, NY (United States); Vila, Maya R. [Institut de Recerca, Hospital Universitari de la Vall d' Hebron, Barcelona (Spain)

    2011-04-08

    Highlights: {yields} We impaired TK2 expression in Ost TK1{sup -} cells via siRNA-mediated interference (TK2{sup -}). {yields} TK2 impairment caused severe mitochondrial DNA (mtDNA) depletion in quiescent cells. {yields} Despite mtDNA depletion, TK2{sup -} cells show high cytochrome oxidase activity. {yields} Depletion of mtDNA occurs without imbalance in the mitochondrial dNTP pool. {yields} Nuclear-encoded ENT1, DNA-pol {gamma}, TFAM and TP gene expression is lowered in TK2{sup -} cells. -- Abstract: The mitochondrial DNA (mtDNA) depletion syndrome comprises a clinically heterogeneous group of diseases characterized by reductions of the mtDNA abundance, without associated point mutations or rearrangements. We have developed the first in vitro model to study of mtDNA depletion due to reduced mitochondrial thymidine kinase 2 gene (TK2) expression in order to understand the molecular mechanisms involved in mtDNA depletion syndrome due to TK2 mutations. Small interfering RNA targeting TK2 mRNA was used to decrease TK2 expression in Ost TK1{sup -} cells, a cell line devoid of endogenous thymidine kinase 1 (TK1). Stable TK2-deficient cell lines showed a reduction of TK2 levels close to 80%. In quiescent conditions, TK2-deficient cells showed severe mtDNA depletion, also close to 80% the control levels. However, TK2-deficient clones showed increased cytochrome c oxidase activity, higher cytochrome c oxidase subunit I transcript levels and higher subunit II protein expression respect to control cells. No alterations of the deoxynucleotide pools were found, whereas a reduction in the expression of genes involved in nucleoside/nucleotide homeostasis (human equilibrative nucleoside transporter 1, thymidine phosphorylase) and mtDNA maintenance (DNA-polymerase {gamma}, mitochondrial transcription factor A) was observed. Our findings highlight the importance of cellular compensatory mechanisms that enhance the expression of respiratory components to ensure respiratory activity

  1. Thymidine kinase 2 deficiency-induced mitochondrial DNA depletion causes abnormal development of adipose tissues and adipokine levels in mice.

    Directory of Open Access Journals (Sweden)

    Joan Villarroya

    Full Text Available Mammal adipose tissues require mitochondrial activity for proper development and differentiation. The components of the mitochondrial respiratory chain/oxidative phosphorylation system (OXPHOS are encoded by both mitochondrial and nuclear genomes. The maintenance of mitochondrial DNA (mtDNA is a key element for a functional mitochondrial oxidative activity in mammalian cells. To ascertain the role of mtDNA levels in adipose tissue, we have analyzed the alterations in white (WAT and brown (BAT adipose tissues in thymidine kinase 2 (Tk2 H126N knockin mice, a model of TK2 deficiency-induced mtDNA depletion. We observed respectively severe and moderate mtDNA depletion in TK2-deficient BAT and WAT, showing both tissues moderate hypotrophy and reduced fat accumulation. Electron microscopy revealed altered mitochondrial morphology in brown but not in white adipocytes from TK2-deficient mice. Although significant reduction in mtDNA-encoded transcripts was observed both in WAT and BAT, protein levels from distinct OXPHOS complexes were significantly reduced only in TK2-deficient BAT. Accordingly, the activity of cytochrome c oxidase was significantly lowered only in BAT from TK2-deficient mice. The analysis of transcripts encoding up to fourteen components of specific adipose tissue functions revealed that, in both TK2-deficient WAT and BAT, there was a consistent reduction of thermogenesis related gene expression and a severe reduction in leptin mRNA. Reduced levels of resistin mRNA were found in BAT from TK2-deficient mice. Analysis of serum indicated a dramatic reduction in circulating levels of leptin and resistin. In summary, our present study establishes that mtDNA depletion leads to a moderate impairment in mitochondrial respiratory function, especially in BAT, causes substantial alterations in WAT and BAT development, and has a profound impact in the endocrine properties of adipose tissues.

  2. Desmin common mutation is associated with multi-systemic disease manifestations and depletion of mitochondria and mitochondrial DNA

    Directory of Open Access Journals (Sweden)

    Elizabeth eMcCormick

    2015-06-01

    Full Text Available Desmin (DES is a major muscle scaffolding protein that also functions to anchor mitochondria. Pathogenic DES mutations, however, have not previously been recognized as a cause of multi-systemic mitochondrial disease. Here, we describe a 45-year-old man who presented to The Children’s Hospital of Philadelphia Mitochondrial-Genetics Diagnostic Clinic for evaluation of progressive cardiac, neuromuscular, gastrointestinal, and mood disorders. Muscle biopsy at age 45 was remarkable for cytoplasmic bodies, as well as ragged red fibers and SDH positive/COX negative fibers that were suggestive of a mitochondrial myopathy. Muscle also showed significant reductions in mitochondrial content (16% of control mean for citrate synthase activity and mitochondrial DNA (35% of control mean. His family history was significant for cardiac conduction defects and myopathy in multiple maternal relatives. Multiple single gene and panel-based sequencing studies were unrevealing. Whole exome sequencing identified a known pathogenic p.S13F mutation in DES that had previously been associated with desmin-related myopathy. Desmin-related myopathy is an autosomal dominant disorder characterized by right ventricular hypertrophic cardiomyopathy, myopathy, and arrhythmias. However, neuropathy, gastrointestinal dysfunction, and depletion of both mitochondria and mitochondrial DNA have not previously been widely recognized in this disorder. Recognition that mitochondrial dysfunction occurs in desmin-related myopathy clarifies the basis for the multi-systemic manifestations, as are typical of primary mitochondrial disorders. Understanding the mitochondrial pathophysiology of desmin-related myopathy highlights the possibility of new therapies for the otherwise untreatable and often fatal class of disease. We postulate that drug treatments aimed at improving mitochondrial biogenesis or reducing oxidative stress may be effective therapies to ameliorate the effects of desmin

  3. [Clinical features and DGUOK mutations of an infant with mitochondrial DNA depletion syndrome].

    Science.gov (United States)

    Deng, Mei; Lin, Wei-Xia; Guo, Li; Zhang, Zhan-Hui; Song, Yuan-Zong

    2016-06-01

    The aim of this study was to investigate the clinical features and DGUOK gene mutations of an infant with mitochondrial DNA depletion syndrome (MDS). The patient (more than 7 months old) manifested as hepatosplenomegaly, abnormal liver function, nystagmus and psychomotor retardation. Genetic DNA was extracted from peripheral blood samples of the patient and her parents. Targeted Exome Sequencing was performed to explore the genetic causes. Sanger sequencing was carried out to confirm the detected mutations. The sequencing results showed that the patient was a compound heterozygote for c.679G>A and c.817delT in the DGUOK gene. The former was a reportedly pathogenic missense mutation of maternal origin, while the latter, a frameshift mutation from the father, has not been described yet. The findings in this study expand the mutation spectrum of DGUOK gene, and provide molecular evidence for the etiologic diagnosis of the patient as well as for the genetic counseling and prenatal diagnosis in the family. PMID:27324545

  4. Potentially diagnostic electron paramagnetic resonance spectra elucidate the underlying mechanism of mitochondrial dysfunction in the deoxyguanosine kinase deficient rat model of a genetic mitochondrial DNA depletion syndrome.

    Science.gov (United States)

    Bennett, Brian; Helbling, Daniel; Meng, Hui; Jarzembowski, Jason; Geurts, Aron M; Friederich, Marisa W; Van Hove, Johan L K; Lawlor, Michael W; Dimmock, David P

    2016-03-01

    A novel rat model for a well-characterized human mitochondrial disease, mitochondrial DNA depletion syndrome with associated deoxyguanosine kinase (DGUOK) deficiency, is described. The rat model recapitulates the pathologic and biochemical signatures of the human disease. The application of electron paramagnetic (spin) resonance (EPR) spectroscopy to the identification and characterization of respiratory chain abnormalities in the mitochondria from freshly frozen tissue of the mitochondrial disease model rat is introduced. EPR is shown to be a sensitive technique for detecting mitochondrial functional abnormalities in situ and, here, is particularly useful in characterizing the redox state changes and oxidative stress that can result from depressed expression and/or diminished specific activity of the distinct respiratory chain complexes. As EPR requires no sample preparation or non-physiological reagents, it provides information on the status of the mitochondrion as it was in the functioning state. On its own, this information is of use in identifying respiratory chain dysfunction; in conjunction with other techniques, the information from EPR shows how the respiratory chain is affected at the molecular level by the dysfunction. It is proposed that EPR has a role in mechanistic pathophysiological studies of mitochondrial disease and could be used to study the impact of new treatment modalities or as an additional diagnostic tool. PMID:26773591

  5. Induction of acquired resistance to anti estrogen by reversible mitochondrial DNA depletion in breast cancer cell line

    Science.gov (United States)

    Naito, Akihiro; Carcel-Trullols, Jaime; Xie, Cheng-hui; Evans, Teresa T; Mizumachi, Takatsugu; Higuchi, Masahiro

    2008-01-01

    Although the net benefits of tamoxifen in adjuvant breast cancer therapy have been proven, the recurrence of the cancer in an aggressive and hormone independent form has been highly problematic. We previously demonstrated the important role mitochondrial DNA (mtDNA) plays in hormone-independence in prostate cancer. Here, the role of mtDNA in breast cancer progression was investigated. We established hydroxytamoxifen (4-OHT) resistant HTRMCF by growing MCF-7, a human breast adenocarcinoma cells, in the presence of 4-OHT. HTRMCF was cross-resistant to 4-OHT and ICI182,780 concurrent with the depletion of mtDNA. To further investigate the role of mtDNA depletion, MCF-7 was depleted of mtDNA by treatment with ethidium bromide. MCFρ0 was resistant to both 4-OHT and ICI182,780. Furthermore, cybrid (MCFcyb) prepared by fusion MCFρ0 with platelet to transfer mtDNA showed susceptibility to anti-estrogen. Surprisingly, after withdrawal of 4-OHT for 8 weeks, HTRMCF and their clones became susceptible to both drugs concurrent with a recovery of mtDNA. Herein, our results substantiated the first evidence that the depletion of mtDNA induced by hormone therapy triggers a shift to acquired resistance to hormone therapy in breast cancer. In addition, we showed that mtDNA depletion can be reversed, rendering the cancer cells susceptible to anti-estrogen. The hormone independent phenotype can be reversed should be a step toward more effective treatments for estrogen-responsive breast cancer. PMID:17990320

  6. Screen for abnormal mitochondrial phenotypes in mouse embryonic stem cells identifies a model for succinyl-CoA ligase deficiency and mtDNA depletion

    Directory of Open Access Journals (Sweden)

    Taraka R. Donti

    2014-02-01

    Full Text Available Mutations in subunits of succinyl-CoA synthetase/ligase (SCS, a component of the citric acid cycle, are associated with mitochondrial encephalomyopathy, elevation of methylmalonic acid (MMA, and mitochondrial DNA (mtDNA depletion. A FACS-based retroviral-mediated gene trap mutagenesis screen in mouse embryonic stem (ES cells for abnormal mitochondrial phenotypes identified a gene trap allele of Sucla2 (Sucla2SAβgeo, which was used to generate transgenic mice. Sucla2 encodes the ADP-specific β-subunit isoform of SCS. Sucla2SAβgeo homozygotes exhibited recessive lethality, with most mutants dying late in gestation (e18.5. Mutant placenta and embryonic (e17.5 brain, heart and muscle showed varying degrees of mtDNA depletion (20–60%. However, there was no mtDNA depletion in mutant liver, where the gene is not normally expressed. Elevated levels of MMA were observed in embryonic brain. SCS-deficient mouse embryonic fibroblasts (MEFs demonstrated a 50% reduction in mtDNA content compared with wild-type MEFs. The mtDNA depletion resulted in reduced steady state levels of mtDNA encoded proteins and multiple respiratory chain deficiencies. mtDNA content could be restored by reintroduction of Sucla2. This mouse model of SCS deficiency and mtDNA depletion promises to provide insights into the pathogenesis of mitochondrial diseases with mtDNA depletion and into the biology of mtDNA maintenance. In addition, this report demonstrates the power of a genetic screen that combines gene trap mutagenesis and FACS analysis in mouse ES cells to identify mitochondrial phenotypes and to develop animal models of mitochondrial dysfunction.

  7. Coenzyme Q10 Administration Increases Brain Mitochondrial Concentrations and Exerts Neuroprotective Effects

    Science.gov (United States)

    Matthews, Russell T.; Yang, Lichuan; Browne, Susan; Baik, Myong; Flint Beal, M.

    1998-07-01

    Coenzyme Q10 is an essential cofactor of the electron transport chain as well as a potent free radical scavenger in lipid and mitochondrial membranes. Feeding with coenzyme Q10 increased cerebral cortex concentrations in 12- and 24-month-old rats. In 12-month-old rats administration of coenzyme Q10 resulted in significant increases in cerebral cortex mitochondrial concentrations of coenzyme Q10. Oral administration of coenzyme Q10 markedly attenuated striatal lesions produced by systemic administration of 3-nitropropionic acid and significantly increased life span in a transgenic mouse model of familial amyotrophic lateral sclerosis. These results show that oral administration of coenzyme Q10 increases both brain and brain mitochondrial concentrations. They provide further evidence that coenzyme Q10 can exert neuroprotective effects that might be useful in the treatment of neurodegenerative diseases.

  8. Whole exome sequencing identifies a homozygous POLG2 missense variant in an infant with fulminant hepatic failure and mitochondrial DNA depletion.

    Science.gov (United States)

    Varma, Hemant; Faust, Phyllis L; Iglesias, Alejandro D; Lagana, Stephen M; Wou, Karen; Hirano, Michio; DiMauro, Salvatore; Mansukani, Mahesh M; Hoff, Kirsten E; Nagy, Peter L; Copeland, William C; Naini, Ali B

    2016-10-01

    Mitochondrial DNA (mtDNA) depletion syndrome manifests as diverse early-onset diseases that affect skeletal muscle, brain and liver function. Mutations in several nuclear DNA-encoded genes cause mtDNA depletion. We report on a patient, a 3-month-old boy who presented with hepatic failure, and was found to have severe mtDNA depletion in liver and muscle. Whole-exome sequencing identified a homozygous missense variant (c.544C > T, p.R182W) in the accessory subunit of mitochondrial DNA polymerase gamma (POLG2), which is required for mitochondrial DNA replication. This variant is predicted to disrupt a critical region needed for homodimerization of the POLG2 protein and cause loss of processive DNA synthesis. Both parents were phenotypically normal and heterozygous for this variant. Heterozygous mutations in POLG2 were previously associated with progressive external ophthalmoplegia and mtDNA deletions. This is the first report of a patient with a homozygous mutation in POLG2 and with a clinical presentation of severe hepatic failure and mitochondrial depletion.

  9. Antitumor effect of methionine-depleting total parenteral nutrition with doxorubicin administration on Yoshida sarcoma-bearing rats.

    Science.gov (United States)

    Goseki, N; Yamazaki, S; Endo, M; Onodera, T; Kosaki, G; Hibino, Y; Kuwahata, T

    1992-04-01

    Methionine-depleting total parenteral nutrition (methionine-depleting TPN), which infuses an amino acid solution devoid of L-methionine and L-cysteine as the sole protein source, showed enhancement of the effect of several anti-cancer agents. In this study, the combined effect of the methionine-depleting TPN with the administration of doxorubicin was examined in Yoshida sarcoma (YS)-bearing rats with regard to effects on the primary tumor growth, the extension of metastasis, and the host animal's life span. In the first experiment, immediately after receiving methionine-depleting TPN for 8 days, the animals were killed. Pathologic findings evaluated tumor growth in the implanted site and extension of the metastasis. In the second experiment, the survival period was determined after animals received methionine-depleting TPN for 10 days, with subsequent oral feeding until they died naturally. Proliferation of YS was markedly suppressed. In particular, hematogenous metastasis, which is a characteristic of YS, was suppressed, and a longer survival period (42.7 +/- 15.6 days, mean +/- SD) was attained in rats in the group treated with the methionine-depleting TPN combined with the administration of doxorubicin.

  10. Effect of acetaminophen administration to rats chronically exposed to depleted uranium

    International Nuclear Information System (INIS)

    The extensive use of depleted uranium (DU) in both civilian and military applications results in the increase of the number of human beings exposed to this compound. We previously found that DU chronic exposure induces the expression of CYP enzymes involved in the metabolism of xenobiotics (drugs). In order to evaluate the consequences of these changes on the metabolism of a drug, rats chronically exposed to DU (40 mg/l) were treated by acetaminophen (APAP, 400 mg/kg) at the end of the 9-month contamination. Acetaminophen is considered as a safe drug within the therapeutic range but in the case of overdose or in sensitive animals, hepatotoxicity and nephrotoxicity could occur. In the present work, plasma concentration of APAP was higher in the DU group compared to the non-contaminated group. In addition, administration of APAP to the DU-exposed rats increased plasma ALT (p < 0.01) and AST (p < 0.05) more rapidly than in the control group. Nevertheless, no histological alteration of the liver was observed but renal injury characterized by incomplete proximal tubular cell necrosis was higher for the DU-exposed rats. Moreover, in the kidney, CYP2E1 gene expression, an important CYP responsible for APAP bioactivation and toxicity, is increased (p < 0.01) in the DU-exposed group compared to the control group. In the liver, CYP's activities were decreased between control and DU-exposed rats. These results could explain the worse elimination of APAP in the plasma and confirm our hypothesis of a modification of the drug metabolism following a DU chronic contamination

  11. Mitochondrial genome depletion in human liver cells abolishes bile acid-induced apoptosis: role of the Akt/mTOR survival pathway and Bcl-2 family proteins.

    Science.gov (United States)

    Marin, Jose J G; Hernandez, Alicia; Revuelta, Isabel E; Gonzalez-Sanchez, Ester; Gonzalez-Buitrago, Jose M; Perez, Maria J

    2013-08-01

    Acute accumulation of bile acids in hepatocytes may cause cell death. However, during long-term exposure due to prolonged cholestasis, hepatocytes may develop a certain degree of chemoresistance to these compounds. Because mitochondrial adaptation to persistent oxidative stress may be involved in this process, here we have investigated the effects of complete mitochondrial genome depletion on the response to bile acid-induced hepatocellular injury. A subline (Rho) of human hepatoma SK-Hep-1 cells totally depleted of mitochondrial DNA (mtDNA) was obtained, and bile acid-induced concentration-dependent activation of apoptosis/necrosis and survival signaling pathways was studied. In the absence of changes in intracellular ATP content, Rho cells were highly resistant to bile acid-induced apoptosis and partially resistant to bile acid-induced necrosis. In Rho cells, both basal and bile acid-induced generation of reactive oxygen species (ROS), such as hydrogen peroxide and superoxide anion, was decreased. Bile acid-induced proapoptotic signals were also decreased, as evidenced by a reduction in the expression ratios Bax-α/Bcl-2, Bcl-xS/Bcl-2, and Bcl-xS/Bcl-xL. This was mainly due to a downregulation of Bax-α and Bcl-xS. Moreover, in these cells the Akt/mTOR pathway was constitutively activated in a ROS-independent manner and remained similarly activated in the presence of bile acid treatment. In contrast, ERK1/2 activation was constitutively reduced and was not activated by incubation with bile acids. In conclusion, these results suggest that impaired mitochondrial function associated with mtDNA alterations, which may occur in liver cells during prolonged cholestasis, may activate mechanisms of cell survival accounting for an enhanced resistance of hepatocytes to bile acid-induced apoptosis. PMID:23597504

  12. Depleted skeletal muscle mitochondrial DNA, hyperlactatemia, and decreased oxidative capacity in HIV-infected patients on highly active antiretroviral therapy

    DEFF Research Database (Denmark)

    Haugaard, Steen B; Andersen, Ove; Pedersen, Steen B;

    2005-01-01

    hyperlactatemia is associated with depletion of skeletal muscle (sm)-mtDNA and decreased oxidative capacity in HIV-infected patients on NRTI based highly active antiretroviral therapy (HAART) and whether HIV infection itself is associated with sm-mtDNA depletion. Sm-mtDNA was determined in 42 HIV...... in part could be mediated through an enhanced pro-inflammatory response....

  13. The Effect of Growth Hormone Administration on the Regulation of Mitochondrial Apoptosis in-Vivo

    Directory of Open Access Journals (Sweden)

    James Keane

    2015-06-01

    Full Text Available The purpose of this study was to determine whether recombinant human growth hormone (rhGH would show any significant effects on the expression of apoptosis regulating proteins in peripheral blood mononuclear cells (PBMCs. Additionally, the potential for post-transcriptional regulation of gene expression by miRNA was assessed in two cellular compartments, the cytosol and the mitochondria. Ten male subjects were subcutaneously injected with either rhGH (1 mg or saline (0.9% for seven consecutive days in a double-blinded fashion. Blood sampling was undertaken prior to treatment administration and over a period of three weeks following treatment cessation. Bcl-2 and Bak gene and protein expression levels were measured in PBMCs, while attention was also directed to the expression of miR-181a and miR-125b, known translational inhibitors of Bcl-2 and Bak respectively. Results showed that rhGH significantly decreased Bak protein concentrations compared to placebo samples for up to 8 days post treatment. While cytosolic miRNA expression was not found to be significantly affected by rhGH, measurement of the expression of miR-125b in mitochondrial fractions showed a significant down-regulation eight days post-rhGH administration. These findings suggest that rhGH induces short-term anti-apoptotic effects which may be partially mediated through a novel pathway that alters the concentration of mitochondrially-associated miRNAs.

  14. Effects of decreased lactate accumulation after dichloroacetate administration on exercise training–induced mitochondrial adaptations in mouse skeletal muscle

    OpenAIRE

    Hoshino, Daisuke; TAMURA, Yuki; Masuda, Hiroyuki; Matsunaga, Yutaka; Hatta, Hideo

    2015-01-01

    Recent studies suggested that lactate accumulation can be a signal for mitochondrial biogenesis in skeletal muscle. We investigated whether reductions in lactate concentrations in response to dichloroacetate (DCA), an activator of pyruvate dehydrogenase, attenuate mitochondrial adaptations after exercise training in mice. We first confirmed that DCA administration (200 mg/kg BW by i.p. injection) 10 min before exercise decreased muscle and blood lactate concentrations after high-intensity int...

  15. Exercise-Induced Changes in Caveolin-1, Depletion of Mitochondrial Cholesterol, and the Inhibition of Mitochondrial Swelling in Rat Skeletal Muscle but Not in the Liver

    Directory of Open Access Journals (Sweden)

    Damian Jozef Flis

    2016-01-01

    Full Text Available The reduction in cholesterol in mitochondria, observed after exercise, is related to the inhibition of mitochondrial swelling. Caveolin-1 (Cav-1 plays an essential role in the regulation of cellular cholesterol metabolism and is required by various signalling pathways. Therefore, the aim of this study was to investigate the effect of prolonged swimming on the mitochondrial Cav-1 concentration; additionally, we identified the results of these changes as they relate to the induction of changes in the mitochondrial swelling and cholesterol in rat skeletal muscle and liver. Male Wistar rats were divided into a sedentary control group and an exercise group. The exercised rats swam for 3 hours and were burdened with an additional 3% of their body weight. After the cessation of exercise, their quadriceps femoris muscles and livers were immediately removed for experimentation. The exercise protocol caused an increase in the Cav-1 concentration in crude muscle mitochondria; this was related to a reduction in the cholesterol level and an inhibition of mitochondrial swelling. There were no changes in rat livers, with the exception of increased markers of oxidative stress in mitochondria. These data indicate the possible role of Cav-1 in the adaptive change in the rat muscle mitochondria following exercise.

  16. VARIATION IN MITOCHONDRIAL-DNA LEVELS IN MUSCLE FROM NORMAL CONTROLS - IS DEPLETION OF MTDNA IN PATIENTS WITH MITOCHONDRIAL MYOPATHY A DISTINCT CLINICAL SYNDROME

    NARCIS (Netherlands)

    POULTON, J; SEWRY, C; POTTER, CG; BOUGERON, T; CHRETIEN, D; WIJBURG, FA; MORTEN, KJ; BROWN, G

    1995-01-01

    Recent studies have identified a group of patients with cytochrome oxidase (COX) deficiency presenting in infancy associated with a deficiency of mtDNA in muscle or other affected tissue (Moraes et al 1991). We used a navel approach to compare the level of mitochondrial (mtDNA) compared to nuclear D

  17. Thiosemicarbazone p-Substituted Acetophenone Derivatives Promote the Loss of Mitochondrial Δψ, GSH Depletion, and Death in K562 Cells.

    Science.gov (United States)

    Pessoto, Felipe S; Yokomizo, Cesar H; Prieto, Tatiana; Fernandes, Cleverton S; Silva, Alan P; Kaiser, Carlos R; Basso, Ernani A; Nantes, Iseli L

    2015-01-01

    A series of thiosemicarbazone (TSC) p-substituted acetophenone derivatives were synthesized and chemically characterized. The p-substituents appended to the phenyl group of the TSC structures were hydrogen, fluor, chlorine, methyl, and nitro, producing compounds named TSC-H, TSC-F, TSC-Cl, TSC-Me, and TSC-NO2, respectively. The TSC compounds were evaluated for their capacity to induce mitochondrial permeability, to deplete mitochondrial thiol content, and to promote cell death in the K562 cell lineage using flow cytometry and fluorescence microscopy. TSC-H, TSC-F, and TSC-Cl exhibited a bell-shaped dose-response curve for the induction of apoptosis in K562 cells due to the change from apoptosis to necrosis as the principal mechanism of cell death at the highest tested doses. TSC-Me and TSC-NO2 exhibited a typical dose-response profile, with a half maximal effective concentration of approximately 10 µM for cell death. Cell death was also evaluated using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, which revealed lower toxicity of these compounds for peripheral blood mononuclear cells than for K562 cells. The possible mechanisms leading to cell death are discussed based on the observed effects of the new TSC compounds on the cellular thiol content and on mitochondrial bioenergetics. PMID:26075034

  18. Thiosemicarbazone p-Substituted Acetophenone Derivatives Promote the Loss of Mitochondrial Δψ, GSH Depletion, and Death in K562 Cells

    Directory of Open Access Journals (Sweden)

    Felipe S. Pessoto

    2015-01-01

    Full Text Available A series of thiosemicarbazone (TSC p-substituted acetophenone derivatives were synthesized and chemically characterized. The p-substituents appended to the phenyl group of the TSC structures were hydrogen, fluor, chlorine, methyl, and nitro, producing compounds named TSC-H, TSC-F, TSC-Cl, TSC-Me, and TSC-NO2, respectively. The TSC compounds were evaluated for their capacity to induce mitochondrial permeability, to deplete mitochondrial thiol content, and to promote cell death in the K562 cell lineage using flow cytometry and fluorescence microscopy. TSC-H, TSC-F, and TSC-Cl exhibited a bell-shaped dose-response curve for the induction of apoptosis in K562 cells due to the change from apoptosis to necrosis as the principal mechanism of cell death at the highest tested doses. TSC-Me and TSC-NO2 exhibited a typical dose-response profile, with a half maximal effective concentration of approximately 10 µM for cell death. Cell death was also evaluated using the 3-(4,5-dimethylthiazol-2-yl-2,5-diphenyltetrazolium bromide (MTT assay, which revealed lower toxicity of these compounds for peripheral blood mononuclear cells than for K562 cells. The possible mechanisms leading to cell death are discussed based on the observed effects of the new TSC compounds on the cellular thiol content and on mitochondrial bioenergetics.

  19. ATP Depletion Via Mitochondrial F1F0 Complex by Lethal Factor is an Early Event in B. Anthracis-Induced Sudden Cell Death

    Directory of Open Access Journals (Sweden)

    Mitchell W. Woodberry

    2009-08-01

    Full Text Available Bacillus anthracis’ primary virulence factor is a tripartite anthrax toxin consisting of edema factor (EF, lethal factor (LF and protective antigen (PA. In complex with PA, EF and LF are internalized via receptor-mediated endocytosis. EF is a calmodulin- dependent adenylate cyclase that induces tissue edema. LF is a zinc-metalloprotease that cleaves members of mitogen-activated protein kinase kinases. Lethal toxin (LT: PA plus LF-induced death of macrophages is primarily attributed to expression of the sensitive Nalp1b allele, inflammasome formation and activation of caspase-1, but early events that initiate these processes are unknown. Here we provide evidence that an early essential event in pyroptosis of alveolar macrophages is LF-mediated depletion of cellular ATP. The underlying mechanism involves interaction of LF with F1F0-complex gamma and beta subunits leading to increased ATPase activity in mitochondria. In support, mitochondrial DNA-depleted MH-S cells have decreased F1F0 ATPase activity due to the lack of F06 and F08 polypeptides and show increased resistance to LT. We conclude that ATP depletion is an important early event in LT-induced sudden cell death and its prevention increases survival of toxin-sensitive cells.

  20. Knockout of Slc25a19 causes mitochondrial thiamine pyrophosphate depletion, embryonic lethality, CNS malformations, and anemia

    Science.gov (United States)

    Lindhurst, Marjorie J.; Fiermonte, Giuseppe; Song, Shiwei; Struys, Eduard; De Leonardis, Francesco; Schwartzberg, Pamela L.; Chen, Amy; Castegna, Alessandra; Verhoeven, Nanda; Mathews, Christopher K.; Palmieri, Ferdinando; Biesecker, Leslie G.

    2006-01-01

    SLC25A19 mutations cause Amish lethal microcephaly (MCPHA), which markedly retards brain development and leads to α-ketoglutaric aciduria. Previous data suggested that SLC25A19, also called DNC, is a mitochondrial deoxyribonucleotide transporter. We generated a knockout mouse model of Slc25a19. These animals had 100% prenatal lethality by embryonic day 12. Affected embryos at embryonic day 10.5 have a neural-tube closure defect with ruffling of the neural fold ridges, a yolk sac erythropoietic failure, and elevated α-ketoglutarate in the amniotic fluid. We found that these animals have normal mitochondrial ribo- and deoxyribonucleoside triphosphate levels, suggesting that transport of these molecules is not the primary role of SLC25A19. We identified thiamine pyrophosphate (ThPP) transport as a candidate function of SLC25A19 through homology searching and confirmed it by using transport assays of the recombinant reconstituted protein. The mitochondria of Slc25a19−/− and MCPHA cells have undetectable and markedly reduced ThPP content, respectively. The reduction of ThPP levels causes dysfunction of the α-ketoglutarate dehydrogenase complex, which explains the high levels of this organic acid in MCPHA and suggests that mitochondrial ThPP transport is important for CNS development. PMID:17035501

  1. Knockout of Slc25a19 causes mitochondrial thiamine pyrophosphate depletion, embryonic lethality, CNS malformations, and anemia

    OpenAIRE

    Lindhurst, Marjorie J.; Fiermonte, Giuseppe; Song, Shiwei; Struys, Eduard; De Leonardis, Francesco; Schwartzberg, Pamela L.; Chen, Amy; Castegna, Alessandra; Verhoeven, Nanda; Christopher K Mathews; Palmieri, Ferdinando; Biesecker, Leslie G

    2006-01-01

    SLC25A19 mutations cause Amish lethal microcephaly (MCPHA), which markedly retards brain development and leads to α-ketoglutaric aciduria. Previous data suggested that SLC25A19, also called DNC, is a mitochondrial deoxyribonucleotide transporter. We generated a knockout mouse model of Slc25a19. These animals had 100% prenatal lethality by embryonic day 12. Affected embryos at embryonic day 10.5 have a neural-tube closure defect with ruffling of the neural fold ridges, a yolk sac erythropoieti...

  2. Apaf-1-deficient fog mouse cell apoptosis involves hypopolarization of the mitochondrial inner membrane,ATP depletion and citrate accumulation

    Institute of Scientific and Technical Information of China (English)

    Iyoko Katoh; Shingo Sato; Nahoko Fukunishi; Hiroki Yoshida; Takasuke Imai; Shun-ichi Kurata

    2008-01-01

    To explore how the intrinsic apoptosis pathway is controlled in the spontaneous fog (forebrain overgrowth) mutant mice with an Apaf1 splicing deficiency,we examined spleen and bone marrow cells from Apaf1+/+(+/+) and Apaf1fog/fog (fog/fog) mice for initiator caspase-9 activation by cellular stresses.When the mitochondrial inner membrane potential (△Ψm) was disrupted by staurosporine,+/+ cells but not fog/fog cells activated caspase-9 to cause apoptosis,indicating the lack of apoptosomc (apoptosis protease activating factor 1 (Apaf-1)/cytochrome c/(d)ATP/procaspase-9) function in fog/fog cells.However,when a marginal (~20%) decrease in △Ψm was caused by hydrogen peroxide (0.1 mM),peroxynitrite donor 3-morpholinosydnonimine (0.1 mM) and UV-C irradiation (20 J/m2),both +/+ and fog/fog cells triggeredprocaspase-9 auto-processing and its downstream cascade activation.Supporting our previous results,procaspase-9 pre-existing in the mitochondria induced its auto-processing before the cytosolic caspase activation regardless of the geuotypes.Cellular ATP concentration significantly decreased under the hypoactive AΨm condition.Furthermore,we detected accumulation of citrate,a kosmotrope known to facilitate procaspase-9 dimerization,probably due to a feedback control of the Krebs cycle by the electron transfer system.Thus,mitochondrial in situ caspase-9 activation may be caused by the major metabolic reactions in response to physiological stresses,which may represent a mode of Apaf-1-independent apoptosis hypothesized from recent genetic studies.

  3. Efficacy of oral and intraperitoneal administration of CBMIDA for removing uranium in rats after parenteral injections of depleted uranium

    International Nuclear Information System (INIS)

    The efficacy of oral administration of the chelating agent catechol-3, 6-bis(methyliminodiacetic acid) (CBMIDA) for removing uranium from rats after intraperitoneal (i.p.) and intramuscular (i.m.) injections of depleted uranium (DU) was examined and the results with those by the i.p. injection of CBMIDA were compared. In Experiment 1, after a single i.p. injection of 8 mg kg-1 of DU of rat's body weight, 35 8-week-old male rats were divided into seven groups consisting of five rats each. Three groups were administered with CBMIDA 240, 720 or 1200 mg kg-1 of rat's body weight orally once a day, and three other groups received an i.p. injection of 240, 480 or 720 mg kg-1 CBMIDA for 3 d, starting 30 min after DU injection on the first day. One DU group received no CBMIDA. The remaining five intact rats were used as a control group. Rats were killed 6 d after DU injection. In Experiment 2, the 35 male rats that received a single i.m. injection of 8 mg kg-1 DU were divided into seven groups, and the rats of each group received the same doses of CBMIDA on the same schedules of treatment as those described in Experiment 1. The results obtained in Experiment 1 indicated that orally administered CBMIDA significantly increased the excretion of uranium at doses of 720 and 1200 mg kg-1 and decreased uranium concentrations, particularly in the kidney, at all the doses tested, and the effects were almost equal to those of the i.p. injection. The lack of increases in creatinine and blood urea nitrogen in serum indicated that CBMIDA is efficacious in preventing the renal dysfunction caused by uranium. In Experiment 2, oral administration of CBMIDA significantly increased uranium excretion and significantly decreased uranium concentrations, particularly in the kidneys, at all the doses tested, and the effects were almost equal to those of the i.p. injection. However, these effects of CBMIDA on the i.m.-injected DU were lower than those of the i.p.-injected DU in Experiment 1. These

  4. Gender differences in hyperthermia and regional 5-HT and 5-HIAA depletion in the brain following MDMA administration in rats

    NARCIS (Netherlands)

    Wallinga, Alinde E.; Grahlmann, Carolin; Granneman, Ramon A.; Koolhaas, Jaap M.; Buwalda, Bauke

    2011-01-01

    In the present research the role of gender in MDMA-induced hyperthermia and serotonin depletion is studied by injecting male and female male rats with MDMA or saline 3 times (i.p.) with 3 h interval at dosages of 0.3, 1, 3 or 9 mg/kg at an ambient temperature of 25 degrees C. The acute hyperthermia

  5. A transient increase in lipid peroxidation primes preadipocytes for delayed mitochondrial inner membrane permeabilization and ATP depletion during prolonged exposure to fatty acids

    OpenAIRE

    Rogers, Carlyle; Davis, Barbara; Neufer, P. Darrell; Murphy, Michael P.; Anderson, Ethan J.; Robidoux, Jacques

    2013-01-01

    Preadipocytes are periodically subjected to fatty acid (FA) concentrations that are potentially cytotoxic. We tested the hypothesis that prolonged exposure of preadipocytes of human origin to a physiologically relevant mix of FAs leads to mitochondrial inner membrane (MIM) permeabilization and ultimately to mitochondrial crisis. We found that exposure of preadipocytes to FAs led to progressive cyclosporin A-sensitive MIM permeabilization, which in turn caused reduction in MIM potential (ΔΨM),...

  6. Effects of coenzyme Q(10) administration on its tissue concentrations, mitochondrial oxidant generation, and oxidative stress in the rat.

    Science.gov (United States)

    Kwong, Linda K; Kamzalov, Sergey; Rebrin, Igor; Bayne, Anne-Cécile V; Jana, Chandan K; Morris, Paul; Forster, Michael J; Sohal, Rajindar S

    2002-09-01

    Coenzyme Q (CoQ(10)) is a component of the mitochondrial electron transport chain and also a constituent of various cellular membranes. It acts as an important in vivo antioxidant, but is also a primary source of O(2)(-*)/H(2)O(2) generation in cells. CoQ has been widely advocated to be a beneficial dietary adjuvant. However, it remains controversial whether oral administration of CoQ can significantly enhance its tissue levels and/or can modulate the level of oxidative stress in vivo. The objective of this study was to determine the effect of dietary CoQ supplementation on its content in various tissues and their mitochondria, and the resultant effect on the in vivo level of oxidative stress. Rats were administered CoQ(10) (150 mg/kg/d) in their diets for 4 and 13 weeks; thereafter, the amounts of CoQ(10) and CoQ(9) were determined by HPLC in the plasma, homogenates of the liver, kidney, heart, skeletal muscle, brain, and mitochondria of these tissues. Administration of CoQ(10) increased plasma and mitochondria levels of CoQ(10) as well as its predominant homologue CoQ(9). Generally, the magnitude of the increases was greater after 13 weeks than 4 weeks. The level of antioxidative defense enzymes in liver and skeletal muscle homogenates and the rate of hydrogen peroxide generation in heart, brain, and skeletal muscle mitochondria were not affected by CoQ supplementation. However, a reductive shift in plasma aminothiol status and a decrease in skeletal muscle mitochondrial protein carbonyls were apparent after 13 weeks of supplementation. Thus, CoQ supplementation resulted in an elevation of CoQ homologues in tissues and their mitochondria, a selective decrease in protein oxidative damage, and an increase in antioxidative potential in the rat.

  7. Defects of mitochondrial DNA replication.

    Science.gov (United States)

    Copeland, William C

    2014-09-01

    Mitochondrial DNA is replicated by DNA polymerase γ in concert with accessory proteins such as the mitochondrial DNA helicase, single-stranded DNA binding protein, topoisomerase, and initiating factors. Defects in mitochondrial DNA replication or nucleotide metabolism can cause mitochondrial genetic diseases due to mitochondrial DNA deletions, point mutations, or depletion, which ultimately cause loss of oxidative phosphorylation. These genetic diseases include mitochondrial DNA depletion syndromes such as Alpers or early infantile hepatocerebral syndromes, and mitochondrial DNA deletion disorders, such as progressive external ophthalmoplegia, ataxia-neuropathy, or mitochondrial neurogastrointestinal encephalomyopathy. This review focuses on our current knowledge of genetic defects of mitochondrial DNA replication (POLG, POLG2, C10orf2, and MGME1) that cause instability of mitochondrial DNA and mitochondrial disease.

  8. Acute effects of TCDD administration:special emphasis on testicular and sperm mitochondrial function

    Institute of Scientific and Technical Information of China (English)

    Paula C Mota; Renata S Tavares; Marlia Cordeiro; Susana P Pereira; Stephen J Publicover; Paulo J Oliveira; Joo Ramalho-Santos

    2012-01-01

    Objective: The goal of this study was to verify if 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) could have any effect on male germ cells mitochondria and in this way add new insights in how male reproductive alterations observed in other studies occur. Methods:In vivo and in vitro approaches using rat testis and human sperm as models were employed to evaluate TCDD effects on testicular and sperm mitochondria after 24 h of exposure. Results:Testicular mitochondria from TCDD-treated rats presented no differences in the bioenergetic parameters monitored except for a significantly higher electric membrane potential in the presence of ADP, corroborated when TCDD was directly added to testicular mitochondria from untreated rats. Nevertheless, sperm mitochondrial membrane potential, motility, viability, capacitation and acrosomal integrity did not change after TCDD treatment. Moreover, only few sperm cells exposed to TCDD increased their intracellular Ca2+concentration. Conlusions:TCDD can interact directly with rat testicular mitochondria inducing small changes. This effect, however, does not seem to occur in human sperm or it may be insufficient to induce significant alterations as observed by the maintenance of sperm function.

  9. A transient increase in lipid peroxidation primes preadipocytes for delayed mitochondrial inner membrane permeabilization and ATP depletion during prolonged exposure to fatty acids.

    Science.gov (United States)

    Rogers, Carlyle; Davis, Barbara; Neufer, P Darrell; Murphy, Michael P; Anderson, Ethan J; Robidoux, Jacques

    2014-02-01

    Preadipocytes are periodically subjected to fatty acid (FA) concentrations that are potentially cytotoxic. We tested the hypothesis that prolonged exposure of preadipocytes of human origin to a physiologically relevant mix of FAs leads to mitochondrial inner membrane (MIM) permeabilization and ultimately to mitochondrial crisis. We found that exposure of preadipocytes to FAs led to progressive cyclosporin A-sensitive MIM permeabilization, which in turn caused a reduction in MIM potential, oxygen consumption, and ATP synthetic capacity and, ultimately, death. Additionally, we showed that FAs induce a transient increase in intramitochondrial reactive oxygen species (ROS) and lipid peroxide production, lasting roughly 30 and 120min for the ROS and lipid peroxides, respectively. MIM permeabilization and its deleterious consequences including mitochondrial crisis and cell death were prevented by treating the cells with the mitochondrial FA uptake inhibitor etomoxir, the mitochondrion-selective superoxide and lipid peroxide antioxidants MitoTempo and MitoQ, or the lipid peroxide and reactive carbonyl scavenger l-carnosine. FAs also promoted a delayed oxidative stress phase. However, the beneficial effects of etomoxir, MitoTempo, and l-carnosine were lost by delaying the treatment by 2h, suggesting that the initial phase was sufficient to prime the cells for the delayed MIM permeabilization and mitochondrial crisis. It also suggested that the second ROS production phase is a consequence of this loss in mitochondrial health. Altogether, our data suggest that approaches designed to diminish intramitochondrial ROS or lipid peroxide accumulation, as well as MIM permeabilization, are valid mechanism-based therapeutic avenues to prevent the loss in preadipocyte metabolic fitness associated with prolonged exposure to elevated FA levels. PMID:24269897

  10. Pharmacokinetics, efficacy prediction indexes, and residue depletion of ribavirin in Atlantic salmon's (Salmo salar) muscle after oral administration in feed.

    Science.gov (United States)

    San Martín, B; Muñoz, R; Cornejo, J; Martínez, M A; Araya-Jordán, C; Maddaleno, A; Anadón, A

    2016-08-01

    Ribavirin is an antiviral used in human medicine, but it has not been authorized for use in veterinary medicine although it is effective against infectious salmon anemia (ISA) virus, between others. In this study, we present a pharmacokinetic profile of ribavirin in Atlantic salmon (Salmo salar), efficacy prediction indexes, and the measure of its withdrawal time. To determine the pharmacokinetic profile, fishes were orally administered with a single ribavirin dose of 1.6 mg/kg bw, and then, plasma concentrations were measured at different times. From the time-vs.-concentration curve, Cmax = 413.57 ng/mL, Tmax  = 6.96 h, AUC = 21394.01 μg·h/mL, t1/2  = 81.61 h, and K10  = 0.0421/h were obtained. Ribavirin reached adequate concentrations during the pharmacokinetic study, with prediction indexes of Cmax /IC50  = 20.7, AUC/IC50  = 1069.7, and T>IC50  = 71 h, where IC is the inhibitory concentration 50%. For ribavirin depletion study, fishes were orally administered with a dairy dose of 1.6 mg/kg bw during 10 days. Concentrations were measured on edible tissue on different days post-treatment. A linear regression of the time vs. concentration was conducted, obtaining a withdrawal time of 1966 °C days. Results obtained reveal that the dose of 1.6 mg/kg bw orally administered is effective for ISA virus, originating a reasonable withdrawal period within the productive schedules of Atlantic salmon. PMID:26960624

  11. Effect of short-term thyroxine administration on energy metabolism and mitochondrial efficiency in humans.

    Directory of Open Access Journals (Sweden)

    Darcy L Johannsen

    Full Text Available The physiologic effects of triiodothyronine (T3 on metabolic rate are well-documented; however, the effects of thyroxine (T4 are less clear despite its wide-spread use to treat thyroid-related disorders and other non-thyroidal conditions. Here, we investigated the effects of acute (3-day T4 supplementation on energy expenditure at rest and during incremental exercise. Furthermore, we used a combination of in situ and in vitro approaches to measure skeletal muscle metabolism before and after T4 treatment. Ten healthy, euthyroid males were given 200 µg T4 (levothyroxine per day for 3 days. Energy expenditure was measured at rest and during exercise by indirect calorimetry, and skeletal muscle mitochondrial function was assessed by in situ ATP flux ((31P MRS and in vitro respiratory control ratio (RCR, state 3/state 4 rate of oxygen uptake using a Clark-type electrode before and after acute T4 treatment. Thyroxine had a subtle effect on resting metabolic rate, increasing it by 4% (p = 0.059 without a change in resting ATP demand (i.e., ATP flux of the vastus lateralis. Exercise efficiency did not change with T4 treatment. The maximal capacity to produce ATP (state 3 respiration and the coupled state of the mitochondria (RCR were reduced by approximately 30% with T4 (p = 0.057 and p = 0.04, respectively. Together, the results suggest that T4, although less metabolically active than T3, reduces skeletal muscle efficiency and modestly increases resting metabolism even after short-term supplementation. Our findings may be clinically relevant given the expanding application of T4 to treat non-thyroidal conditions such as obesity and weight loss.

  12. Depleted energy charge and increased pulmonary endothelial permeability induced by mitochondrial complex I inhibition are mitigated by coenzyme Q1 in the isolated perfused rat lung.

    Science.gov (United States)

    Bongard, Robert D; Yan, Ke; Hoffmann, Raymond G; Audi, Said H; Zhang, Xiao; Lindemer, Brian J; Townsley, Mary I; Merker, Marilyn P

    2013-12-01

    Mitochondrial dysfunction is associated with various forms of lung injury and disease that also involve alterations in pulmonary endothelial permeability, but the relationship, if any, between the two is not well understood. This question was addressed by perfusing isolated intact rat lung with a buffered physiological saline solution in the absence or presence of the mitochondrial complex I inhibitor rotenone (20 μM). Compared to control, rotenone depressed whole lung tissue ATP from 5.66 ± 0.46 (SEM) to 2.34 ± 0.15 µmol · g(-1) dry lung, with concomitant increases in the ADP:ATP and AMP:ATP ratios. Rotenone also increased lung perfusate lactate (from 12.36 ± 1.64 to 38.62 ± 3.14 µmol · 15 min(-1) perfusion · g(-1) dry lung) and the lactate:pyruvate ratio, but had no detectable impact on lung tissue GSH:GSSG redox status. The amphipathic quinone coenzyme Q1 (CoQ1; 50 μM) mitigated the impact of rotenone on the adenine nucleotide balance, wherein mitigation was blocked by NAD(P)H-quinone oxidoreductase 1 or mitochondrial complex III inhibitors. In separate studies, rotenone increased the pulmonary vascular endothelial filtration coefficient (Kf) from 0.043 ± 0.010 to 0.156 ± 0.037 ml · min(-1) · cm H2O(-1) · g(-1) dry lung, and CoQ1 protected against the effect of rotenone on Kf. A second complex I inhibitor, piericidin A, qualitatively reproduced the impact of rotenone on Kf and the lactate:pyruvate ratio. Taken together, the observations imply that pulmonary endothelial barrier integrity depends on mitochondrial bioenergetics as reflected in lung tissue ATP levels and that compensatory activation of whole lung glycolysis cannot protect against pulmonary endothelial hyperpermeability in response to mitochondrial blockade. The study further suggests that low-molecular-weight amphipathic quinones may have therapeutic utility in protecting lung barrier function in mitochondrial insufficiency.

  13. Intra-Peritoneal Administration of Mitochondrial DNA Provokes Acute Lung Injury and Systemic Inflammation via Toll-Like Receptor 9.

    Science.gov (United States)

    Zhang, Lemeng; Deng, Songyun; Zhao, Shuangping; Ai, Yuhang; Zhang, Lina; Pan, Pinhua; Su, Xiaoli; Tan, Hongyi; Wu, Dongdong

    2016-01-01

    The pathogenesis of sepsis is complex. Mitochondrial dysfunction, which is responsible for energy metabolism, intrinsic apoptotic pathway, oxidative stress, and systemic inflammatory responses, is closely related with severe sepsis induced death. Mitochondria DNA (mtDNA) contain un-methylated cytosine phosphate guanine (CpG) motifs, which exhibit immune stimulatory capacities. The aim of this study was to investigate the role and mechanism of mtDNA release on lipopolysaccharide (LPS) induced acute lung injury (ALI) and systemic inflammation. Following LPS injection, plasma mtDNA copies peak at 8 h. Compared with wild-type (WT) mice, mtDNA in toll like receptor 4 knockout (TLR4 KO) mice were significantly decreased. MtDNA intra-peritoneal administration causes apparent ALI as demonstrated by increased lung injury score, bronchoalveolar lavage fluid (BALF) total protein and wet/dry (W/D) ratio; mtDNA injection also directly provokes systemic inflammation, as demonstrated by increased IL-1β, IL-6, high-mobility group protein B1 (HMGB1) level; while nuclear DNA (nDNA) could not induce apparent ALI and systemic inflammation. However, compared with WT mice, TLR4 KO could not protect from mtDNA induced ALI and systemic inflammation. Specific TLR9 inhibitor, ODN 2088 pretreatment can significantly attenuate mtDNA induced ALI and systemic inflammation, as demonstrated by improved lung injury score, decreased lung wet/dry ratio, BALF total protein concentration, and decreased systemic level of IL-1β, IL-6 and HMGB1. MtDNA administration activates the expression of p-P38 mitogen-activated protein kinases (MAPK) in lung tissue and specific TLR9 inhibitor pretreatment can attenuate this activation. Thus, LPS-induced mtDNA release occurs in a TLR4-dependent manner, and mtDNA causes acute lung injury and systemic inflammation in a TLR9-dependent and TLR4-independent manner. PMID:27589725

  14. Biological evaluation of new nickel(II) metallates: Synthesis, DNA/protein binding and mitochondrial mediated apoptosis in human lung cancer cells (A549) via ROS hypergeneration and depletion of cellular antioxidant pool.

    Science.gov (United States)

    Kalaivani, P; Saranya, S; Poornima, P; Prabhakaran, R; Dallemer, F; Vijaya Padma, V; Natarajan, K

    2014-07-23

    A series of novel nickel(II) thiosemicarbazone complexes(1-4) have been prepared and characterized by various spectral, analytical techniques and X-ray crystallography. Further, their efficacy to interact with CT-DNA/BSA has been explored. From the binding studies, it is inferred that complex 4 found to be more active than other complexes. The complexes bound with CT-DNA by intercalation mode. Moreover, static quenching was observed for their interaction with BSA. The new complexes were tested for their in vitro cytotoxicity against human lung adenocarcinoma (A549) cell line. The results showed that the new complexes exhibited significant degree of cytotoxicity at given experimental condition. Further, the results of LDH and NO release supported the cytotoxic nature of the complexes. The observed cytotoxicity of the complexes may be routed through ROS-hypergeneration and lipid-peroxidation with subsequent depletion of cellular antioxidant pool (GSH, SOD, CAT, GPx and GST) resulted in the reduction of mitochondrial-membrane potential, caspase-3 activation and DNA fragmentation. Thus, the data from the present study disclose that the complexes could induce apoptosis in A549 cells through mitochondrial mediated fashion and inhibited the migration of lung cancer cells and by metastasis. PMID:24946146

  15. Administration

    DEFF Research Database (Denmark)

    Bogen handler om den praksis, vi kalder administration. Vi er i den offentlige sektor i Danmark hos kontorfolkene med deres sagsmapper, computere, telefoner,, lovsamlinger,, retningslinier og regneark. I bogen udfoldes en mangfoldighed af konkrete historier om det administrative arbejde fra...... forskellige områder i den offentlige sektor. Hensigten er at forstå den praksis og faglighed der knytter sig til det administrative arbejde...

  16. 50 CFR 216.15 - Depleted species.

    Science.gov (United States)

    2010-10-01

    ... Assistant Administrator as depleted under the provisions of the MMPA. (a) Hawaiian monk seal (Monachus schauinslandi). (b) Bowhead whale (Balaena mysticetus). (c) North Pacific fur seal (Callorhinus...

  17. 线粒体DNA耗竭综合征1例临床特点和DGUOK基因突变分析%Clinical features and DGUOK mutations of an infant with mitochondrial DNA depletion syndrome

    Institute of Scientific and Technical Information of China (English)

    邓梅; 林伟霞; 郭丽; 张占会; 宋元宗

    2016-01-01

    The aim of this study was to investigate the clinical features and DGUOK gene mutations of an infant with mitochondrial DNA depletion syndrome (MDS). The patient (more than 7 months old) manifested as hepatosplenomegaly, abnormal liver function, nystagmus and psychomotor retardation. Genetic DNA was extracted from peripheral blood samples of the patient and her parents. Targeted Exome Sequencing was performed to explore the genetic causes. Sanger sequencing was carried out to confirm the detected mutations. The sequencing results showed that the patient was a compound heterozygote for c.679G>A and c.817delT in the DGUOK gene. The former was a reportedly pathogenic missense mutation of maternal origin, while the latter, a frameshift mutation from the father, has not been described yet. The findings in this study expand the mutation spectrum of DGUOK gene, and provide molecular evidence for the etiologic diagnosis of the patient as well as for the genetic counseling and prenatal diagnosis in the family.%该文报道1例线粒体DNA耗竭综合征患儿的临床特征及DGUOK基因突变特点。患儿女,婴儿期起病,表现为肝脾肿大、肝功能异常、眼球震颤和精神运动发育迟缓等。提取患儿及其父母外周血DNA标本,采用外显子组捕获测序技术检测致病突变,并对检测到的突变进行Sanger测序验证。结果显示患儿为DGUOK基因突变c.679G>A和c.817delT的复合杂合子,前一个突变来自于母亲,为已报道致病性突变;后者来自于父亲,是一个未见文献报道的新突变。该研究扩展了DGOUK基因突变谱,为患儿病因诊断及该家系的遗传咨询和产前诊断提供了分子依据。

  18. Clodronate treatment significantly depletes macrophages in chickens

    OpenAIRE

    Kameka, Amber M.; Haddadi, Siamak; Jamaldeen, Fathima Jesreen; Moinul, Prima; He, Xiao T.; Nawazdeen, Fathima Hafsa P.; Bonfield, Stephan; Sharif, Shayan; van Rooijen, Nico; Abdul-Careem, Mohamed Faizal

    2014-01-01

    Macrophages function as phagocytes and antigen-presenting cells in the body. As has been demonstrated in mammals, administration of clodronate [dichloromethylene bisphosphonate (Cl2MBP)] encapsulated liposomes results in depletion of macrophages. Although this compound has been used in chickens, its effectiveness in depleting macrophages has yet to be fully determined. Here, we show that a single administration of clodronate liposomes to chickens results in a significant depletion of macropha...

  19. Assessment for Decision-Makers Scientiic Assessment of Ozone Depletion: 2014 World Meteorological Organization United Nations Environment Programme National Oceanic and Atmospheric Administration National Aeronautics and Space Administration European Commission

    OpenAIRE

    Huret, Nathalie; Legras, Bernard

    2014-01-01

    Actions taken under the Montreal Protocol have led to decreases in the atmospheric abundance of controlledozone-depleting substances (ODSs), and are enabling the return of the ozone layer toward 1980 levels.• The sum of the measured tropospheric abundances of substances controlled under the MontrealProtocol continues to decrease. Most of the major controlled ODSs are decreasing largely as projected, andhydrochlorofluorocarbons (HCFCs) and halon-1301 are still increasing. Unknown or unreported...

  20. Mitochondrial DNA plasticity is an essential inducer of tumorigenesis.

    Science.gov (United States)

    Lee, W T Y; Cain, J E; Cuddihy, A; Johnson, J; Dickinson, A; Yeung, K-Y; Kumar, B; Johns, T G; Watkins, D N; Spencer, A; St John, J C

    2016-01-01

    Although mitochondrial DNA has been implicated in diseases such as cancer, its role remains to be defined. Using three models of tumorigenesis, namely glioblastoma multiforme, multiple myeloma and osteosarcoma, we show that mitochondrial DNA plays defining roles at early and late tumour progression. Specifically, tumour cells partially or completely depleted of mitochondrial DNA either restored their mitochondrial DNA content or actively recruited mitochondrial DNA, which affected the rate of tumorigenesis. Nevertheless, non-depleted tumour cells modulated mitochondrial DNA copy number at early and late progression in a mitochondrial DNA genotype-specific manner. In glioblastoma multiforme and osteosarcoma, this was coupled with loss and gain of mitochondrial DNA variants. Changes in mitochondrial DNA genotype affected tumour morphology and gene expression patterns at early and late progression. Importantly, this identified a subset of genes that are essential to early progression. Consequently, mitochondrial DNA and commonly expressed early tumour-specific genes provide novel targets against tumorigenesis.

  1. IL-6-deficient Mice Are Susceptible to Ethanol-induced Hepatic Steatosis: IL-6 Protects against Ethanol-induced Oxidative Stress and Mitochondrial Permeability Transition in the Liver

    Institute of Scientific and Technical Information of China (English)

    OsamaEl-Assal; FengHong; Won-HoKim; SvetlanaRadaeva; BinGao

    2004-01-01

    Interleukin-6 (IL-6)-deficient mice are prone to ethanol-induced apoptosis and steatosis in the liver; however,the underlying mechanism is not fully understood. Mitochondrial dysfunction caused by oxidative stress is an early event that plays an important role in the pathogenesis of alcoholic liver disease. Therefore, we hypothesize that the protective role of IL-6 in ethanol-induced liver injury is mediated via suppression of ethanol-induced oxidative stress and mitochondrial dysfunction. To test this hypothesis, we examined the effects of IL-6 on ethanol-induced oxidative stress, mitochondrial injury, and energy depletion in the livers of IL-6 (-/-) mice and hepatocytes from ethanol-fed rats. Ethanol consumption leads to stronger induction of malondialdehyde (MDA) in IL-6 (-/-) mice compared to wild-type control mice, which can be corrected by administration of IL-6. In vitro,IL-6 treatment prevents ethanol-mediated induction of reactive oxygen species (ROS), MDA, mitochondrial permeability transition (MPT), and ethanol-mediated depletion of adenosine triphosphate (ATP) in hepatocytes from ethanol-fed rats. Administration of IL-6 in vivo also reverses ethanol-induced MDA and ATP depletion in hepatocytes. Finally, IL-6 treatment induces metallothionein protein expression, but not superoxide dismutase and glutathione peroxidase in cultured hepatocytes. In conclusion, IL-6 protects against ethanol-induced oxidative stress and mitochondrial dysfunction in hepatocytes v/a induction of metallothionein protein expression, which mav account for the nrotective role of IL-6 in alcoholic liver disease.

  2. IL-6-deficient Mice Are Susceptible to Ethanol-induced Hepatic Steatosis: IL-6 Protects against Ethanol-induced Oxidative Stress and Mitochondrial Permeability Transition in the Liver

    Institute of Scientific and Technical Information of China (English)

    Osama El-Assal; Feng Hong; Won-Ho Kim; Svetlana Radaeva; Bin Gao

    2004-01-01

    Interleukin-6 (IL-6)-deficient mice are prone to ethanol-induced apoptosis and steatosis in the liver; however, the underlying mechanism is not fully understood. Mitochondrial dysfunction caused by oxidative stress is an early event that plays an important role in the pathogenesis of alcoholic liver disease. Therefore, we hypothesize that the protective role of IL-6 in ethanol-induced liver injury is mediated via suppression of ethanol-induced oxidative stress and mitochondrial dysfunction. To test this hypothesis, we examined the effects of IL-6 on ethanol-induced oxidative stress, mitochondrial injury, and energy depletion in the livers of IL-6 (-/-) mice and hepatocytes from ethanol-fed rats. Ethanol consumption leads to stronger induction of malondialdehyde (MDA) in IL-6 (-/-) mice compared to wild-type control mice, which can be corrected by administration of IL-6. In vitro,IL-6 treatment prevents ethanol-mediated induction of reactive oxygen species (ROS), MDA, mitochondrial permeability transition (MPT), and ethanol-mediated depletion of adenosine triphosphate (ATP) in hepatocytes from ethanol-fed rats. Administration of IL-6 in vivo also reverses ethanol-induced MDA and ATP depletion in hepatocytes. Finally, IL-6 treatment induces metallothionein protein expression, but not superoxide dismutase and glutathione peroxidase in cultured hepatocytes. In conclusion, IL-6 protects against ethanol-induced oxidative stress and mitochondrial dysfunction in hepatocytes via induction of metallothionein protein expression, which may account for the protective role of IL-6 in alcoholic liver disease.

  3. Effects of maternal L-tryptophan depletion and corticosterone administration on neurobehavioral adjustments in mouse dams and their adolescent and adult daughters.

    Science.gov (United States)

    Zoratto, Francesca; Berry, Alessandra; Anzidei, Francesca; Fiore, Marco; Alleva, Enrico; Laviola, Giovanni; Macrì, Simone

    2011-08-01

    Major depressive disorder (MDD), a pathology characterized by mood and neurovegetative disturbances, depends on a multi-factorial contribution of individual predisposition (e.g., diminished serotonergic transmission) and environmental factors (e.g., neonatal abuse or neglect). Despite its female-biased prevalence, MDD basic research has mainly focused on male rodents. Most of present models of depression are also devalued due to the fact that they typically address only one of the aforementioned pathogenetic factors. In this paper we first describe the basic principles behind mouse model development and evaluation and then articulate that current models of depression are intrinsically devalued due to poor construct and/or external validity. We then report a first attempt to overcome this limitation through the design of a mouse model in which the genetic and the environmental components of early risk factors for depression are mimicked together. Environmental stress is mimicked through the supplementation of corticosterone in the maternal drinking water while biological predisposition is mimicked through maternal access to an L-tryptophan (the serotonin precursor) deficient diet during the first week of lactation. CD1 dams and their offspring exposed to the L-tryptophan deficient diet (T) and to corticosterone (80mg/l; C) were compared to animal facility reared (AFR) subjects. T and C mice served as intermediate reference groups. Adolescent TC offspring, compared to AFR mice, showed decreased time spent floating in the forced-swim test and increased time spent in the open sectors of an elevated 0-maze. Adult TC offspring showed reduced preference for novelty, decreased breakpoints in the progressive ratio operant procedure and major alterations in central BDNF levels and altered HPA regulation. The route of administration and the possibility to control the independent variables predisposing to depressive-like symptoms disclose novel avenues towards the development

  4. Mitochondrial haplogroups

    DEFF Research Database (Denmark)

    Benn, Marianne; Schwartz, Marianne; Nordestgaard, Børge G;

    2008-01-01

    Rare mutations in the mitochondrial genome may cause disease. Mitochondrial haplogroups defined by common polymorphisms have been associated with risk of disease and longevity. We tested the hypothesis that common haplogroups predict risk of ischemic cardiovascular disease, morbidity from other...

  5. Mitochondrial Diseases

    Science.gov (United States)

    ... disorder, something goes wrong with this process. Mitochondrial diseases are a group of metabolic disorders. Mitochondria are ... cells and cause damage. The symptoms of mitochondrial disease can vary. It depends on how many mitochondria ...

  6. DEPLETED URANIUM TECHNICAL WORK

    Science.gov (United States)

    The Depleted Uranium Technical Work is designed to convey available information and knowledge about depleted uranium to EPA Remedial Project Managers, On-Scene Coordinators, contractors, and other Agency managers involved with the remediation of sites contaminated with this mater...

  7. SUCLA2相关脑肌病型线粒体DNA耗竭综合征一例并文献复习%SUCLA2-related encephalomyopathic mitochondrial DNA depletion syndrome: a case report and review of literature

    Institute of Scientific and Technical Information of China (English)

    刘志梅; 方方; 丁昌红; 吴沪生; 吕俊兰; 伍妘

    2014-01-01

    丙二酸轻度升高,血C3和C4DC轻度升高.头颅MRI为基底节受累和脑萎缩样改变,以双侧尾状核、壳核对称性病变为主.25例中19例来自欧洲,其中的13例来自法罗群岛,为SUCLA2 c.534+ 1G>A纯合突变.结论 SUCLA2相关脑肌病型线粒体DNA耗竭综合征临床特征为:生后或婴儿早期出现严重肌张力低下、喂养困难、生长迟缓、发育迟滞(尤其是运动)、听力损害等;血乳酸增高,尿甲基丙二酸轻度增高,血C3和C4DC轻度升高;头颅MRI为双侧对称性尾状核、壳核受累,伴有脑萎缩样改变.发现SUCLA2致病性突变可确诊.%Objective To analyze the clinical characteristics of SUCLA2-related encephalomyopathic mitochondrial DNA depletion syndrome (MDS) in one patient,and review the latest clinical research reports.Method Clinical,laboratory and genetic data of one case of SUCLA2-related encephalomyopathic MDS diagnosed by department of Neurology,Beijing Children's Hospital in November,2013 were reported,and through taking "SUCLA2" as key words to search at CNKI,Wanfang,PubMed and the Human Gene Mutation Database (HGMD) professional to date,the clinical characteristics of 24 reported cases of SUCLA2-related encephalomyopathic MDS in international literature in combination with our case were analyzed.Result (1) The patient was 5 years and 9 months old,born as a term small for gestational age infant whose birth weight was 2 400 g,and presented since birth with severe muscular hypotonia,feeding difficulties,failure to thrive,psychomotor retardation and hearing impairment.Until now,he still showed severe developmental retardation,together with muscular atrophy,thoracocyllosis and scoliosis,and facial features.The patient is the first born from consanguineous healthy parents,whose relationship is cousins.Laboratory tests showed urinary excretion of mild methylmalonic acid (MMA),elevated plasma lactate concentration,and increased C3-carnitine and C4-dicarboxylic-carnitine in plasma carnitine ester

  8. Depleted Uranium Management

    International Nuclear Information System (INIS)

    The paper considers radiological and toxic impact of the depleted uranium on the human health. Radiological influence of depleted uranium is less for 60 % than natural uranium due to the decreasing of short-lived isotopes uranium-234 and uranium-235 after enrichment. The formation of radioactive aerosols and their impact on the human are mentioned. Use of the depleted uranium weapons has also a chemical effect on intake due to possible carcinogenic influence on kidney. Uranium-236 in the substance of the depleted uranium is determined. The fact of beta-radiation formation in the uranium-238 decay is regarded. This effect practically is the same for both depleted and natural uranium. Importance of toxicity of depleted uranium, as the heavier chemical substance, has a considerable contribution to the population health. The paper analyzes risks regarding the use of the depleted uranium weapons. There is international opposition against using weapons with depleted uranium. Resolution on effects of the use of armaments and ammunitions containing depleted uranium was five times supported by the United Nations (USA, United Kingdom, France and Israel did not support). The decision for banning of depleted uranium weapons was supported by the European Parliament

  9. Mitochondrial biogenesis: pharmacological approaches.

    Science.gov (United States)

    Valero, Teresa

    2014-01-01

    ), myoclonic epilepsy with ragged-red fibers (MERRF), mitochondrial encephalomyopathy, lactic acidosis and strokelike episodes (MELAS), Leber's hereditary optic neuropathy (LHON), the syndrome of neurogenic muscle weakness, ataxia and retinitis pigmentosa (NARP), and Leigh's syndrome. Likewise, other diseases in which mitochondrial dysfunction plays a very important role include neurodegenerative diseases, diabetes or cancer. Generally, in mitochondrial diseases a mutation in the mitochondrial DNA leads to a loss of functionality of the OXPHOS system and thus to a depletion of ATP and overproduction of ROS, which can, in turn, induce further mtDNA mutations. The work by Yu-Ting Wu, Shi-Bei Wu, and Yau-Huei Wei (Department of Biochemistry and Molecular Biology, National Yang-Ming University, Taiwan) [4] focuses on the aforementioned mitochondrial diseases with special attention to the compensatory mechanisms that prompt mitochondria to produce more energy even under mitochondrial defect-conditions. These compensatory mechanisms include the overexpression of antioxidant enzymes, mitochondrial biogenesis and overexpression of respiratory complex subunits, as well as metabolic shift to glycolysis. The pathways observed to be related to mitochondrial biogenesis as a compensatory adaptation to the energetic deficits in mitochondrial diseases are described (PGC- 1, Sirtuins, AMPK). Several pharmacological strategies to trigger these signaling cascades, according to these authors, are the use of bezafibrate to activate the PPAR-PGC-1α axis, the activation of AMPK by resveratrol and the use of Sirt1 agonists such as quercetin or resveratrol. Other strategies currently used include the addition of antioxidant supplements to the diet (dietary supplementation with antioxidants) such as L-carnitine, coenzyme Q10,MitoQ10 and other mitochondria-targeted antioxidants,N-acetylcysteine (NAC), vitamin C, vitamin E vitamin K1, vitamin B, sodium pyruvate or -lipoic acid. As aforementioned, other

  10. New therapeutic approach: diphenyl diselenide reduces mitochondrial dysfunction in acetaminophen-induced acute liver failure.

    Directory of Open Access Journals (Sweden)

    Nélson R Carvalho

    Full Text Available The acute liver failure (ALF induced by acetaminophen (APAP is closely related to oxidative damage and depletion of hepatic glutathione, consequently changes in cell energy metabolism and mitochondrial dysfunction have been observed after APAP overdose. Diphenyl diselenide [(PhSe2], a simple organoselenium compound with antioxidant properties, previously demonstrated to confer hepatoprotection. However, little is known about the protective mechanism on mitochondria. The main objective of this study was to investigate the effects (PhSe2 to reduce mitochondrial dysfunction and, secondly, compare in the liver homogenate the hepatoprotective effects of the (PhSe2 to the N-acetylcysteine (NAC during APAP-induced ALF to validate our model. Mice were injected intraperitoneal with APAP (600 mg/kg, (PhSe2 (15.6 mg/kg, NAC (1200 mg/kg, APAP+(PhSe2 or APAP+NAC, where the (PhSe2 or NAC treatment were given 1 h following APAP. The liver was collected 4 h after overdose. The plasma alanine and aspartate aminotransferase activities increased after APAP administration. APAP caused a remarkable increase of oxidative stress markers (lipid peroxidation, reactive species and protein carbonylation and decrease of the antioxidant defense in the liver homogenate and mitochondria. APAP caused a marked loss in the mitochondrial membrane potential, the mitochondrial ATPase activity, and the rate of mitochondrial oxygen consumption and increased the mitochondrial swelling. All these effects were significantly prevented by (PhSe2. The effectiveness of (PhSe2 was similar at a lower dose than NAC. In summary, (PhSe2 provided a significant improvement to the mitochondrial redox homeostasis and the mitochondrial bioenergetics dysfunction caused by membrane permeability transition in the hepatotoxicity APAP-induced.

  11. Mitochondrial Myopathy

    Science.gov (United States)

    ... NINDS supports research focused on effective treatments and cures for mitochondrial myopathies and other mitochondrial diseases. Scientists are investigating the possible benefits of exercise programs and nutritional supplements, primarily natural and synthetic versions of CoQ10. While CoQ10 has ...

  12. Bezafibrate improves mitochondrial function in the CNS of a mouse model of mitochondrial encephalopathy

    OpenAIRE

    Noe, Natalie; Dillon, Lloye; Lellek, Veronika; Diaz, Francisca; Hida, Aline; Carlos T. Moraes; Wenz, Tina

    2012-01-01

    Mitochondrial dysfunction frequently affects the central nervous system. Here, we investigated the effect of bezafibrate treatment on neuronal mitochondrial function and its impact on the progression of a mitochondrial encephalopathy. We used a murine model with a forebrain-specific cytochrome c oxidase deficiency caused by conditional deletion of the COX10 gene. In this mouse model, bezafibrate-administration improved the phenotype of the mice associated with an increase in mitochondrial pro...

  13. Depleted uranium in Japan

    International Nuclear Information System (INIS)

    In Japan, depleted uranium ammunition is regarded as nuclear weapons and meets with fierce opposition. The fact that US Marines mistakenly fired bullets containing depleted uranium on an island off Okinawa during training exercises in December 1995 and January 1996, also contributes. The overall situation in this area in Japan is outlined. (P.A.)

  14. Mitochondrial cytopathies.

    Science.gov (United States)

    El-Hattab, Ayman W; Scaglia, Fernando

    2016-09-01

    Mitochondria are found in all nucleated human cells and perform a variety of essential functions, including the generation of cellular energy. Most of mitochondrial proteins are encoded by the nuclear DNA (nDNA) whereas a very small fraction is encoded by the mitochondrial DNA (mtDNA). Mutations in mtDNA or mitochondria-related nDNA genes can result in mitochondrial dysfunction which leads to a wide range of cellular perturbations including aberrant calcium homeostasis, excessive reactive oxygen species production, dysregulated apoptosis, and insufficient energy generation to meet the needs of various organs, particularly those with high energy demand. Impaired mitochondrial function in various tissues and organs results in the multi-organ manifestations of mitochondrial diseases including epilepsy, intellectual disability, skeletal and cardiac myopathies, hepatopathies, endocrinopathies, and nephropathies. Defects in nDNA genes can be inherited in an autosomal or X-linked manners, whereas, mtDNA is maternally inherited. Mitochondrial diseases can result from mutations of nDNA genes encoding subunits of the electron transport chain complexes or their assembly factors, proteins associated with the mitochondrial import or networking, mitochondrial translation factors, or proteins involved in mtDNA maintenance. MtDNA defects can be either point mutations or rearrangements. The diagnosis of mitochondrial disorders can be challenging in many cases and is based on clinical recognition, biochemical screening, histopathological studies, functional studies, and molecular genetic testing. Currently, there are no satisfactory therapies available for mitochondrial disorders that significantly alter the course of the disease. Therapeutic options include symptomatic treatment, cofactor supplementation, and exercise. PMID:26996063

  15. Management of depleted uranium

    International Nuclear Information System (INIS)

    Large stocks of depleted uranium have arisen as a result of enrichment operations, especially in the United States and the Russian Federation. Countries with depleted uranium stocks are interested in assessing strategies for the use and management of depleted uranium. The choice of strategy depends on several factors, including government and business policy, alternative uses available, the economic value of the material, regulatory aspects and disposal options, and international market developments in the nuclear fuel cycle. This report presents the results of a depleted uranium study conducted by an expert group organised jointly by the OECD Nuclear Energy Agency and the International Atomic Energy Agency. It contains information on current inventories of depleted uranium, potential future arisings, long term management alternatives, peaceful use options and country programmes. In addition, it explores ideas for international collaboration and identifies key issues for governments and policy makers to consider. (authors)

  16. Water Depletion Threatens Agriculture

    Science.gov (United States)

    Brauman, K. A.; Richter, B. D.; Postel, S.; Floerke, M.; Malsy, M.

    2014-12-01

    Irrigated agriculture is the human activity that has by far the largest impact on water, constituting 85% of global water consumption and 67% of global water withdrawals. Much of this water use occurs in places where water depletion, the ratio of water consumption to water availability, exceeds 75% for at least one month of the year. Although only 17% of global watershed area experiences depletion at this level or more, nearly 30% of total cropland and 60% of irrigated cropland are found in these depleted watersheds. Staple crops are particularly at risk, with 75% of global irrigated wheat production and 65% of irrigated maize production found in watersheds that are at least seasonally depleted. Of importance to textile production, 75% of cotton production occurs in the same watersheds. For crop production in depleted watersheds, we find that one half to two-thirds of production occurs in watersheds that have not just seasonal but annual water shortages, suggesting that re-distributing water supply over the course of the year cannot be an effective solution to shortage. We explore the degree to which irrigated production in depleted watersheds reflects limitations in supply, a byproduct of the need for irrigation in perennially or seasonally dry landscapes, and identify heavy irrigation consumption that leads to watershed depletion in more humid climates. For watersheds that are not depleted, we evaluate the potential impact of an increase in irrigated production. Finally, we evaluate the benefits of irrigated agriculture in depleted and non-depleted watersheds, quantifying the fraction of irrigated production going to food production, animal feed, and biofuels.

  17. Disruption of mitochondrial DNA replication in Drosophila increases mitochondrial fast axonal transport in vivo.

    Directory of Open Access Journals (Sweden)

    Rehan M Baqri

    Full Text Available Mutations in mitochondrial DNA polymerase (pol gamma cause several progressive human diseases including Parkinson's disease, Alper's syndrome, and progressive external ophthalmoplegia. At the cellular level, disruption of pol gamma leads to depletion of mtDNA, disrupts the mitochondrial respiratory chain, and increases susceptibility to oxidative stress. Although recent studies have intensified focus on the role of mtDNA in neuronal diseases, the changes that take place in mitochondrial biogenesis and mitochondrial axonal transport when mtDNA replication is disrupted are unknown. Using high-speed confocal microscopy, electron microscopy and biochemical approaches, we report that mutations in pol gamma deplete mtDNA levels and lead to an increase in mitochondrial density in Drosophila proximal nerves and muscles, without a noticeable increase in mitochondrial fragmentation. Furthermore, there is a rise in flux of bidirectional mitochondrial axonal transport, albeit with slower kinesin-based anterograde transport. In contrast, flux of synaptic vesicle precursors was modestly decreased in pol gamma-alpha mutants. Our data indicate that disruption of mtDNA replication does not hinder mitochondrial biogenesis, increases mitochondrial axonal transport, and raises the question of whether high levels of circulating mtDNA-deficient mitochondria are beneficial or deleterious in mtDNA diseases.

  18. Oral administration of amino acidic supplements improves protein and energy profiles in skeletal muscle of aged rats: elongation of functional performance and acceleration of mitochondrial recovery in adenosine triphosphate after exhaustive exertion.

    Science.gov (United States)

    Chen Scarabelli, Carol; McCauley, Roy B; Yuan, Zhaokan; Di Rezze, Justin; Patel, David; Putt, Jeff; Raddino, Riccardo; Allebban, Zuhair; Abboud, John; Scarabelli, Gabriele M; Chilukuri, Karuna; Gardin, Julius; Saravolatz, Louis; Faggian, Giuseppe; Mazzucco, Alessandro; Scarabelli, Tiziano M

    2008-06-01

    Sarcopenia is an inevitable age-related degenerative process chiefly characterized by decreased synthesis of muscle proteins and impaired mitochondrial function, leading to progressive loss of muscle mass. Here, we sought to probe whether long-term administration of oral amino acids (AAs) can increase protein and adenosine triphosphate (ATP) content in the gastrocnemius muscle of aged rats, enhancing functional performance. To this end, 6- and 24-month-old male Fisher 344 rats were divided into 3 groups: group A (6-month-old rats) and group B (24-month-old rats) were used as adult and senescent control group, respectively, while group C (24-month-old rats) was used as senescent treated group and underwent 1-month oral treatment with a mixture of mainly essential AAs. Untreated senescent animals exhibited a 30% reduction in total and fractional protein content, as well as a 50% reduction in ATP content and production, compared with adult control rats (p supplementation with mixed AAs significantly improved protein and high-energy phosphate content, as well as the rate of mitochondrial ATP production, conforming their values to those of adult control animals (p energy substrates in the gastrocnemius muscle of treated aged rats paralleled a significant enhancement in functional performance assessed by swim test, with dramatic elongation of maximal exertion times compared with untreated senescent rats (p supplementation with oral AAs improved protein and energy profiles in the gastrocnemius of treated rats, enhancing functional performance and accelerating high-energy phosphate recovery after exhaustive exertion.

  19. In Vivo Depletion of T Lymphocytes.

    Science.gov (United States)

    Laky, Karen; Kruisbeek, Ada M

    2016-01-01

    In vivo depletion of T lymphocytes is a means of studying the role of specific T cell populations during defined phases of in vivo immune responses. In this unit, a protocol is provided for injecting monoclonal antibodies (mAbs) into wild-type adult mice. Depletion of the appropriate subset of cells is verified by flow cytometry analysis of lymph node and spleen cell suspensions in pilot experiments. Once conditions have been established, depleted mice can be used to study the impact of T cell subsets on a variety of in vivo immune responses. The depleted condition may be maintained by repeated injections of the monoclonal antibody, or reversed by normal thymopoiesis following discontinuation of antibody administration. PMID:27038463

  20. Uses of depleted uranium

    International Nuclear Information System (INIS)

    The depleted uranium is that in which percentage of uranium-235 fission executable is less than 0.2% or 0.3%. It is usually caused by the process of reprocessing the nuclear fuel burning, and also mixed with some other radioactive elements such as uranium 236, 238 and plutonium 239. The good features of the depleted uranium are its high density, low price and easily mined. So, the specifications for depleted uranium make it one of the best materials in case you need to have objects small in size, but quite heavy regarding its size. Uses of deplet ed uranium were relatively increased in domestic industrial uses as well as some uses in nuclear industry in the last few years. So it has increased uses in many areas of military and peaceful means such as: in balancing the giant air crafts, ships and missiles and in the manufacture of some types of concrete with severe hardness. (author)

  1. Mitochondrial Gene Therapy Augments Mitochondrial Physiology in a Parkinson's Disease Cell Model

    OpenAIRE

    Keeney, Paula M; Quigley, Caitlin K.; Dunham, Lisa D.; Papageorge, Christina M.; Iyer, Shilpa; Thomas, Ravindar R.; Schwarz, Kathleen M.; Trimmer, Patricia A; Khan, Shaharyar M.; Portell, Francisco R.; Bergquist, Kristen E.; Bennett, James P.

    2009-01-01

    Neurodegeneration in Parkinson's disease (PD) affects mainly dopaminergic neurons in the substantia nigra, where age-related, increasing percentages of cells lose detectable respiratory activity associated with depletion of intact mitochondrial DNA (mtDNA). Replenishment of mtDNA might improve neuronal bioenergetic function and prevent further cell death. We developed a technology (“ProtoFection”) that uses recombinant human mitochondrial transcription factor A (TFAM) engineered with an N-ter...

  2. Intrinsic Depletion or Not

    DEFF Research Database (Denmark)

    Klösgen, Beate; Bruun, Sara; Hansen, Søren;

    with an AFM (2).    The intuitive explanation for the depletion based on "hydrophobic mismatch" between the obviously hydrophilic bulk phase of water next to the hydrophobic polymer. It would thus be an intrinsic property of all interfaces between non-matching materials. The detailed physical interaction path......  The presence of a depletion layer of water along extended hydrophobic interfaces, and a possibly related formation of nanobubbles, is an ongoing discussion. The phenomenon was initially reported when we, years ago, chose thick films (~300-400Å) of polystyrene as cushions between a crystalline...

  3. Intrinsic Depletion or Not

    DEFF Research Database (Denmark)

    Klösgen, Beate; Bruun, Sara; Hansen, Søren;

    with an AFM (2). The intuitive explanation for the depletion based on "hydrophobic mismatch" between the obviously hydrophilic bulk phase of water next to the hydrophobic polymer. It would thus be an intrinsic property of all interfaces between non-matching materials. The detailed physical interaction path......  The presence of a depletion layer of water along extended hydrophobic interfaces, and a possibly related formation of nanobubbles, is an ongoing discussion. The phenomenon was initially reported when we, years ago, chose thick films (~300-400Å) of polystyrene as cushions between a crystalline...

  4. Shear-affected depletion interaction

    NARCIS (Netherlands)

    July, C.; Kleshchanok, D.; Lang, P.R.

    2012-01-01

    We investigate the influence of flow fields on the strength of the depletion interaction caused by disc-shaped depletants. At low mass concentration of discs, it is possible to continuously decrease the depth of the depletion potential by increasing the applied shear rate until the depletion force i

  5. The Case of Ozone Depletion

    Science.gov (United States)

    Lambright, W. Henry

    2005-01-01

    While the National Aeronautics and Space Administration (NASA) is widely perceived as a space agency, since its inception NASA has had a mission dedicated to the home planet. Initially, this mission involved using space to better observe and predict weather and to enable worldwide communication. Meteorological and communication satellites showed the value of space for earthly endeavors in the 1960s. In 1972, NASA launched Landsat, and the era of earth-resource monitoring began. At the same time, in the late 1960s and early 1970s, the environmental movement swept throughout the United States and most industrialized countries. The first Earth Day event took place in 1970, and the government generally began to pay much more attention to issues of environmental quality. Mitigating pollution became an overriding objective for many agencies. NASA's existing mission to observe planet Earth was augmented in these years and directed more toward environmental quality. In the 1980s, NASA sought to plan and establish a new environmental effort that eventuated in the 1990s with the Earth Observing System (EOS). The Agency was able to make its initial mark via atmospheric monitoring, specifically ozone depletion. An important policy stimulus in many respects, ozone depletion spawned the Montreal Protocol of 1987 (the most significant international environmental treaty then in existence). It also was an issue critical to NASA's history that served as a bridge linking NASA's weather and land-resource satellites to NASA s concern for the global changes affecting the home planet. Significantly, as a global environmental problem, ozone depletion underscored the importance of NASA's ability to observe Earth from space. Moreover, the NASA management team's ability to apply large-scale research efforts and mobilize the talents of other agencies and the private sector illuminated its role as a lead agency capable of crossing organizational boundaries as well as the science-policy divide.

  6. AFSC/REFM: Pacific cod Localized Depletion Study

    Data.gov (United States)

    National Oceanic and Atmospheric Administration, Department of Commerce — Data from Localized Depletion study for Pacific cod 2001-2005. Study was conducted using cod pot gear to measure localized abundance of Pacific cod inside and...

  7. Depletion of intense fields

    CERN Document Server

    Seipt, D; Marklund, M; Bulanov, S S

    2016-01-01

    The interaction of charged particles and photons with intense electromagnetic fields gives rise to multi-photon Compton and Breit-Wheeler processes. These are usually described in the framework of the external field approximation, where the electromagnetic field is assumed to have infinite energy. However, the multi-photon nature of these processes implies the absorption of a significant number of photons, which scales as the external field amplitude cubed. As a result, the interaction of a highly charged electron bunch with an intense laser pulse can lead to significant depletion of the laser pulse energy, thus rendering the external field approximation invalid. We provide relevant estimates for this depletion and find it to become important in the interaction between fields of amplitude $a_0 \\sim 10^3$ and electron bunches with charges of the order of nC.

  8. Capital expenditure and depletion

    Energy Technology Data Exchange (ETDEWEB)

    Rech, O.; Saniere, A

    2003-07-01

    In the future, the increase in oil demand will be covered for the most part by non conventional oils, but conventional sources will continue to represent a preponderant share of the world oil supply. Their depletion represents a complex challenge involving technological, economic and political factors. At the same time, there is reason for concern about the decrease in exploration budgets at the major oil companies. (author)

  9. Capital expenditure and depletion

    International Nuclear Information System (INIS)

    In the future, the increase in oil demand will be covered for the most part by non conventional oils, but conventional sources will continue to represent a preponderant share of the world oil supply. Their depletion represents a complex challenge involving technological, economic and political factors. At the same time, there is reason for concern about the decrease in exploration budgets at the major oil companies. (author)

  10. Depletion of florfenicol amine, marker residue of florfenicol, from the edible fillet of tilapia (Oreochromis niloticus x O. niloticus and O. niloticus x O. aureus) following florfenicol administration in feed

    Science.gov (United States)

    Gaikowski, M.P.; Mushtaq, M.; Cassidy, P.; Meinertz, J.R.; Schleis, S.M.; Sweeney, D.; Endris, R.G.

    2010-01-01

    Aquaflor??, a 50% feed premix containing the broad spectrum antibacterial agent florfenicol is available globally to control mortality associated with economically significant systemic bacterial diseases of fish. Florfenicol (FFC) is effective in controlling mortality associated with Streptococcus iniae in tilapia Oreochromis sp. when administered in medicated feed at a dose of 15 mg/kg bodyweight (BW)/d for 10 consecutive days. Our objective was to characterize the depletion of the FFC marker residue, florfenicol amine (FFA), from the edible tissue of market-weight Nile tilapia O. niloticus x O. niloticus and hybrid tilapia O. niloticus x O. aureus offered feed medicated with FFC at a nominal dose rate of 15 mg/kg BW/d for 12 days. Near market-weight tilapia were obtained from a commercial tilapia farm, distributed to 2 single pass (one for Nile tilapia and one for hybrid tilapia), flow-through systems and maintained at 27 ??C under a 15 h light:9 h dark photoperiod over a 41-d pre-dosing period. During the dosing period, tilapia were offered feed medicated with FFC at a concentration of 1.479 g/kg at 1% BW daily divided in three equal offerings. The initial 10-d dosing period was extended to 12 d because one tank did not consume > 75% of the feed offered during the first two dosing days. The total dose consumed by fish in each of the 2 tanks ranged from 147 to 167 mg/kg. Once during the pre-dose period and on days 1, 2, 4, 7, 14, 21, and 28 of the post-dose period, groups of fish were indiscriminately removed from each tank, measured for weight and length, scaled, filleted, and the skin-on fillets stored at <-70 ??C. Frozen fillets were individually homogenized, extracted, and FFA concentration was determined by high-performance liquid chromatography with UV detection. Florfenicol amine is rapidly eliminated from tilapia fillet after withdrawal from medication and depletion followed first-order kinetics with an estimated half-life of 2.32 d. The FFA tolerance

  11. Ozone-depleting Substances (ODS)

    Data.gov (United States)

    U.S. Environmental Protection Agency — This site includes all of the ozone-depleting substances (ODS) recognized by the Montreal Protocol. The data include ozone depletion potentials (ODP), global...

  12. What Is Mitochondrial DNA?

    Science.gov (United States)

    ... DNA What is mitochondrial DNA? What is mitochondrial DNA? Although most DNA is packaged in chromosomes within ... proteins. For more information about mitochondria and mitochondrial DNA: Molecular Expressions, a web site from the Florida ...

  13. Stratospheric ozone depletion

    International Nuclear Information System (INIS)

    The amount of stratospheric ozone and the reduction of the ozone layer vary according to seasons and latitudes. At present total and vertical ozone is monitored over all Austria. The mean monthly ozone levels between 1994 and 2000 are presented. Data on stratospheric ozone and UV-B radiation are published daily on the home page http: www.lebesministerium.at. The use of ozone depleting substances such as chlorofluorocarbons (CFCs), hydrochlorofluorocarbons (HCFCs) is provided. Besides, the national measures taken to reduce their use. Figs. 2, Tables 2. (nevyjel)

  14. Protective effect of bacoside A on cigarette smoking-induced brain mitochondrial dysfunction in rats.

    Science.gov (United States)

    Anbarasi, Kothandapani; Vani, Ganapathy; Devi, Chennam Srinivasulu Shyamala

    2005-01-01

    Chronic exposure to cigarette smoke affects the structure and function of mitochondria, which may account for the pathogenesis of smoking-related diseases. Bacopa monniera Linn., used in traditional Indian medicine for various neurological disorders, was shown to possess mitrochondrial membrane-stabilizing properties in the rat brain during exposure to morphine. We investigated the protective effect of bacoside A, the active principle of Bacopa monniera, against mitochondrial dysfunction in rat brain induced by cigarette smoke. Male Wistar albino rats were exposed to cigarette smoke and administered bacoside A for a period of 12 weeks. The mitochondrial damage in the brain was assessed by examining the levels of lipid peroxides, cholesterol, phospholipid, cholesterol/phospholipid (C/P) ratio, and the activities of isocitrate dehydrogenase, alpha-ketoglutarate dehydrogenase, succinate dehydrogenase, malate dehydrogenase, NADH dehydrogenase, and cytochrome C oxidase. The oxidative phosphorylation (rate of succinate oxidation, respiratory control ratio and ADP/O ratio, and the levels of ATP) was evaluated for the assessment of mitochondrial functional capacity. We found significantly elevated levels of lipid peroxides, cholesterol, and C/P ratio, and decreased levels of phospholipids and mitochondrial enzymes in the rats exposed to cigarette smoke. Measurement of oxidative phosphorylation revealed a marked depletion in all the variables studied. Administration of bacoside A prevented the structural and functional impairment of mitochondria upon exposure to cigarette smoke. From the results, we suggest that chronic cigarette smoke exposure induces damage to the mitochondria and that bacoside A protects the brain from this damage by maintaining the structural and functional integrity of the mitochondrial membrane.

  15. Riddle of depleted uranium

    International Nuclear Information System (INIS)

    Depleted Uranium (DU) is the waste product of uranium enrichment from the manufacturing of fuel rods for nuclear reactors in nuclear power plants and nuclear power ships. DU may also results from the reprocessing of spent nuclear reactor fuel. Potentially DU has both chemical and radiological toxicity with two important targets organs being the kidney and the lungs. DU is made into a metal and, due to its availability, low price, high specific weight, density and melting point as well as its pyrophoricity; it has a wide range of civilian and military applications. Due to the use of DU over the recent years, there appeared in some press on health hazards that are alleged to be due to DU. In these paper properties, applications, potential environmental and health effects of DU are briefly reviewed

  16. Depleted uranium: Metabolic disruptor?

    International Nuclear Information System (INIS)

    The presence of uranium in the environment can lead to long-term contamination of the food chain and of water intended for human consumption and thus raises many questions about the scientific and societal consequences of this exposure on population health. Although the biological effects of chronic low-level exposure are poorly understood, results of various recent studies show that contamination by depleted uranium (DU) induces subtle but significant biological effects at the molecular level in organs including the brain, liver, kidneys and testicles. For the first time, it has been demonstrated that DU induces effects on several metabolic pathways, including those metabolizing vitamin D, cholesterol, steroid hormones, acetylcholine and xenobiotics. This evidence strongly suggests that DU might well interfere with many metabolic pathways. It might thus contribute, together with other man-made substances in the environment, to increased health risks in some regions. (authors)

  17. Topical or oral administration with an extract of Polypodium leucotomos prevents acute sunburn and psoralen-induced phototoxic reactions as well as depletion of Langerhans cells in human skin

    Energy Technology Data Exchange (ETDEWEB)

    Gonzalez, S.; Pathak, M.A.; Fitzpatrick, T.B. [Massachusetts General Hospital, Harvard Medical School, Dept. of Dermatology, Boston, MA (United States); Cuevas, J. [Hospital Universitario de Guadalajara, Dept. of Pathology, Guadalajara (Spain); Villarrubia, V.G. [I.F. Cantabria SA, Medical Dept., Immunology Sect., Madrid (Spain)

    1997-12-31

    Sunburn, immune suppression, photo-aging, and skin cancers result from uncontrolled overexposure of human skin to solar ultraviolet radiation (UVR). Preventive measures, including photo-protection, are helpful and can be achieved by topical sun-screening agents. Polypodium leucotomos (PL) has been used for the treatment of inflammatory diseases and has shown some in vitro and in vivo immunomodulating properties. Its beneficial photo-protective effects in the treatment of vitiligo and its antioxidant properties encouraged us to evaluate in vivo the potentially useful photo-protective property of natural extract of PL after topical application or oral ingestion. Twenty-one healthy volunteers [either untreated or treated with oral psoralens (8-MOP or 5-MOP)] were enrolled in this study and exposed to solar radiation for evaluation of the following clinical parameters: immediate pigment darkening (IPD), minimal erythema dose (MED), minimal melanogenic dose (MMD), and minimal phototoxic dose (MPD) before and after topical or oral administration of PL. Immunohistochemical assessment of CD1a-expressing epidermal cells were also performed. PL was found to be photo-protective after topical application as well as oral administration. PL increased UV dose required for IPD (P<0.01), MED (P<0.001) and MPD (P<0.001). After oral administration of PL, MED increased 2.,8{+-}0.59 times and MPD increased 2.75{+-}0.5 and 6.8{+-}1.3 times depending upon the type of psoralen used. Immunohistochemical study revealed photo-protection of Langherhans cells by oral as well as topical PL. The observed photo-protective activities of oral or topical PL reveal a new avenue in examining the potentially useful field of systemic photo-protection and suggests that PL can be used as adjunct treatment and can make photochemotherapy and phototherapy possibly safe and effective when the control of cutaneous phototoxicity to PUVA or UVB is a limiting factor in such photo-therapies. (au). 50 refs.

  18. Mitochondrial involvement in drug-induced liver injury.

    Science.gov (United States)

    Pessayre, Dominique; Mansouri, Abdellah; Berson, Alain; Fromenty, Bernard

    2010-01-01

    Mitochondrial dysfunction is a major mechanism of liver injury. A parent drug or its reactive metabolite can trigger outer mitochondrial membrane permeabilization or rupture due to mitochondrial permeability transition. The latter can severely deplete ATP and cause liver cell necrosis, or it can instead lead to apoptosis by releasing cytochrome c, which activates caspases in the cytosol. Necrosis and apoptosis can trigger cytolytic hepatitis resulting in lethal fulminant hepatitis in some patients. Other drugs severely inhibit mitochondrial function and trigger extensive microvesicular steatosis, hypoglycaemia, coma, and death. Milder and more prolonged forms of drug-induced mitochondrial dysfunction can also cause macrovacuolar steatosis. Although this is a benign liver lesion in the short-term, it can progress to steatohepatitis and then to cirrhosis. Patient susceptibility to drug-induced mitochondrial dysfunction and liver injury can sometimes be explained by genetic or acquired variations in drug metabolism and/or elimination that increase the concentration of the toxic species (parent drug or metabolite). Susceptibility may also be increased by the presence of another condition, which also impairs mitochondrial function, such as an inborn mitochondrial cytopathy, beta-oxidation defect, certain viral infections, pregnancy, or the obesity-associated metabolic syndrome. Liver injury due to mitochondrial dysfunction can have important consequences for pharmaceutical companies. It has led to the interruption of clinical trials, the recall of several drugs after marketing, or the introduction of severe black box warnings by drug agencies. Pharmaceutical companies should systematically investigate mitochondrial effects during lead selection or preclinical safety studies. PMID:20020267

  19. LHON: Mitochondrial Mutations and More.

    Science.gov (United States)

    Kirches, E

    2011-03-01

    Leber's hereditary optic neuropathy (LHON) is a mitochondrial disorder leading to severe visual impairment or even blindness by death of retinal ganglion cells (RGCs). The primary cause of the disease is usually a mutation of the mitochondrial genome (mtDNA) causing a single amino acid exchange in one of the mtDNA-encoded subunits of NADH:ubiquinone oxidoreductase, the first complex of the electron transport chain. It was thus obvious to accuse neuronal energy depletion as the most probable mediator of neuronal death. The group of Valerio Carelli and other authors have nicely shown that energy depletion shapes the cell fate in a LHON cybrid cell model. However, the cybrids used were osteosarcoma cells, which do not fully model neuronal energy metabolism. Although complex I mutations may cause oxidative stress, a potential pathogenetic role of the latter was less taken into focus. The hypothesis of bioenergetic failure does not provide a simple explanation for the relatively late disease onset and for the incomplete penetrance, which differs remarkably between genders. It is assumed that other genetic and environmental factors are needed in addition to the 'primary LHON mutations' to elicit RGC death. Relevant nuclear modifier genes have not been identified so far. The review discusses the unresolved problems of a pathogenetic hypothesis based on ATP decline and/or ROS-induced apoptosis in RGCs.

  20. Mitochondrial Dynamics and Mitochondrial Dysfunction in Diabetes.

    Science.gov (United States)

    Wada, Jun; Nakatsuka, Atsuko

    2016-06-01

    The mitochondria are involved in active and dynamic processes, such as mitochondrial biogenesis, fission, fusion and mitophagy to maintain mitochondrial and cellular functions. In obesity and type 2 diabetes, impaired oxidation, reduced mitochondrial contents, lowered rates of oxidative phosphorylation and excessive reactive oxygen species (ROS) production have been reported. Mitochondrial biogenesis is regulated by various transcription factors such as peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α), peroxisome proliferator-activated receptors (PPARs), estrogen-related receptors (ERRs), and nuclear respiratory factors (NRFs). Mitochondrial fusion is promoted by mitofusin 1 (MFN1), mitofusin 2 (MFN2) and optic atrophy 1 (OPA1), while fission is governed by the recruitment of dynamin-related protein 1 (DRP1) by adaptor proteins such as mitochondrial fission factor (MFF), mitochondrial dynamics proteins of 49 and 51 kDa (MiD49 and MiD51), and fission 1 (FIS1). Phosphatase and tensin homolog (PTEN)-induced putative kinase 1 (PINK1) and PARKIN promote DRP1-dependent mitochondrial fission, and the outer mitochondrial adaptor MiD51 is required in DRP1 recruitment and PARKIN-dependent mitophagy. This review describes the molecular mechanism of mitochondrial dynamics, its abnormality in diabetes and obesity, and pharmaceuticals targeting mitochondrial biogenesis, fission, fusion and mitophagy. PMID:27339203

  1. Increased intrinsic mitochondrial function in humans with mitochondrial haplogroup H

    DEFF Research Database (Denmark)

    Larsen, Steen; Díez-Sánchez, Carmen; Rabøl, Rasmus;

    2014-01-01

    and determined their mitochondrial haplogroup, mitochondrial oxidative phosphorylation capacity (OXPHOS), mitochondrial content (citrate synthase (CS)) and VO2max. Intrinsic mitochondrial function is calculated as mitochondrial OXPHOS capacity divided by mitochondrial content (CS). Haplogroup H showed a 30......% higher intrinsic mitochondrial function compared with the other haplo group U. There was no relationship between haplogroups and VO2max. In skeletal muscle from men with mitochondrial haplogroup H, an increased intrinsic mitochondrial function is present....

  2. The Toxicity of Depleted Uranium

    OpenAIRE

    Wayne Briner

    2010-01-01

    Depleted uranium (DU) is an emerging environmental pollutant that is introduced into the environment primarily by military activity. While depleted uranium is less radioactive than natural uranium, it still retains all the chemical toxicity associated with the original element. In large doses the kidney is the target organ for the acute chemical toxicity of this metal, producing potentially lethal tubular necrosis. In contrast, chronic low dose exposure to depleted uranium may not produce a c...

  3. Topical or oral administration with an extract of Polypodium leucotomos prevents acute sunburn and psoralen-induced phototoxic reactions as well as depletion of Langerhans cells in human skin

    International Nuclear Information System (INIS)

    Sunburn, immune suppression, photo-aging, and skin cancers result from uncontrolled overexposure of human skin to solar ultraviolet radiation (UVR). Preventive measures, including photo-protection, are helpful and can be achieved by topical sun-screening agents. Polypodium leucotomos (PL) has been used for the treatment of inflammatory diseases and has shown some in vitro and in vivo immunomodulating properties. Its beneficial photo-protective effects in the treatment of vitiligo and its antioxidant properties encouraged us to evaluate in vivo the potentially useful photo-protective property of natural extract of PL after topical application or oral ingestion. Twenty-one healthy volunteers [either untreated or treated with oral psoralens (8-MOP or 5-MOP)] were enrolled in this study and exposed to solar radiation for evaluation of the following clinical parameters: immediate pigment darkening (IPD), minimal erythema dose (MED), minimal melanogenic dose (MMD), and minimal phototoxic dose (MPD) before and after topical or oral administration of PL. Immunohistochemical assessment of CD1a-expressing epidermal cells were also performed. PL was found to be photo-protective after topical application as well as oral administration. PL increased UV dose required for IPD (P<0.01), MED (P<0.001) and MPD (P<0.001). After oral administration of PL, MED increased 2.,8±0.59 times and MPD increased 2.75±0.5 and 6.8±1.3 times depending upon the type of psoralen used. Immunohistochemical study revealed photo-protection of Langherhans cells by oral as well as topical PL. The observed photo-protective activities of oral or topical PL reveal a new avenue in examining the potentially useful field of systemic photo-protection and suggests that PL can be used as adjunct treatment and can make photochemotherapy and phototherapy possibly safe and effective when the control of cutaneous phototoxicity to PUVA or UVB is a limiting factor in such photo-therapies. (au)

  4. Depleted zinc: Properties, application, production

    International Nuclear Information System (INIS)

    The addition of ZnO, depleted in the Zn-64 isotope, to the water of boiling water nuclear reactors lessens the accumulation of Co-60 on the reactor interior surfaces, reduces radioactive wastes and increases the reactor service-life because of the inhibitory action of zinc on inter-granular stress corrosion cracking. To the same effect depleted zinc in the form of acetate dihydrate is used in pressurized water reactors. Gas centrifuge isotope separation method is applied for production of depleted zinc on the industrial scale. More than 20 years of depleted zinc application history demonstrates its benefits for reduction of NPP personnel radiation exposure and combating construction materials corrosion.

  5. Depleted zinc: Properties, application, production.

    Science.gov (United States)

    Borisevich, V D; Pavlov, A V; Okhotina, I A

    2009-01-01

    The addition of ZnO, depleted in the Zn-64 isotope, to the water of boiling water nuclear reactors lessens the accumulation of Co-60 on the reactor interior surfaces, reduces radioactive wastes and increases the reactor service-life because of the inhibitory action of zinc on inter-granular stress corrosion cracking. To the same effect depleted zinc in the form of acetate dihydrate is used in pressurized water reactors. Gas centrifuge isotope separation method is applied for production of depleted zinc on the industrial scale. More than 20 years of depleted zinc application history demonstrates its benefits for reduction of NPP personnel radiation exposure and combating construction materials corrosion.

  6. Mitochondrial DNA dynamics during in vitro culture and pluripotency induction of a bovine Rho0 cell line.

    Science.gov (United States)

    Pessôa, L V F; Bressan, F F; Chiaratti, M R; Pires, P R L; Perecin, F; Smith, L C; Meirelles, F V

    2015-10-30

    Large number of cellular changes and diseases are related to mutations in the mitochondrial DNA copy number. Cell culture in the presence of ethidium bromide is a known way of depleting mitochondrial DNA and is a useful model for studying such conditions. Interestingly, the morphology of these depleted cells resembles that of pluripotent cells, as they present larger and fragmented mitochondria with poorly developed cristae. Herein, we aimed to study the mechanisms responsible for the control of mitochondrial DNA replication during mitochondrial DNA depletion mediated by ethidium bromide and during the in vitro induction of cellular pluripotency with exogenous transcription factor expression in a bovine model. This article reports the generation of a bovine Rho0 mesenchymal cell line and describes the analysis of mitochondrial DNA copy number in a time-dependent manner. The expression of apoptosis and mitochondrial-related genes in the cells during mitochondrial DNA repletion were also analyzed. The dynamics of mitochondrial DNA during both the depletion process and in vitro reprogramming are discussed. It was possible to obtain bovine mesenchymal cells almost completely depleted of their mitochondrial DNA content (over 90%). However, the production of induced pluripotent stem cells from the transduction of both control and Rho0 bovine mesenchymal cells with human reprograming factors was not successful.

  7. A role of taurine in mitochondrial function

    DEFF Research Database (Denmark)

    Hansen, Svend Høime; Andersen, Mogens Larsen; Cornett, Claus;

    2010-01-01

    The mitochondrial pH gradient across the inner-membrane is stabilised by buffering of the matrix. A low-molecular mass buffer compound has to be localised in the matrix to maintain its alkaline pH value. Taurine is found ubiquitously in animal cells with concentrations in the millimolar range...... and its pKa value is determined to 9.0 (25 degrees C) and 8.6 (37 degrees C), respectively. Localisation of such a low-molecular buffer in the mitochondrial matrix, transforms the matrix into a biochemical reaction chamber for the important matrix-localised enzyme systems. Three acyl-CoA dehydrogenase...... enzymes, which are pivotal for beta-oxidation of fatty acids, are demonstrated to have optimal activity in a taurine buffer. By application of the model presented, taurine depletion caused by hyperglycemia could provide a link between mitochondrial dysfunction and diabetes....

  8. The Toxicity of Depleted Uranium

    Directory of Open Access Journals (Sweden)

    Wayne Briner

    2010-01-01

    Full Text Available Depleted uranium (DU is an emerging environmental pollutant that is introduced into the environment primarily by military activity. While depleted uranium is less radioactive than natural uranium, it still retains all the chemical toxicity associated with the original element. In large doses the kidney is the target organ for the acute chemical toxicity of this metal, producing potentially lethal tubular necrosis. In contrast, chronic low dose exposure to depleted uranium may not produce a clear and defined set of symptoms. Chronic low-dose, or subacute, exposure to depleted uranium alters the appearance of milestones in developing organisms. Adult animals that were exposed to depleted uranium during development display persistent alterations in behavior, even after cessation of depleted uranium exposure. Adult animals exposed to depleted uranium demonstrate altered behaviors and a variety of alterations to brain chemistry. Despite its reduced level of radioactivity evidence continues to accumulate that depleted uranium, if ingested, may pose a radiologic hazard. The current state of knowledge concerning DU is discussed.

  9. Depletable resources and the economy.

    NARCIS (Netherlands)

    Heijman, W.J.M.

    1991-01-01

    The subject of this thesis is the depletion of scarce resources. The main question to be answered is how to avoid future resource crises. After dealing with the complex relation between nature and economics, three important concepts in relation with resource depletion are discussed: steady state, ti

  10. Stratospheric ozone depletion.

    Science.gov (United States)

    Rowland, F Sherwood

    2006-05-29

    Solar ultraviolet radiation creates an ozone layer in the atmosphere which in turn completely absorbs the most energetic fraction of this radiation. This process both warms the air, creating the stratosphere between 15 and 50 km altitude, and protects the biological activities at the Earth's surface from this damaging radiation. In the last half-century, the chemical mechanisms operating within the ozone layer have been shown to include very efficient catalytic chain reactions involving the chemical species HO, HO2, NO, NO2, Cl and ClO. The NOX and ClOX chains involve the emission at Earth's surface of stable molecules in very low concentration (N2O, CCl2F2, CCl3F, etc.) which wander in the atmosphere for as long as a century before absorbing ultraviolet radiation and decomposing to create NO and Cl in the middle of the stratospheric ozone layer. The growing emissions of synthetic chlorofluorocarbon molecules cause a significant diminution in the ozone content of the stratosphere, with the result that more solar ultraviolet-B radiation (290-320 nm wavelength) reaches the surface. This ozone loss occurs in the temperate zone latitudes in all seasons, and especially drastically since the early 1980s in the south polar springtime-the 'Antarctic ozone hole'. The chemical reactions causing this ozone depletion are primarily based on atomic Cl and ClO, the product of its reaction with ozone. The further manufacture of chlorofluorocarbons has been banned by the 1992 revisions of the 1987 Montreal Protocol of the United Nations. Atmospheric measurements have confirmed that the Protocol has been very successful in reducing further emissions of these molecules. Recovery of the stratosphere to the ozone conditions of the 1950s will occur slowly over the rest of the twenty-first century because of the long lifetime of the precursor molecules. PMID:16627294

  11. Testing fully depleted CCD

    Science.gov (United States)

    Casas, Ricard; Cardiel-Sas, Laia; Castander, Francisco J.; Jiménez, Jorge; de Vicente, Juan

    2014-08-01

    The focal plane of the PAU camera is composed of eighteen 2K x 4K CCDs. These devices, plus four spares, were provided by the Japanese company Hamamatsu Photonics K.K. with type no. S10892-04(X). These detectors are 200 μm thick fully depleted and back illuminated with an n-type silicon base. They have been built with a specific coating to be sensitive in the range from 300 to 1,100 nm. Their square pixel size is 15 μm. The read-out system consists of a Monsoon controller (NOAO) and the panVIEW software package. The deafualt CCD read-out speed is 133 kpixel/s. This is the value used in the calibration process. Before installing these devices in the camera focal plane, they were characterized using the facilities of the ICE (CSIC- IEEC) and IFAE in the UAB Campus in Bellaterra (Barcelona, Catalonia, Spain). The basic tests performed for all CCDs were to obtain the photon transfer curve (PTC), the charge transfer efficiency (CTE) using X-rays and the EPER method, linearity, read-out noise, dark current, persistence, cosmetics and quantum efficiency. The X-rays images were also used for the analysis of the charge diffusion for different substrate voltages (VSUB). Regarding the cosmetics, and in addition to white and dark pixels, some patterns were also found. The first one, which appears in all devices, is the presence of half circles in the external edges. The origin of this pattern can be related to the assembly process. A second one appears in the dark images, and shows bright arcs connecting corners along the vertical axis of the CCD. This feature appears in all CCDs exactly in the same position so our guess is that the pattern is due to electrical fields. Finally, and just in two devices, there is a spot with wavelength dependence whose origin could be the result of a defectous coating process.

  12. Aprataxin localizes to mitochondria and preserves mitochondrial function

    DEFF Research Database (Denmark)

    Sykora, Peter; Croteau, Deborah L; Bohr, Vilhelm A;

    2011-01-01

    are expressed in the human brain, with highest production in the cerebellum. Depletion of aprataxin in human SH-SY5Y neuroblastoma cells and primary skeletal muscle myoblasts results in mitochondrial dysfunction, which is revealed by reduced citrate synthase activity and mtDNA copy number. Moreover, mt...

  13. Mitochondrial RNA granules: Compartmentalizing mitochondrial gene expression.

    Science.gov (United States)

    Jourdain, Alexis A; Boehm, Erik; Maundrell, Kinsey; Martinou, Jean-Claude

    2016-03-14

    In mitochondria, DNA replication, gene expression, and RNA degradation machineries coexist within a common nondelimited space, raising the question of how functional compartmentalization of gene expression is achieved. Here, we discuss the recently characterized "mitochondrial RNA granules," mitochondrial subdomains with an emerging role in the regulation of gene expression. PMID:26953349

  14. Depletable resources and the economy.

    OpenAIRE

    Heijman, W. J. M.

    1991-01-01

    The subject of this thesis is the depletion of scarce resources. The main question to be answered is how to avoid future resource crises. After dealing with the complex relation between nature and economics, three important concepts in relation with resource depletion are discussed: steady state, time preference and efficiency.For the steady state, three variants are distinguished; the stationary state, the physical steady state and the state of steady growth. It is concluded that the so-call...

  15. The mitochondrial acyl carrier protein (ACP) coordinates mitochondrial fatty acid synthesis with iron sulfur cluster biogenesis.

    Science.gov (United States)

    Van Vranken, Jonathan G; Jeong, Mi-Young; Wei, Peng; Chen, Yu-Chan; Gygi, Steven P; Winge, Dennis R; Rutter, Jared

    2016-01-01

    Mitochondrial fatty acid synthesis (FASII) and iron sulfur cluster (FeS) biogenesis are both vital biosynthetic processes within mitochondria. In this study, we demonstrate that the mitochondrial acyl carrier protein (ACP), which has a well-known role in FASII, plays an unexpected and evolutionarily conserved role in FeS biogenesis. ACP is a stable and essential subunit of the eukaryotic FeS biogenesis complex. In the absence of ACP, the complex is destabilized resulting in a profound depletion of FeS throughout the cell. This role of ACP depends upon its covalently bound 4'-phosphopantetheine (4-PP)-conjugated acyl chain to support maximal cysteine desulfurase activity. Thus, it is likely that ACP is not simply an obligate subunit but also exploits the 4-PP-conjugated acyl chain to coordinate mitochondrial fatty acid and FeS biogenesis. PMID:27540631

  16. Altered Mitochondrial Dynamics and TBI Pathophysiology.

    Science.gov (United States)

    Fischer, Tara D; Hylin, Michael J; Zhao, Jing; Moore, Anthony N; Waxham, M Neal; Dash, Pramod K

    2016-01-01

    Mitochondrial function is intimately linked to cellular survival, growth, and death. Mitochondria not only generate ATP from oxidative phosphorylation, but also mediate intracellular calcium buffering, generation of reactive oxygen species (ROS), and apoptosis. Electron leakage from the electron transport chain, especially from damaged or depolarized mitochondria, can generate excess free radicals that damage cellular proteins, DNA, and lipids. Furthermore, mitochondrial damage releases pro-apoptotic factors to initiate cell death. Previous studies have reported that traumatic brain injury (TBI) reduces mitochondrial respiration, enhances production of ROS, and triggers apoptotic cell death, suggesting a prominent role of mitochondria in TBI pathophysiology. Mitochondria maintain cellular energy homeostasis and health via balanced processes of fusion and fission, continuously dividing and fusing to form an interconnected network throughout the cell. An imbalance of these processes, particularly an excess of fission, can be detrimental to mitochondrial function, causing decreased respiration, ROS production, and apoptosis. Mitochondrial fission is regulated by the cytosolic GTPase, dynamin-related protein 1 (Drp1), which translocates to the mitochondrial outer membrane (MOM) to initiate fission. Aberrant Drp1 activity has been linked to excessive mitochondrial fission and neurodegeneration. Measurement of Drp1 levels in purified hippocampal mitochondria showed an increase in TBI animals as compared to sham controls. Analysis of cryo-electron micrographs of these mitochondria also showed that TBI caused an initial increase in the length of hippocampal mitochondria at 24 h post-injury, followed by a significant decrease in length at 72 h. Post-TBI administration of Mitochondrial division inhibitor-1 (Mdivi-1), a pharmacological inhibitor of Drp1, prevented this decrease in mitochondria length. Mdivi-1 treatment also reduced the loss of newborn neurons in the

  17. Gastrin-releasing peptide receptor antagonist or N-acetylcysteine combined with omeprazol protect against mitochondrial complex II inhibition in a rat model of gastritis.

    Science.gov (United States)

    Rezin, Gislaine T; Petronilho, Fabricia C; Araújo, João H; Gonçalves, Cinara L; Daufenbach, Juliana F; Cardoso, Mariane R; Roesler, Rafael; Schwartsmann, Gilberto; Dal-Pizzol, Felipe; Streck, Emilio L

    2011-03-01

    The pathophysiology of gastritis involves an imbalance between gastric acid attack and mucosal defence. In addition, the gastric mucosal injury results in adenosine triphosphate (ATP) depletion leading to mitochondrial dysfunction. Several studies have shown the association of mitochondrial disorders with gastrointestinal dysfunction. In the present study, we investigated the activity of mitochondrial respiratory chain complexes activity in the stomach of rats with gastritis induced by indomethacin (IDM) and treated with omeprazole (OM), N-acetylcysteine (NAC) and the gastrin-releasing peptide receptor (GRPR) antagonist RC-3095. Adult male Wistar rats were pre-treated for 7 days with OM, NAC, RC-3095, combination of OM plus RC-3095, OM plus NAC and water (control). The animals were then submitted to fasting for 24 hr; IDM was administered. The rats were killed 6 hr later, and the stomachs were used for evaluation of macroscopic damage and respiratory chain activity. Our results showed that complex I and IV activities were not affected by administration of IDM. On the other hand, complex II and III activities were inhibited. In addition, OM plus RC-3095 and OM plus NAC did not reverse complex II activity inhibition. However, the complex III activity inhibition was reversed only with the combined use of OM plus RC-3095 and OM plus NAC. Our results are in agreement with previous studies indicating mitochondrial dysfunction in the pathophysiology of gastrointestinal tract disease and we suggest that GRPR antagonism might be a novel therapeutic strategy in gastritis. PMID:21138529

  18. Strokes in mitochondrial diseases

    Directory of Open Access Journals (Sweden)

    N V Pizova

    2012-01-01

    Full Text Available It is suggested that mitochondrial diseases might be identified in 22—33% of cryptogenic stroke cases in young subjects. The incidence of mitochondrial disorders in patients with stroke is unknown; it is 0.8 to 7.2% according to the data of some authors. The paper gives data on the prevalence, pathogenesis, and clinical manifestations of mitochondrial diseases, such as mitochondrial encephalopathy, lactic acidosis, and stroke-like syndrome (MELAS and insulin-like episodes; myoclonic epilepsy and ragged-red fibers (MERRF syndrome, and Kearns-Sayre syndrome (sporadic multisystem mitochondrial pathology.

  19. Ca2+ signals regulate mitochondrial metabolism by stimulating CREB-mediated expression of the mitochondrial Ca2+ uniporter gene MCU.

    Science.gov (United States)

    Shanmughapriya, Santhanam; Rajan, Sudarsan; Hoffman, Nicholas E; Zhang, Xueqian; Guo, Shuchi; Kolesar, Jill E; Hines, Kevin J; Ragheb, Jonathan; Jog, Neelakshi R; Caricchio, Roberto; Baba, Yoshihiro; Zhou, Yandong; Kaufman, Brett A; Cheung, Joseph Y; Kurosaki, Tomohiro; Gill, Donald L; Madesh, Muniswamy

    2015-03-03

    Cytosolic Ca2+ signals, generated through the coordinated translocation of Ca2+ across the plasma membrane (PM) and endoplasmic reticulum (ER) membrane, mediate diverse cellular responses. Mitochondrial Ca2+ is important for mitochondrial function, and when cytosolic Ca2+ concentration becomes too high, mitochondria function as cellular Ca2+ sinks. By measuring mitochondrial Ca2+ currents, we found that mitochondrial Ca2+ uptake was reduced in chicken DT40 B lymphocytes lacking either the ER-localized inositol trisphosphate receptor (IP3R), which releases Ca2+ from the ER, or Orai1 or STIM1, components of the PM-localized Ca2+ -permeable channel complex that mediates store-operated calcium entry (SOCE) in response to depletion of ER Ca2+ stores. The abundance of MCU, the pore-forming subunit of the mitochondrial Ca2+ uniporter, was reduced in cells deficient in IP3R, STIM1, or Orai1. Chromatin immunoprecipitation and promoter reporter analyses revealed that the Ca2+ -regulated transcription factor CREB (cyclic adenosine monophosphate response element-binding protein) directly bound the MCU promoter and stimulated expression. Lymphocytes deficient in IP3R, STIM1, or Orai1 exhibited altered mitochondrial metabolism, indicating that Ca2+ released from the ER and SOCE-mediated signals modulates mitochondrial function. Thus, our results showed that a transcriptional regulatory circuit involving Ca2+ -dependent activation of CREB controls the Ca2+ uptake capability of mitochondria and hence regulates mitochondrial metabolism.

  20. Nonlinear lower hybrid wave depletion

    International Nuclear Information System (INIS)

    Two numerical ray tracing codes with focusing are used to compute lower hybrid daughter wave amplification by quasi-mode parametric decay. The first code, LHPUMP provides a numerical pump model on a grid. This model is used by a second code, LHFQM which computes daughter wave amplification inside the pump extent and follows the rays until their energy is absorbed by the plasma. An analytic model is then used to estimate pump depletion based on the numerical results. Results for PLT indicate strong pump depletion at the plasma edge at high density operation for the 800 Mhz wave frequency, but weak depletion for the 2.45 Ghz experiment. This is proposed to be the mechanism responsible for the high density limit for current drive as well as for the difficulty to heat ions

  1. Uncoupling Mitochondrial Respiration for Diabesity.

    Science.gov (United States)

    Larrick, James W; Larrick, Jasmine W; Mendelsohn, Andrew R

    2016-08-01

    Until recently, the mechanism of adaptive thermogenesis was ascribed to the expression of uncoupling protein 1 (UCP1) in brown and beige adipocytes. UCP1 is known to catalyze a proton leak of the inner mitochondrial membrane, resulting in uncoupled oxidative metabolism with no production of adenosine triphosphate and increased energy expenditure. Thus increasing brown and beige adipose tissue with augmented UCP1 expression is a viable target for obesity-related disorders. Recent work demonstrates an UCP1-independent pathway to uncouple mitochondrial respiration. A secreted enzyme, PM20D1, enriched in UCP1+ adipocytes, exhibits catalytic and hydrolytic activity to reversibly form N-acyl amino acids. N-acyl amino acids act as endogenous uncouplers of mitochondrial respiration at physiological concentrations. Administration of PM20D1 or its products, N-acyl amino acids, to diet-induced obese mice improves glucose tolerance by increasing energy expenditure. In short-term studies, treated animals exhibit no toxicity while experiencing 10% weight loss primarily of adipose tissue. Further study of this metabolic pathway may identify novel therapies for diabesity, the disease state associated with diabetes and obesity. PMID:27378359

  2. Altered Mitochondrial Dynamics and TBI Pathophysiology

    Directory of Open Access Journals (Sweden)

    Tara Diane Fischer

    2016-03-01

    Full Text Available Mitochondrial function is intimately linked to cellular survival, growth, and death. Mitochondria not only generate ATP from oxidative phosphorylation, but also mediate intracellular calcium buffering, generation of reactive oxygen species (ROS, and apoptosis. Electron leakage from the electron transport chain, especially from damaged or depolarized mitochondria, can generate excess free radicals that damage cellular proteins, DNA, and lipids. Furthermore, mitochondrial damage releases pro-apoptotic factors to initiate cell death. Previous studies have reported that traumatic brain injury (TBI reduces mitochondrial respiration, enhances production of ROS, and triggers apoptotic cell death, suggesting a prominent role of mitochondria in TBI pathophysiology. Mitochondria maintain cellular energy homeostasis and health via balanced processes of fusion and fission, continuously dividing and fusing to form an interconnected network throughout the cell. An imbalance of these processes, particularly an excess of fission, can be detrimental to mitochondrial function, causing decreased respiration, ROS production, and apoptosis. Mitochondrial fission is regulated by the cytosolic GTPase, dynamin-related protein 1 (Drp1, which translocates to the mitochondrial outer membrane to initiate fission. Aberrant Drp1 activity has been linked to excessive mitochondrial fission and neurodegeneration. Measurement of Drp1 levels in purified hippocampal mitochondria showed an increase in TBI animals as compared to sham controls. Analysis of cryo-electron micrographs of these mitochondria also showed that TBI caused an initial increase in the length of hippocampal mitochondria at 24 hours post-injury, followed by a significant decrease in length at 72 hours. Post-TBI administration of Mdivi-1, a pharmacological inhibitor of Drp1, prevented this decrease in mitochondria length. Mdivi-1 treatment also reduced the loss of newborn neurons in the hippocampus and improved

  3. Scoliosis in Mitochondrial Myopathy

    OpenAIRE

    Li, Zheng; Shen, Jianxiong; Liang, Jinqian

    2015-01-01

    Abstract The mitochondrial myopathies include a diverse group of disorders characterized by morphological abnormalities of muscle mitochondria. Little is reported about spinal deformity associated with this syndrome. This study presents a case of scoliosis occurring in the setting of mitochondrial myopathies and explores the possible mechanisms between the 2 diseases. A previously unreported scoliosis in mitochondrial myopathies is described. The patient was a 16-year-old Chinese adolescent b...

  4. Mitochondrial morphology and cardiovascular disease

    OpenAIRE

    Ong, Sang-Bing; Hausenloy, Derek J

    2010-01-01

    Mitochondria are dynamic and are able to interchange their morphology between elongated interconnected mitochondrial networks and a fragmented disconnected arrangement by the processes of mitochondrial fusion and fission, respectively. Changes in mitochondrial morphology are regulated by the mitochondrial fusion proteins (mitofusins 1 and 2, and optic atrophy 1) and the mitochondrial fission proteins (dynamin-related peptide 1 and mitochondrial fission protein 1) and have been implicated in a...

  5. Primer retention owing to the absence of RNase H1 is catastrophic for mitochondrial DNA replication.

    Science.gov (United States)

    Holmes, J Bradley; Akman, Gokhan; Wood, Stuart R; Sakhuja, Kiran; Cerritelli, Susana M; Moss, Chloe; Bowmaker, Mark R; Jacobs, Howard T; Crouch, Robert J; Holt, Ian J

    2015-07-28

    Encoding ribonuclease H1 (RNase H1) degrades RNA hybridized to DNA, and its function is essential for mitochondrial DNA maintenance in the developing mouse. Here we define the role of RNase H1 in mitochondrial DNA replication. Analysis of replicating mitochondrial DNA in embryonic fibroblasts lacking RNase H1 reveals retention of three primers in the major noncoding region (NCR) and one at the prominent lagging-strand initiation site termed Ori-L. Primer retention does not lead immediately to depletion, as the persistent RNA is fully incorporated in mitochondrial DNA. However, the retained primers present an obstacle to the mitochondrial DNA polymerase γ in subsequent rounds of replication and lead to the catastrophic generation of a double-strand break at the origin when the resulting gapped molecules are copied. Hence, the essential role of RNase H1 in mitochondrial DNA replication is the removal of primers at the origin of replication.

  6. Mitochondria-targeted antioxidant mitotempo protects mitochondrial function against amyloid beta toxicity in primary cultured mouse neurons.

    Science.gov (United States)

    Hu, Hongtao; Li, Mo

    2016-09-01

    Mitochondrial defects including excess reactive oxygen species (ROS) production and compromised ATP generation are featured pathology in Alzheimer's disease (AD). Amyloid beta (Aβ)-mediated mitochondrial ROS overproduction disrupts intra-neuronal Redox balance, in turn exacerbating mitochondrial dysfunction leading to neuronal injury. Previous studies have found the beneficial effects of mitochondria-targeted antioxidants in preventing mitochondrial dysfunction and neuronal injury in AD animal and cell models, suggesting that mitochondrial ROS scavengers hold promise for the treatment of this neurological disorder. In this study, we have determined that mitotempo, a novel mitochondria-targeted antioxidant protects mitochondrial function from the toxicity of Aβ in primary cultured neurons. Our results showed that Aβ-promoted mitochondrial superoxide production and neuronal lipid oxidation were significantly suppressed by the application of mitotempo. Moreover, mitotempo also demonstrated protective effects on mitochondrial bioenergetics evidenced by preserved mitochondrial membrane potential, cytochrome c oxidase activity as well as ATP production. In addition, the Aβ-induced mitochondrial DNA (mtDNA) depletion and decreased expression levels of mtDNA replication-related DNA polymerase gamma (DNA pol γ) and Twinkle were substantially mitigated by mitotempo. Therefore, our study suggests that elimination of excess mitochondrial ROS rescues mitochondrial function in Aβ-insulted neruons; and mitotempo has the potential to be a promising therapeutic agent to protect mitochondrial and neuronal function in AD. PMID:27444386

  7. Mitochondria-targeted antioxidant mitotempo protects mitochondrial function against amyloid beta toxicity in primary cultured mouse neurons.

    Science.gov (United States)

    Hu, Hongtao; Li, Mo

    2016-09-01

    Mitochondrial defects including excess reactive oxygen species (ROS) production and compromised ATP generation are featured pathology in Alzheimer's disease (AD). Amyloid beta (Aβ)-mediated mitochondrial ROS overproduction disrupts intra-neuronal Redox balance, in turn exacerbating mitochondrial dysfunction leading to neuronal injury. Previous studies have found the beneficial effects of mitochondria-targeted antioxidants in preventing mitochondrial dysfunction and neuronal injury in AD animal and cell models, suggesting that mitochondrial ROS scavengers hold promise for the treatment of this neurological disorder. In this study, we have determined that mitotempo, a novel mitochondria-targeted antioxidant protects mitochondrial function from the toxicity of Aβ in primary cultured neurons. Our results showed that Aβ-promoted mitochondrial superoxide production and neuronal lipid oxidation were significantly suppressed by the application of mitotempo. Moreover, mitotempo also demonstrated protective effects on mitochondrial bioenergetics evidenced by preserved mitochondrial membrane potential, cytochrome c oxidase activity as well as ATP production. In addition, the Aβ-induced mitochondrial DNA (mtDNA) depletion and decreased expression levels of mtDNA replication-related DNA polymerase gamma (DNA pol γ) and Twinkle were substantially mitigated by mitotempo. Therefore, our study suggests that elimination of excess mitochondrial ROS rescues mitochondrial function in Aβ-insulted neruons; and mitotempo has the potential to be a promising therapeutic agent to protect mitochondrial and neuronal function in AD.

  8. Depleted uranium induces disruption of energy homeostasis and oxidative stress in isolated rat brain mitochondria.

    Science.gov (United States)

    Shaki, Fatemeh; Hosseini, Mir-Jamal; Ghazi-Khansari, Mahmoud; Pourahmad, Jalal

    2013-06-01

    Depleted uranium (DU) is emerging as an environmental pollutant primarily due to its military applications. Gulf War veterans with embedded DU showed cognitive disorders that suggest that the central nervous system is a target of DU. Recent evidence has suggested that DU could induce oxidative stress and mitochondrial dysfunction in brain tissue. However, the underlying mechanisms of DU toxicity in brain mitochondria are not yet well understood. Brain mitochondria were obtained using differential centrifugation and were incubated with different concentrations (50, 100 and 200 μM) of uranyl acetate (UA) as a soluble salt of U(238) for 1 h. In this research, mitochondrial ROS production, collapse of mitochondrial membrane potential and mitochondrial swelling were examined by flow cytometry following the addition of UA. Meanwhile, mitochondrial sources of ROS formation were determined using specific substrates and inhibitors. Complex II and IV activity and also the extent of lipid peroxidation and glutathione (GSH) oxidation were detected via spectroscopy. Furthermore, we investigated the concentration of ATP and ATP/ADP ratio using luciferase enzyme and cytochrome c release from mitochondria which was detected by ELISA kit. UA caused concentration-dependent elevation of succinate-linked mitochondrial ROS production, lipid peroxidation, GSH oxidation and inhibition of mitochondrial complex II. UA also induced mitochondrial permeability transition, ATP production decrease and increase in cytochrome c release. Pre-treatment with antioxidants significantly inhibited all the above mentioned toxic effects of UA. This study suggests that mitochondrial oxidative stress and impairment of oxidative phosphorylation in brain mitochondria may play a key role in DU neurotoxicity as reported in Gulf War Syndrome. PMID:23629690

  9. Mitochondrial Dynamics in Diabetes

    OpenAIRE

    Yoon, Yisang; Galloway, Chad A.; Jhun, Bong Sook; Yu, Tianzheng

    2011-01-01

    Mitochondria are at the center of cellular energy metabolism and regulate cell life and death. The cell biological aspect of mitochondria, especially mitochondrial dynamics, has drawn much attention through implications in human pathology, including neurological disorders and metabolic diseases. Mitochondrial fission and fusion are the main processes governing the morphological plasticity and are controlled by multiple factors, including mechanochemical enzymes and accessory proteins. Emergin...

  10. Ozone Depletion from Nearby Supernovae

    CERN Document Server

    Gehrels, N; Jackman, C H; Cannizzo, J K; Mattson, B J; Chen, W; Gehrels, Neil; Laird, Claude M.; Jackman, Charles H.; Cannizzo, John K.; Mattson, Barbara J.; Chen, Wan

    2003-01-01

    Estimates made in the 1970's indicated that a supernova occurring within tens of parsecs of Earth could have significant effects on the ozone layer. Since that time, improved tools for detailed modeling of atmospheric chemistry have been developed to calculate ozone depletion, and advances have been made in theoretical modeling of supernovae and of the resultant gamma-ray spectra. In addition, one now has better knowledge of the occurrence rate of supernovae in the galaxy, and of the spatial distribution of progenitors to core-collapse supernovae. We report here the results of two-dimensional atmospheric model calculations that take as input the spectral energy distribution of a supernova, adopting various distances from Earth and various latitude impact angles. In separate simulations we calculate the ozone depletion due to both gamma-rays and cosmic rays. We find that for the combined ozone depletion roughly to double the ``biologically active'' UV flux received at the surface of the Earth, the supernova mu...

  11. Ozone Depletion from Nearby Supernovae

    Science.gov (United States)

    Gehrels, Neil; Laird, Claude M.; Jackman, Charles H.; Cannizzo, John K.; Mattson, Barbara J.; Chen, Wan; Bhartia, P. K. (Technical Monitor)

    2002-01-01

    Estimates made in the 1970's indicated that a supernova occurring within tens of parsecs of Earth could have significant effects on the ozone layer. Since that time improved tools for detailed modeling of atmospheric chemistry have been developed to calculate ozone depletion, and advances have been made also in theoretical modeling of supernovae and of the resultant gamma ray spectra. In addition, one now has better knowledge of the occurrence rate of supernovae in the galaxy, and of the spatial distribution of progenitors to core-collapse supernovae. We report here the results of two-dimensional atmospheric model calculations that take as input the spectral energy distribution of a supernova, adopting various distances from Earth and various latitude impact angles. In separate simulations we calculate the ozone depletion due to both gamma rays and cosmic rays. We find that for the combined ozone depletion from these effects roughly to double the 'biologically active' UV flux received at the surface of the Earth, the supernova must occur at approximately or less than 8 parsecs.

  12. HD depletion in starless cores

    CERN Document Server

    Sipilä, O; Harju, J

    2013-01-01

    Aims: We aim to investigate the abundances of light deuterium-bearing species such as HD, H2D+ and D2H+ in a gas-grain chemical model including an extensive description of deuterium and spin state chemistry, in physical conditions appropriate to the very centers of starless cores. Methods: We combine a gas-grain chemical model with radiative transfer calculations to simulate density and temperature structure in starless cores. The chemical model includes deuterated forms of species with up to 4 atoms and the spin states of the light species H2, H2+ and H3+ and their deuterated forms. Results: We find that HD eventually depletes from the gas phase because deuterium is efficiently incorporated to grain-surface HDO, resulting in inefficient HD production on grains. HD depletion has consequences not only on the abundances of e.g. H2D+ and D2H+, whose production depends on the abundance of HD, but also on the spin state abundance ratios of the various light species, when compared with the complete depletion model ...

  13. Mitochondrial Cyclophilin D in Vascular Oxidative Stress and Hypertension.

    Science.gov (United States)

    Itani, Hana A; Dikalova, Anna E; McMaster, William G; Nazarewicz, Rafal R; Bikineyeva, Alfiya T; Harrison, David G; Dikalov, Sergey I

    2016-06-01

    Vascular superoxide (O˙2 (-)) and inflammation contribute to hypertension. The mitochondria are an important source of O˙2 (-); however, the regulation of mitochondrial O˙2 (-) and the antihypertensive potential of targeting the mitochondria remain poorly defined. Angiotensin II and inflammatory cytokines, such as interleukin 17A and tumor necrosis factor-α (TNFα) significantly contribute to hypertension. We hypothesized that angiotensin II and cytokines co-operatively induce cyclophilin D (CypD)-dependent mitochondrial O˙2 (-) production in hypertension. We tested whether CypD inhibition attenuates endothelial oxidative stress and reduces hypertension. CypD depletion in CypD(-/-) mice prevents overproduction of mitochondrial O˙2 (-) in angiotensin II-infused mice, attenuates hypertension by 20 mm Hg, and improves vascular relaxation compared with wild-type C57Bl/6J mice. Treatment of hypertensive mice with the specific CypD inhibitor Sanglifehrin A reduces blood pressure by 28 mm Hg, inhibits production of mitochondrial O˙2 (-) by 40%, and improves vascular relaxation. Angiotensin II-induced hypertension was associated with CypD redox activation by S-glutathionylation, and expression of the mitochondria-targeted H2O2 scavenger, catalase, abolished CypD S-glutathionylation, prevented stimulation mitochondrial O˙2 (-), and attenuated hypertension. The functional role of cytokine-angiotensin II interplay was confirmed by co-operative stimulation of mitochondrial O˙2 (-) by 3-fold in cultured endothelial cells and impairment of aortic relaxation incubated with combination of angiotensin II, interleukin 17A, and tumor necrosis factor-α which was prevented by CypD depletion or expression of mitochondria-targeted SOD2 and catalase. These data support a novel role of CypD in hypertension and demonstrate that targeting CypD decreases mitochondrial O˙2 (-), improves vascular relaxation, and reduces hypertension. PMID:27067720

  14. Novel TK2 mutations as a cause of delayed muscle maturation in mtDNA depletion syndrome.

    Science.gov (United States)

    Termglinchan, Thanes; Hisamatsu, Seito; Ohmori, Junko; Suzumura, Hiroshi; Sumitomo, Noriko; Imataka, George; Arisaka, Osamu; Murakami, Nobuyuki; Minami, Narihiro; Akihiko, Ishiyama; Sasaki, Masayuki; Goto, Yuichi; Noguchi, Satoru; Nonaka, Ikuya; Mitsuhashi, Satomi; Nishino, Ichizo

    2016-10-01

    Recessive mutations in TK2 cause a severe mitochondrial DNA depletion syndrome (MDS),(1) characterized by severe myopathy from early infancy. Recent reports have suggested a wider clinical spectrum including encephalomyopathic form.(1,2) We report a patient with infantile-onset fatal encephalomyopathy presenting with extreme muscle fiber immaturity.

  15. Dual Effect of Phosphate Transport on Mitochondrial Ca2+ Dynamics.

    Science.gov (United States)

    Wei, An-Chi; Liu, Ting; O'Rourke, Brian

    2015-06-26

    The large inner membrane electrochemical driving force and restricted volume of the matrix confer unique constraints on mitochondrial ion transport. Cation uptake along with anion and water movement induces swelling if not compensated by other processes. For mitochondrial Ca(2+) uptake, these include activation of countertransporters (Na(+)/Ca(2+) exchanger and Na(+)/H(+) exchanger) coupled to the proton gradient, ultimately maintained by the proton pumps of the respiratory chain, and Ca(2+) binding to matrix buffers. Inorganic phosphate (Pi) is known to affect both the Ca(2+) uptake rate and the buffering reaction, but the role of anion transport in determining mitochondrial Ca(2+) dynamics is poorly understood. Here we simultaneously monitor extra- and intra-mitochondrial Ca(2+) and mitochondrial membrane potential (ΔΨm) to examine the effects of anion transport on mitochondrial Ca(2+) flux and buffering in Pi-depleted guinea pig cardiac mitochondria. Mitochondrial Ca(2+) uptake proceeded slowly in the absence of Pi but matrix free Ca(2+) ([Ca(2+)]mito) still rose to ~50 μm. Pi (0.001-1 mm) accelerated Ca(2+) uptake but decreased [Ca(2+)]mito by almost 50% while restoring ΔΨm. Pi-dependent effects on Ca(2+) were blocked by inhibiting the phosphate carrier. Mitochondrial Ca(2+) uptake rate was also increased by vanadate (Vi), acetate, ATP, or a non-hydrolyzable ATP analog (AMP-PNP), with differential effects on matrix Ca(2+) buffering and ΔΨm recovery. Interestingly, ATP or AMP-PNP prevented the effects of Pi on Ca(2+) uptake. The results show that anion transport imposes an upper limit on mitochondrial Ca(2+) uptake and modifies the [Ca(2+)]mito response in a complex manner. PMID:25963147

  16. Resveratrol attenuates methylglyoxal-induced mitochondrial dysfunction and apoptosis by Sestrin2 induction

    Energy Technology Data Exchange (ETDEWEB)

    Seo, Kyuhwa; Seo, Suho; Han, Jae Yun; Ki, Sung Hwan; Shin, Sang Mi, E-mail: smshin@chosun.ac.kr

    2014-10-15

    Methylglyoxal is found in high levels in the blood and other tissues of diabetic patients and exerts deleterious effects on cells and tissues. Previously, we reported that resveratrol, a polyphenol in grapes, induced the expression of Sestrin2 (SESN2), a novel antioxidant protein, and inhibited hepatic lipogenesis. This study investigated whether resveratrol protects cells from the methylglyoxal-induced toxicity via SESN2 induction. Methylglyoxal significantly induced cell death in HepG2 cells. However, cells pretreated with resveratrol were rescued from methylglyoxal-induced apoptosis. Resveratrol attenuated glutathione (GSH) depletion and ROS production promoted by methylglyoxal. Moreover, mitochondrial damage was observed by methylglyoxal treatment, but resveratrol restored mitochondrial function, as evidenced by the observed lack of mitochondrial permeability transition and increased ADP/ATP ratio. Resveratrol treatment inhibited SESN2 depletion elicited by methylglyoxal. SESN2 overexpression repressed methylglyoxal-induced mitochondrial dysfunction and apoptosis. Likewise, rotenone-induced cytotoxicity was not observed in SESN2 overexpressed cells. Furthermore, siRNA knockdown of SESN2 reduced the ability of resveratrol to prevent methylglyoxal-induced mitochondrial permeability transition. In addition, when mice were exposed to methylglyoxal after infection of Ad-SESN2, the plasma levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) and GSH depletion by methylglyoxal in liver was reduced in Ad-SESN2 infected mice. Our results demonstrated that resveratrol is capable of protecting cells from methylglyoxal-induced mitochondrial dysfunction and oxidative stress via SESN2 induction. - Highlights: • Resveratrol decreased methylglyoxal-induced apoptosis. • Resveratrol attenuated GSH depletion and ROS production promoted by methylglyoxal. • Resveratrol restored the mitochondrial function by Sestrin2 induction. • Induction of Sestrin2

  17. Hydrogen peroxide efflux from muscle mitochondria underestimates matrix superoxide production: a correction using glutathione depletion

    OpenAIRE

    Treberg, Jason R.; Quinlan, Casey L.; Brand, Martin D.

    2010-01-01

    The production of H2O2 by isolated mitochondria is frequently used as a measure of mitochondrial superoxide formation. Matrix superoxide dismutase quantitatively converts matrix superoxide to H2O2. However, matrix enzymes such as the glutathione peroxidases can consume H2O2 and compete with efflux of H2O2, causing an underestimate of superoxide production. To assess this underestimate we depleted matrix glutathione in rat skeletal muscle mitochondria by more than 90% by pretreatment with 1-ch...

  18. Macrophage Depletion in Hypertensive Rats Accelerates Development of Cardiomyopathy

    OpenAIRE

    Zandbergen, H.R.; Sharma, U.C.; S. Gupta; Verjans, J.W.H.; Borne, van den, J.J.G.C.; S Pokharel; Brakel, T.; Duijvestijn, A; Rooijen, van, J.; Maessen, J.G.; Reutelingsperger, C.P.M.; Pinto, Y.; Narula, J.; Hofstra, L

    2009-01-01

    Inflammation contributes to the process of ventricular remodeling after acute myocardial injury. To investigate the role of macrophages in the chronic process of cardiac remodeling, they were selectively depleted by intravenous administration of liposomal clodronate in heart failure-prone hypertensive Ren-2 rats from the age of 7 until 13 weeks. plain liposomes were used for comparison. Liposomal clodronate treatment reduced the number of blood monocytes and decreased the number of macrophage...

  19. A crucial role of the mitochondrial protein import receptor MOM19 for the biogenesis of mitochondria

    OpenAIRE

    Harkness, Troy A. A.; Nargang, Frank E.; van der Klei, Ida; Neupert, Walter; Lill, Roland

    1994-01-01

    The novel genetic method of "sheltered RIP" (repeat induced point mutation) was used to generate a Neurospora crassa mutant in which MOM19, a component of the protein import machinery of the mitochondrial outer membrane, can be depleted. Deficiency in MOM19 resulted in a severe growth defect, but the cells remained viable. The number of mitochondrial profiles was not grossly changed, but mutant mitochondria were highly deficient in cristae membranes, cytochromes, and protein synthesis activit...

  20. Mitochondrial Transfer via Tunneling Nanotubes is an Important Mechanism by Which Mesenchymal Stem Cells Enhance Macrophage Phagocytosis in the In Vitro and In Vivo Models of ARDS

    Science.gov (United States)

    Jackson, Megan V.; Morrison, Thomas J.; Doherty, Declan F.; McAuley, Daniel F.; Matthay, Michael A.; Kissenpfennig, Adrien; O'Kane, Cecilia M.

    2016-01-01

    Abstract Mesenchymal stromal cells (MSC) have been reported to improve bacterial clearance in preclinical models of Acute Respiratory Distress Syndrome (ARDS) and sepsis. The mechanism of this effect is not fully elucidated yet. The primary objective of this study was to investigate the hypothesis that the antimicrobial effect of MSC in vivo depends on their modulation of macrophage phagocytic activity which occurs through mitochondrial transfer. We established that selective depletion of alveolar macrophages (AM) with intranasal (IN) administration of liposomal clodronate resulted in complete abrogation of MSC antimicrobial effect in the in vivo model of Escherichia coli pneumonia. Furthermore, we showed that MSC administration was associated with enhanced AM phagocytosis in vivo. We showed that direct coculture of MSC with monocyte‐derived macrophages enhanced their phagocytic capacity. By fluorescent imaging and flow cytometry we demonstrated extensive mitochondrial transfer from MSC to macrophages which occurred at least partially through tunneling nanotubes (TNT)‐like structures. We also detected that lung macrophages readily acquire MSC mitochondria in vivo, and macrophages which are positive for MSC mitochondria display more pronounced phagocytic activity. Finally, partial inhibition of mitochondrial transfer through blockage of TNT formation by MSC resulted in failure to improve macrophage bioenergetics and complete abrogation of the MSC effect on macrophage phagocytosis in vitro and the antimicrobial effect of MSC in vivo. Collectively, this work for the first time demonstrates that mitochondrial transfer from MSC to innate immune cells leads to enhancement in phagocytic activity and reveals an important novel mechanism for the antimicrobial effect of MSC in ARDS. Stem Cells 2016;34:2210–2223 PMID:27059413

  1. Mitochondrial Transfer via Tunneling Nanotubes is an Important Mechanism by Which Mesenchymal Stem Cells Enhance Macrophage Phagocytosis in the In Vitro and In Vivo Models of ARDS.

    Science.gov (United States)

    Jackson, Megan V; Morrison, Thomas J; Doherty, Declan F; McAuley, Daniel F; Matthay, Michael A; Kissenpfennig, Adrien; O'Kane, Cecilia M; Krasnodembskaya, Anna D

    2016-08-01

    Mesenchymal stromal cells (MSC) have been reported to improve bacterial clearance in preclinical models of Acute Respiratory Distress Syndrome (ARDS) and sepsis. The mechanism of this effect is not fully elucidated yet. The primary objective of this study was to investigate the hypothesis that the antimicrobial effect of MSC in vivo depends on their modulation of macrophage phagocytic activity which occurs through mitochondrial transfer. We established that selective depletion of alveolar macrophages (AM) with intranasal (IN) administration of liposomal clodronate resulted in complete abrogation of MSC antimicrobial effect in the in vivo model of Escherichia coli pneumonia. Furthermore, we showed that MSC administration was associated with enhanced AM phagocytosis in vivo. We showed that direct coculture of MSC with monocyte-derived macrophages enhanced their phagocytic capacity. By fluorescent imaging and flow cytometry we demonstrated extensive mitochondrial transfer from MSC to macrophages which occurred at least partially through tunneling nanotubes (TNT)-like structures. We also detected that lung macrophages readily acquire MSC mitochondria in vivo, and macrophages which are positive for MSC mitochondria display more pronounced phagocytic activity. Finally, partial inhibition of mitochondrial transfer through blockage of TNT formation by MSC resulted in failure to improve macrophage bioenergetics and complete abrogation of the MSC effect on macrophage phagocytosis in vitro and the antimicrobial effect of MSC in vivo. Collectively, this work for the first time demonstrates that mitochondrial transfer from MSC to innate immune cells leads to enhancement in phagocytic activity and reveals an important novel mechanism for the antimicrobial effect of MSC in ARDS. Stem Cells 2016;34:2210-2223.

  2. The anti-cancer agent guttiferone-A permeabilizes mitochondrial membrane: Ensuing energetic and oxidative stress implications

    International Nuclear Information System (INIS)

    Guttiferone-A (GA) is a natural occurring polyisoprenylated benzophenone with cytotoxic action in vitro and anti-tumor action in rodent models. We addressed a potential involvement of mitochondria in GA toxicity (1-25 μM) toward cancer cells by employing both hepatic carcinoma (HepG2) cells and succinate-energized mitochondria, isolated from rat liver. In HepG2 cells GA decreased viability, dissipated mitochondrial membrane potential, depleted ATP and increased reactive oxygen species (ROS) levels. In isolated rat-liver mitochondria GA promoted membrane fluidity increase, cyclosporine A/EGTA-insensitive membrane permeabilization, uncoupling (membrane potential dissipation/state 4 respiration rate increase), Ca2+ efflux, ATP depletion, NAD(P)H depletion/oxidation and ROS levels increase. All effects in cells, except mitochondrial membrane potential dissipation, as well as NADPH depletion/oxidation and permeabilization in isolated mitochondria, were partly prevented by the a NAD(P)H regenerating substrate isocitrate. The results suggest the following sequence of events: 1) GA interaction with mitochondrial membrane promoting its permeabilization; 2) mitochondrial membrane potential dissipation; 3) NAD(P)H oxidation/depletion due to inability of membrane potential-sensitive NADP+ transhydrogenase of sustaining its reduced state; 4) ROS accumulation inside mitochondria and cells; 5) additional mitochondrial membrane permeabilization due to ROS; and 6) ATP depletion. These GA actions are potentially implicated in the well-documented anti-cancer property of GA/structure related compounds. - Graphical abstract: Guttiferone-A permeabilizes mitochondrial membrane and induces cancer cell death Display Omitted Highlights: → We addressed the involvement of mitochondria in guttiferone (GA) toxicity toward cancer cells. → GA promoted membrane permeabilization, membrane potential dissipation, NAD(P)H depletion, ROS accumulation and ATP depletion. → These actions could be

  3. MITOMAP: a human mitochondrial genome database—2004 update

    OpenAIRE

    Brandon, Marty C.; Lott, Marie T.; Nguyen, Kevin Cuong; Spolim, Syawal; Navathe, Shamkant B.; Baldi, Pierre; Wallace, Douglas C.

    2004-01-01

    MITOMAP (http://www.MITOMAP.org), a database for the human mitochondrial genome, has grown rapidly in data content over the past several years as interest in the role of mitochondrial DNA (mtDNA) variation in human origins, forensics, degenerative diseases, cancer and aging has increased dramatically. To accommodate this information explosion, MITOMAP has implemented a new relational database and an improved search engine, and all programs have been rewritten. System administrative changes ha...

  4. Effects of reduced mitochondrial DNA content on secondary mitochondrial toxicant exposure in Caenorhabditis elegans.

    Science.gov (United States)

    Luz, Anthony L; Meyer, Joel N

    2016-09-01

    The mitochondrial genome (mtDNA) is intimately linked to cellular and organismal health, as demonstrated by the fact that mutations in and depletion of mtDNA result in severe mitochondrial disease in humans. However, cells contain hundreds to thousands of copies of mtDNA, which provides genetic redundancy, and creates a threshold effect in which a large percentage of mtDNA must be lost prior to clinical pathogenesis. As certain pharmaceuticals and genetic mutations can result in depletion of mtDNA, and as many environmental toxicants target mitochondria, it is important to understand whether reduced mtDNA will sensitize an individual to toxicant exposure. Here, using ethidium bromide (EtBr), which preferentially inhibits mtDNA replication, we reduced mtDNA 35-55% in the in vivo model organism Caenorhabditis elegans. Chronic, lifelong, low-dose EtBr exposure did not disrupt nematode development or lifespan, and induced only mild alterations in mitochondrial respiration, while having no effect on steady-state ATP levels. Next, we exposed nematodes with reduced mtDNA to the known and suspected mitochondrial toxicants aflatoxin B1, arsenite, paraquat, rotenone or ultraviolet C radiation (UVC). EtBr pre-exposure resulted in mild sensitization of nematodes to UVC and arsenite, had no effect on AfB1 and paraquat, and provided some protection from rotenone toxicity. These mixed results provide a first line of evidence suggesting that reduced mtDNA content may sensitize an individual to certain environmental exposures.

  5. Effects of reduced mitochondrial DNA content on secondary mitochondrial toxicant exposure in Caenorhabditis elegans.

    Science.gov (United States)

    Luz, Anthony L; Meyer, Joel N

    2016-09-01

    The mitochondrial genome (mtDNA) is intimately linked to cellular and organismal health, as demonstrated by the fact that mutations in and depletion of mtDNA result in severe mitochondrial disease in humans. However, cells contain hundreds to thousands of copies of mtDNA, which provides genetic redundancy, and creates a threshold effect in which a large percentage of mtDNA must be lost prior to clinical pathogenesis. As certain pharmaceuticals and genetic mutations can result in depletion of mtDNA, and as many environmental toxicants target mitochondria, it is important to understand whether reduced mtDNA will sensitize an individual to toxicant exposure. Here, using ethidium bromide (EtBr), which preferentially inhibits mtDNA replication, we reduced mtDNA 35-55% in the in vivo model organism Caenorhabditis elegans. Chronic, lifelong, low-dose EtBr exposure did not disrupt nematode development or lifespan, and induced only mild alterations in mitochondrial respiration, while having no effect on steady-state ATP levels. Next, we exposed nematodes with reduced mtDNA to the known and suspected mitochondrial toxicants aflatoxin B1, arsenite, paraquat, rotenone or ultraviolet C radiation (UVC). EtBr pre-exposure resulted in mild sensitization of nematodes to UVC and arsenite, had no effect on AfB1 and paraquat, and provided some protection from rotenone toxicity. These mixed results provide a first line of evidence suggesting that reduced mtDNA content may sensitize an individual to certain environmental exposures. PMID:27566481

  6. United Mitochondrial Disease Foundation

    Science.gov (United States)

    ... to Mitochondrial Disease FAQ's MitoFirst Handbook More Information Mito 101 Symposium Archives Get Connected Find an Event Adult Advisory Council Team Ask The Mito Doc Grand Rounds Kids & Teens Medical Child Abuse ...

  7. "When the going gets tough, who keeps going?" : Depletion sensitivity moderates the ego-depletion effect

    NARCIS (Netherlands)

    Salmon, Stefanie J.; Adriaanse, Marieke A.; De Vet, Emely; Fennis, Bob M.; De Ridder, Denise T. D.

    2014-01-01

    Self-control relies on a limited resource that can get depleted, a phenomenon that has been labeled ego-depletion. We argue that individuals may differ in their sensitivity to depleting tasks, and that consequently some people deplete their self-control resource at a faster rate than others. In thre

  8. Methionine depletion modulates the antitumor and antimetastatic efficacy of ethionine.

    Science.gov (United States)

    Guo, H; Tan, Y; Kubota, T; Moossa, A R; Hoffman, R M

    1996-01-01

    The elevated methionine requirement for the growth of tumors, termed methionine dependence, is a potentially highly effective therapeutic target. To attack this target we are developing anti-methionine chemotherapy. In this study of anti-methionine chemotherapy we have observed that the methionine analog ethionine is synergistic with methionine depletion in arresting the growth of the Yoshida sarcoma both in vitro and when transplanted to nude mice. In contrast, ethionine in vitro in a methionine-containing medium is not effective against Yoshida sarcoma cells. Similarly, ethionine administered along with a methionine-containing diet is ineffective against the Yoshida sarcoma growing in nude mice. A methionine-depleted diet alone is only partially effective against tumor growth. The Yoshida sarcoma gave rise to metastases in 75% of the- organs observed in the mice on the methionine-containing diet, and 43 % of the organs in the mice on the methionine-free diet. In striking contrast, no metastases were observed in the ethionine-treated animals on the methionine-free diet. Anti-methionine chemotherapy consisting of dietary methionine depletion and ethionine administration caused an initial weight loss but the animals weight stabilized resulting in no animal deaths. The synergism of ethionine and methionine depletion is markedly similar in vitro and in vivo suggesting the observed efficacy is due to the specific anti-methionine targeting. Thus methionine depletion highly potentiates the anti-tumor and anti-metastatic effectiveness of ethionine suggesting that anti-methionine chemotherapy consisting of methionine depletion as a modulator of methionine analogs holds great promise as a new, tumor-selective therapeutic approach.

  9. The plant mitochondrial proteome

    DEFF Research Database (Denmark)

    Millar, A.H.; Heazlewood, J.L.; Kristensen, B.K.;

    2005-01-01

    The plant mitochondrial proteome might contain as many as 2000-3000 different gene products, each of which might undergo post-translational modification. Recent studies using analytical methods, such as one-, two- and three-dimensional gel electrophoresis and one- and two-dimensional liquid...... context to be defined for them. There are indications that some of these proteins add novel activities to mitochondrial protein complexes in plants....

  10. Mitochondrial metabolism and diabetes

    OpenAIRE

    Kwak, Soo Heon; Park, Kyong Soo; Lee, Ki‐Up; Lee, Hong Kyu

    2010-01-01

    Abstract The oversupply of calories and sedentary lifestyle has resulted in a rapid increase of diabetes prevalence worldwide. During the past two decades, lines of evidence suggest that mitochondrial dysfunction plays a key role in the pathophysiology of diabetes. Mitochondria are vital to most of the eukaryotic cells as they provide energy in the form of adenosine triphosphate by oxidative phosphorylation. In addition, mitochondrial function is an integral part of glucose‐stimulated insulin...

  11. Mitochondrial dynamics and apoptosis

    OpenAIRE

    Suen, Der-Fen; Norris, Kristi L.; Youle, Richard J.

    2008-01-01

    In healthy cells, mitochondria continually divide and fuse to form a dynamic interconnecting network. The molecular machinery that mediates this organelle fission and fusion is necessary to maintain mitochondrial integrity, perhaps by facilitating DNA or protein quality control. This network disintegrates during apoptosis at the time of cytochrome c release and prior to caspase activation, yielding more numerous and smaller mitochondria. Recent work shows that proteins involved in mitochondri...

  12. The 1988 Antarctic ozone depletion - Comparison with previous year depletions

    Science.gov (United States)

    Schoeberl, Mark R.; Stolarski, Richard S.; Krueger, Arlin J.

    1989-01-01

    The 1988 spring Antarctic ozone depletion was observed by TOMS to be substantially smaller than in recent years. The minimum polar total ozone values declined only 15 percent during September 1988, compared to nearly 50 percent during September 1987. At southern midlatitudes, exceptionally high total ozone values were recorded beginning in July 1988. The total integrated southern hemispheric ozone increased rapidly during the Austral spring, approaching 1980 levels during October. The high midlatitude total ozone values were associated with a substantial increase in eddy activity as indicated by the standard deviation in total ozone in the zonal band 30-60 deg S. Mechanisms through which the increased midlatitude eddy activity could disrupt the formation of the Antarctic ozone hole are briefly discussed.

  13. Mitochondrial myopathy in rats fed with a diet containing beta-guanidine propionic acid, an inhibitor of creatine entry in muscle cells.

    OpenAIRE

    Gori, Z.; De Tata, V.; Pollera, M.; Bergamini, E

    1988-01-01

    In rats with phosphoryl-creatine depletion (fed a standard Randoin-Causeret diet containing 1% beta-guanidine propionic acid) abnormal mitochondria were observed in slow skeletal muscles, often containing paracrystalline inclusions very like those induced by ischaemia or mitochondrial poisons and in human mitochondrial myopathy.

  14. Depleted uranium disposal options evaluation

    International Nuclear Information System (INIS)

    The Department of Energy (DOE), Office of Environmental Restoration and Waste Management, has chartered a study to evaluate alternative management strategies for depleted uranium (DU) currently stored throughout the DOE complex. Historically, DU has been maintained as a strategic resource because of uses for DU metal and potential uses for further enrichment or for uranium oxide as breeder reactor blanket fuel. This study has focused on evaluating the disposal options for DU if it were considered a waste. This report is in no way declaring these DU reserves a ''waste,'' but is intended to provide baseline data for comparison with other management options for use of DU. To PICS considered in this report include: Retrievable disposal; permanent disposal; health hazards; radiation toxicity and chemical toxicity

  15. Depleted Argon from Underground Sources

    International Nuclear Information System (INIS)

    Argon is a strong scintillator and an ideal target for Dark Matter detection; however 39Ar contamination in atmospheric argon from cosmic ray interactions limits the size of liquid argon dark matter detectors due to pile-up. Argon from deep underground is depleted in 39Ar due to the cosmic ray shielding of the earth. In Cortez, Colorado, a CO2 well has been discovered to contain approximately 600 ppm of argon as a contamination in the CO2. We first concentrate the argon locally to 3% in an Ar, N2, and He mixture, from the CO2 through chromatographic gas separation, and then the N2 and He will be removed by continuous distillation to purify the argon. We have collected 26 kg of argon from the CO2 facility and a cryogenic distillation column is under construction at Fermilab to further purify the argon.

  16. The role of myeloid differentiation factor 88 on mitochondrial dysfunction of peritoneal leukocytes during polymicrobial sepsis

    Science.gov (United States)

    Zou, Lin; Chen, Dunjin; Chao, Wei

    2016-01-01

    Objective To investigate the role of myeloid differentiation factor 88 (MyD88) on mitochondrial dysfunction of peritoneal leukocytes during polymicrobial sepsis. Material and methods Polymicrobial peritonitis, a clinically relevant mouse model of sepsis, was generated by cecum ligation and puncture (CLP) in both male C57BL/6J wild-type (WT) and MyD88 knockout (MyD88–/–) mice. Twenty-four hours after surgeries, peritoneal leukocytes were collected and four parameters of mitochondrial function, including total intracellular and mitochondrial ROS burst, mitochondrial membrane depolarization and ATP depletion, were measured by flow cytometry or ATP assay, and then compared. Results Polymicrobial sepsis led to a marked mitochondrial dysfunction of peritoneal leukocytes with total intracellular and mitochondrial ROS overproduction, decreased mitochondrial membrane potential and reduced intracellular ATP production. In comparison, there was no significant difference in the extent of mitochondrial dysfunction of peritoneal leukocytes between WT and MyD88–/– septic mice. Conclusions MyD88 may be not sufficient to regulate mitochondrial dysfunction of peritoneal leukocytes during polymicrobial sepsis. PMID:27536200

  17. Depleted uranium. Nuclear related problems

    International Nuclear Information System (INIS)

    Depleted uranium (DU) has found a military application in Golf War, in Bosnia and in Yugoslavia (Kosovo). In military sense it was very efficient. But the fact that some parts of that ammunition are manufactured from depleted uranium, low level radioactive waste, implies other aspects of this application like radiological, ecological, jurist, ethical and psychological. The subject of this paper is just physical aspect. There are several problems concerning this aspect: production of DU, total amount of DU in the world, 235U/238U relation, radioactivity of DU, measurements, and presence of other radionuclides like plutonium. DU is by product of nuclear technology and represents low-level nuclear waste. Therefore it should be stored. Total amount of DU in the world is about one million tons with an annual increase of 30 000 t. The content of 235U in DU can vary in the range 0.16-0.3%. The total radioactivity of DU is a consequence of 7 radionuclides and amounts 39.42 Bq/mg. This include alpha, beta and gamma radioactivity. Because of characteristics of this radioactivity it is difficult to prospect the terrain except at the site of action. During the impact of DU rods four types of DU particles could be produced: whole penetrators, penetrator parts, big aerosols (>10 μm) and small aerosols (<10 μm). Most of these particles fall locally, although some of them could be find several tens of kilometers away. All these problems have been discussed in this paper. (author)

  18. The Spectrum of Mitochondrial Ultrastructural Defects in Mitochondrial Myopathy.

    Science.gov (United States)

    Vincent, Amy E; Ng, Yi Shiau; White, Kathryn; Davey, Tracey; Mannella, Carmen; Falkous, Gavin; Feeney, Catherine; Schaefer, Andrew M; McFarland, Robert; Gorman, Grainne S; Taylor, Robert W; Turnbull, Doug M; Picard, Martin

    2016-01-01

    Mitochondrial functions are intrinsically linked to their morphology and membrane ultrastructure. Characterizing abnormal mitochondrial structural features may thus provide insight into the underlying pathogenesis of inherited and acquired mitochondrial diseases. Following a systematic literature review on ultrastructural defects in mitochondrial myopathy, we investigated skeletal muscle biopsies from seven subjects with genetically defined mtDNA mutations. Mitochondrial ultrastructure and morphology were characterized using two complimentary approaches: transmission electron microscopy (TEM) and serial block face scanning EM (SBF-SEM) with 3D reconstruction. Six ultrastructural abnormalities were identified including i) paracrystalline inclusions, ii) linearization of cristae and abnormal angular features, iii) concentric layering of cristae membranes, iv) matrix compartmentalization, v) nanotunelling, and vi) donut-shaped mitochondria. In light of recent molecular advances in mitochondrial biology, these findings reveal novel aspects of mitochondrial ultrastructure and morphology in human tissues with implications for understanding the mechanisms linking mitochondrial dysfunction to disease. PMID:27506553

  19. Neurological mitochondrial cytopathies.

    Directory of Open Access Journals (Sweden)

    Mehndiratta M

    2002-04-01

    Full Text Available The mitochondrial cytopathies are genetically and phenotypically heterogeneous group of disorders caused by structural and functional abnormalities in mitochondria. To the best of our knowledge, there are very few studies published from India till date. Selected and confirmed fourteen cases of neurological mitochondrial cytopathies with different clinical syndromes admitted between 1997 and 2000 are being reported. There were 8 male and 6 female patients. The mean age was 24.42+/-11.18 years (range 4-40 years. Twelve patients could be categorized into well-defined syndromes, while two belonged to undefined group. In the defined syndrome categories, three patients had MELAS (mitochondrial encephalopathy, lactic acidosis and stroke like episodes, three had MERRF (myoclonic epilepsy and ragged red fibre myopathy, three cases had KSS (Kearns-Sayre Syndrome and three were diagnosed to be suffering from mitochondrial myopathy. In the uncategorized group, one case presented with paroxysmal kinesogenic dystonia and the other manifested with generalized chorea alone. Serum lactic acid level was significantly increased in all the patients (fasting 28.96+/-4.59 mg%, post exercise 41.02+/-4.93 mg%. Muscle biopsy was done in all cases. Succinic dehydrogenase staining of muscle tissue showed subsarcolemmal accumulation of mitochondria in 12 cases. Mitochondrial DNA study could be performed in one case only and it did not reveal any mutation at nucleotides 3243 and 8344. MRI brain showed multiple infarcts in MELAS, hyperintensities in putaminal areas in chorea and bilateral cerebellar atrophy in MERRF.

  20. Repulsive depletion interactions in colloid polymer mixtures

    OpenAIRE

    Rudhardt, Daniel; Bechinger, Clemens; Leiderer, Paul

    1999-01-01

    Depletion forces in colloidal systems are known to be entirely attractive, as long as the background of macromolecules is small enough that an ideal gas approach is valid. At higher densities, however, structural correlation effects of the macromolecules which lead to additional repulsive parts in the depletion interaction, have to be taken into account. We have measured the depletion interaction between a single polystyrene sphere and a wall in the presence of non-ionic polymer coils. Althou...

  1. Mitochondrial fusion and inheritance of the mitochondrial genome.

    Science.gov (United States)

    Takano, Hiroyoshi; Onoue, Kenta; Kawano, Shigeyuki

    2010-03-01

    Although maternal or uniparental inheritance of mitochondrial genomes is a general rule, biparental inheritance is sometimes observed in protists and fungi,including yeasts. In yeast, recombination occurs between the mitochondrial genomes inherited from both parents.Mitochondrial fusion observed in yeast zygotes is thought to set up a space for DNA recombination. In the last decade,a universal mitochondrial fusion mechanism has been uncovered, using yeast as a model. On the other hand, an alternative mitochondrial fusion mechanism has been identified in the true slime mold Physarum polycephalum.A specific mitochondrial plasmid, mF, has been detected as the genetic material that causes mitochondrial fusion in P. polycephalum. Without mF, fusion of the mitochondria is not observed throughout the life cycle, suggesting that Physarum has no constitutive mitochondrial fusion mechanism.Conversely, mitochondria fuse in zygotes and during sporulation with mF. The complete mF sequence suggests that one gene, ORF640, encodes a fusogen for Physarum mitochondria. Although in general, mitochondria are inherited uniparentally, biparental inheritance occurs with specific sexual crossing in P. polycephalum.An analysis of the transmission of mitochondrial genomes has shown that recombinations between two parental mitochondrial genomes require mitochondrial fusion,mediated by mF. Physarum is a unique organism for studying mitochondrial fusion. PMID:20196232

  2. Ego depletion increases risk-taking.

    Science.gov (United States)

    Fischer, Peter; Kastenmüller, Andreas; Asal, Kathrin

    2012-01-01

    We investigated how the availability of self-control resources affects risk-taking inclinations and behaviors. We proposed that risk-taking often occurs from suboptimal decision processes and heuristic information processing (e.g., when a smoker suppresses or neglects information about the health risks of smoking). Research revealed that depleted self-regulation resources are associated with reduced intellectual performance and reduced abilities to regulate spontaneous and automatic responses (e.g., control aggressive responses in the face of frustration). The present studies transferred these ideas to the area of risk-taking. We propose that risk-taking is increased when individuals find themselves in a state of reduced cognitive self-control resources (ego-depletion). Four studies supported these ideas. In Study 1, ego-depleted participants reported higher levels of sensation seeking than non-depleted participants. In Study 2, ego-depleted participants showed higher levels of risk-tolerance in critical road traffic situations than non-depleted participants. In Study 3, we ruled out two alternative explanations for these results: neither cognitive load nor feelings of anger mediated the effect of ego-depletion on risk-taking. Finally, Study 4 clarified the underlying psychological process: ego-depleted participants feel more cognitively exhausted than non-depleted participants and thus are more willing to take risks. Discussion focuses on the theoretical and practical implications of these findings. PMID:22931000

  3. Mitochondrial dysfunction remodels one-carbon metabolism in human cells

    Science.gov (United States)

    Bao, Xiaoyan Robert; Ong, Shao-En; Goldberger, Olga; Peng, Jun; Sharma, Rohit; Thompson, Dawn A; Vafai, Scott B; Cox, Andrew G; Marutani, Eizo; Ichinose, Fumito; Goessling, Wolfram; Regev, Aviv; Carr, Steven A; Clish, Clary B; Mootha, Vamsi K

    2016-01-01

    Mitochondrial dysfunction is associated with a spectrum of human disorders, ranging from rare, inborn errors of metabolism to common, age-associated diseases such as neurodegeneration. How these lesions give rise to diverse pathology is not well understood, partly because their proximal consequences have not been well-studied in mammalian cells. Here we provide two lines of evidence that mitochondrial respiratory chain dysfunction leads to alterations in one-carbon metabolism pathways. First, using hypothesis-generating metabolic, proteomic, and transcriptional profiling, followed by confirmatory experiments, we report that mitochondrial DNA depletion leads to an ATF4-mediated increase in serine biosynthesis and transsulfuration. Second, we show that lesioning the respiratory chain impairs mitochondrial production of formate from serine, and that in some cells, respiratory chain inhibition leads to growth defects upon serine withdrawal that are rescuable with purine or formate supplementation. Our work underscores the connection between the respiratory chain and one-carbon metabolism with implications for understanding mitochondrial pathogenesis. DOI: http://dx.doi.org/10.7554/eLife.10575.001 PMID:27307216

  4. Adult-onset mitochondrial myopathy.

    Science.gov (United States)

    Fernandez-Sola, J.; Casademont, J.; Grau, J. M.; Graus, F.; Cardellach, F.; Pedrol, E.; Urbano-Marquez, A.

    1992-01-01

    Mitochondrial diseases are polymorphic entities which may affect many organs and systems. Skeletal muscle involvement is frequent in the context of systemic mitochondrial disease, but adult-onset pure mitochondrial myopathy appears to be rare. We report 3 patients with progressive skeletal mitochondrial myopathy starting in adult age. In all cases, the proximal myopathy was the only clinical feature. Mitochondrial pathology was confirmed by evidence of ragged-red fibres in muscle histochemistry, an abnormal mitochondrial morphology in electron microscopy and by exclusion of other underlying diseases. No deletions of mitochondrial DNA were found. We emphasize the need to look for a mitochondrial disorder in some non-specific myopathies starting in adult life. Images Figure 1 Figure 2 PMID:1589382

  5. Cancer: Mitochondrial Origins.

    Science.gov (United States)

    Stefano, George B; Kream, Richard M

    2015-12-01

    The primacy of glucose derived from photosynthesis as an existential source of chemical energy across plant and animal phyla is universally accepted as a core principle in the biological sciences. In mammalian cells, initial processing of glucose to triose phosphate intermediates takes place within the cytosolic glycolytic pathway and terminates with temporal transport of reducing equivalents derived from pyruvate metabolism by membrane-associated respiratory complexes in the mitochondrial matrix. The intra-mitochondrial availability of molecular oxygen as the ultimate electron acceptor drives the evolutionary fashioned chemiosmotic production of ATP as a high-efficiency biological process. The mechanistic bases of carcinogenesis have demonstrated profound alteration of normative mitochondrial function, notably dysregulated respiratory processes. Accordingly, the classic Warburg effect functionally links aerobic glycolysis, aberrant production and release of lactate, and metabolic down-regulation of mitochondrial oxidative processes with the carcinogenetic phenotype. We surmise, however, that aerobic fermentation by cancer cells may also represent a developmental re-emergence of an evolutionarily conserved early phenotype, which was "sidelined" with the emergence of mitochondrial oxidative phosphorylation as a primary mechanism for ATP production in normal cells. Regardless of state-dependent physiological status in mixed populations of cancer cells, it has been established that mitochondria are functionally linked to the initiation of cancer and its progression. Biochemical, molecular, and physiological differences in cancer cell mitochondria, notably mtDNA heteroplasmy and allele-specific expression of selected nuclear genes, may represent major focal points for novel targeting and elimination of cancer cells in metastatic disease afflicting human populations. To date, and despite considerable research efforts, the practical realization of advanced mitochondrial

  6. Mitochondrial calcium uptake.

    Science.gov (United States)

    Williams, George S B; Boyman, Liron; Chikando, Aristide C; Khairallah, Ramzi J; Lederer, W J

    2013-06-25

    Calcium (Ca(2+)) uptake into the mitochondrial matrix is critically important to cellular function. As a regulator of matrix Ca(2+) levels, this flux influences energy production and can initiate cell death. If large, this flux could potentially alter intracellular Ca(2+) ([Ca(2+)]i) signals. Despite years of study, fundamental disagreements on the extent and speed of mitochondrial Ca(2+) uptake still exist. Here, we review and quantitatively analyze mitochondrial Ca(2+) uptake fluxes from different tissues and interpret the results with respect to the recently proposed mitochondrial Ca(2+) uniporter (MCU) candidate. This quantitative analysis yields four clear results: (i) under physiological conditions, Ca(2+) influx into the mitochondria via the MCU is small relative to other cytosolic Ca(2+) extrusion pathways; (ii) single MCU conductance is ∼6-7 pS (105 mM [Ca(2+)]), and MCU flux appears to be modulated by [Ca(2+)]i, suggesting Ca(2+) regulation of MCU open probability (P(O)); (iii) in the heart, two features are clear: the number of MCU channels per mitochondrion can be calculated, and MCU probability is low under normal conditions; and (iv) in skeletal muscle and liver cells, uptake per mitochondrion varies in magnitude but total uptake per cell still appears to be modest. Based on our analysis of available quantitative data, we conclude that although Ca(2+) critically regulates mitochondrial function, the mitochondria do not act as a significant dynamic buffer of cytosolic Ca(2+) under physiological conditions. Nevertheless, with prolonged (superphysiological) elevations of [Ca(2+)]i, mitochondrial Ca(2+) uptake can increase 10- to 1,000-fold and begin to shape [Ca(2+)]i dynamics.

  7. Depleted argon from underground sources

    Energy Technology Data Exchange (ETDEWEB)

    Back, H.O.; /Princeton U.; Alton, A.; /Augustana U. Coll.; Calaprice, F.; Galbiati, C.; Goretti, A.; /Princeton U.; Kendziora, C.; /Fermilab; Loer, B.; /Princeton U.; Montanari, D.; /Fermilab; Mosteiro, P.; /Princeton U.; Pordes, S.; /Fermilab

    2011-09-01

    Argon is a powerful scintillator and an excellent medium for detection of ionization. Its high discrimination power against minimum ionization tracks, in favor of selection of nuclear recoils, makes it an attractive medium for direct detection of WIMP dark matter. However, cosmogenic {sup 39}Ar contamination in atmospheric argon limits the size of liquid argon dark matter detectors due to pile-up. The cosmic ray shielding by the earth means that Argon from deep underground is depleted in {sup 39}Ar. In Cortez Colorado a CO{sub 2} well has been discovered to contain approximately 500ppm of argon as a contamination in the CO{sub 2}. In order to produce argon for dark matter detectors we first concentrate the argon locally to 3-5% in an Ar, N{sub 2}, and He mixture, from the CO{sub 2} through chromatographic gas separation. The N{sub 2} and He will be removed by continuous cryogenic distillation in the Cryogenic Distillation Column recently built at Fermilab. In this talk we will discuss the entire extraction and purification process; with emphasis on the recent commissioning and initial performance of the cryogenic distillation column purification.

  8. Mitochondrial Dysfunction and Psychiatric Disorders

    OpenAIRE

    Shaw-Hwa Jou; Nan-Yin Chiu; Chin-San Liu

    2009-01-01

    Mitochondria are intracellular organelles crucial in the production of cellular energy.Mitochondrial diseases may result from malfunctions in this biochemical cascade. Severalinvestigators have proposed that mitochondrial dysfunction is related to the pathophysiologyof bipolar disorder (BD), major depressive disorder (MDD) and schizophrenia (SZ). Theauthors reviewed recent study findings and tried to delineate the current understanding of thecorrelation between mitochondrial dysfunction and p...

  9. Implications of mitochondrial DNA mutations and mitochondrial dysfunction in tumorigenesis

    Institute of Scientific and Technical Information of China (English)

    Jianxin Lu; Lokendra Kumar Sharma; Yidong Bai

    2009-01-01

    Alterations in oxidative phosphorylation resulting from mitochondrial dysfunction have long been hypothesized to be involved in tumorigenesis. Mitochondria have recently been shown to play an important role in regulating both programmed cell death and cell proliferation. Furthermore, mitochondrial DNA (mtDNA) mutations have been found in various cancer cells. However, the role of these mtDNA mutations in tumorigenesis remains largely unknown. This review focuses on basic mitochondrial genetics, mtDNA mutations and consequential mitochondrial dysfunction associated with cancer. The potential molecular mechanisms, mediating the pathogenesis from mtDNA mutations and mitochondrial dysfunction to tumorigenesis are also discussed.

  10. Effects of Oxidative Alcohol Metabolism on the Mitochondrial Permeability Transition Pore and Necrosis in a Mouse Model of Alcoholic Pancreatitis

    Science.gov (United States)

    SHALBUEVA, NATALIA; MARENINOVA, OLGA A.; GERLOFF, ANDREAS; YUAN, JINGZHEN; WALDRON, RICHARD T.; PANDOL, STEPHEN J.; GUKOVSKAYA, ANNA S.

    2013-01-01

    BACKGROUND & AIMS Opening of the mitochondrial permeability transition pore (MPTP) causes loss of the mitochondrial membrane potential (ΔΨm) and, ultimately, adenosine triphosphate depletion and necrosis. Cells deficient in cyclophilin D (CypD), a component of the MPTP, are resistant to MPTP opening, loss of ΔΨm, and necrosis. Alcohol abuse is a major risk factor for pancreatitis and is believed to sensitize the pancreas to stressors, by poorly understood mechanisms. We investigated the effects of ethanol on the pancreatic MPTP, the mechanisms of these effects, and their role in pancreatitis. METHODS We measured ΔΨm in mouse pancreatic acinar cells incubated with ethanol alone and in combination with physiologic and pathologic concentrations of cholecystokinin-8 (CCK). To examine the role of MPTP, we used ex vivo and in vivo models of pancreatitis, induced in wild-type and CypD−/− mice by a combination of ethanol and CCK. RESULTS Ethanol reduced basal ΔΨm and converted a transient depolarization, induced by physiologic concentrations of CCK, into a sustained decrease in ΔΨm, resulting in reduced cellular adenosine triphosphate and increased necrosis. The effects of ethanol and CCK were mediated by MPTP because they were not observed in CypD−/− acinar cells. Ethanol and CCK activated MPTP through different mechanisms— ethanol by reducing the ratio of oxidized nicotinamide adenine dinucleotide to reduced nicotinamide adenine dinucleotide, as a result of oxidative metabolism, and CCK by increasing cytosolic Ca2+. CypD−/− mice developed a less-severe form of pancreatitis after administration of ethanol and CCK. CONCLUSIONS Oxidative metabolism of ethanol sensitizes pancreatic mitochondria to activate MPTP, leading to mitochondrial failure; this makes the pancreas susceptible to necrotizing pancreatitis. PMID:23103769

  11. Reduction of nuclear encoded enzymes of mitochondrial energy metabolism in cells devoid of mitochondrial DNA

    Energy Technology Data Exchange (ETDEWEB)

    Mueller, Edith E., E-mail: ed.mueller@salk.at [Research Program for Receptor Biochemistry and Tumor Metabolism, Department of Pediatrics, Muellner Hauptstrasse 48, 5020 Salzburg (Austria); Mayr, Johannes A., E-mail: h.mayr@salk.at [Research Program for Receptor Biochemistry and Tumor Metabolism, Department of Pediatrics, Muellner Hauptstrasse 48, 5020 Salzburg (Austria); Zimmermann, Franz A., E-mail: f.zimmermann@salk.at [Research Program for Receptor Biochemistry and Tumor Metabolism, Department of Pediatrics, Muellner Hauptstrasse 48, 5020 Salzburg (Austria); Feichtinger, Rene G., E-mail: r.feichtinger@salk.at [Research Program for Receptor Biochemistry and Tumor Metabolism, Department of Pediatrics, Muellner Hauptstrasse 48, 5020 Salzburg (Austria); Stanger, Olaf, E-mail: o.stanger@rbht.nhs.uk [Department of Cardiac Surgery, Paracelsus Medical University, Muellner Hauptstrasse 48, 5020 Salzburg (Austria); Sperl, Wolfgang, E-mail: w.sperl@salk.at [Research Program for Receptor Biochemistry and Tumor Metabolism, Department of Pediatrics, Muellner Hauptstrasse 48, 5020 Salzburg (Austria); Kofler, Barbara, E-mail: b.kofler@salk.at [Research Program for Receptor Biochemistry and Tumor Metabolism, Department of Pediatrics, Muellner Hauptstrasse 48, 5020 Salzburg (Austria)

    2012-01-20

    Highlights: Black-Right-Pointing-Pointer We examined OXPHOS and citrate synthase enzyme activities in HEK293 cells devoid of mtDNA. Black-Right-Pointing-Pointer Enzymes partially encoded by mtDNA show reduced activities. Black-Right-Pointing-Pointer Also the entirely nuclear encoded complex II and citrate synthase exhibit reduced activities. Black-Right-Pointing-Pointer Loss of mtDNA induces a feedback mechanism that downregulates complex II and citrate synthase. -- Abstract: Mitochondrial DNA (mtDNA) depletion syndromes are generally associated with reduced activities of oxidative phosphorylation (OXPHOS) enzymes that contain subunits encoded by mtDNA. Conversely, entirely nuclear encoded mitochondrial enzymes in these syndromes, such as the tricarboxylic acid cycle enzyme citrate synthase (CS) and OXPHOS complex II, usually exhibit normal or compensatory enhanced activities. Here we report that a human cell line devoid of mtDNA (HEK293 {rho}{sup 0} cells) has diminished activities of both complex II and CS. This finding indicates the existence of a feedback mechanism in {rho}{sup 0} cells that downregulates the expression of entirely nuclear encoded components of mitochondrial energy metabolism.

  12. Blood cell mitochondrial DNA content and premature ovarian aging.

    Directory of Open Access Journals (Sweden)

    Marco Bonomi

    Full Text Available Primary ovarian insufficiency (POI is a critical fertility defect characterized by an anticipated and silent impairment of the follicular reserve, but its pathogenesis is largely unexplained. The frequent maternal inheritance of POI together with a remarkable dependence of ovarian folliculogenesis upon mitochondrial biogenesis and bioenergetics suggested the possible involvement of a generalized mitochondrial defect. Here, we verified the existence of a significant correlation between blood and ovarian mitochondrial DNA (mtDNA content in a group of women undergoing ovarian hyperstimulation (OH, and then aimed to verify whether mtDNA content was significantly altered in the blood cells of POI women. We recruited 101 women with an impaired ovarian reserve: 59 women with premature ovarian failure (POF and 42 poor responders (PR to OH. A Taqman copy number assay revealed a significant mtDNA depletion (P<0.001 in both POF and PR women in comparison with 43 women of similar age and intact ovarian reserve, or 53 very old women with a previous physiological menopause. No pathogenic variations in the mitochondrial DNA polymerase γ (POLG gene were detected in 57 POF or PR women with low blood mtDNA content. In conclusion, blood cell mtDNA depletion is a frequent finding among women with premature ovarian aging, suggesting that a still undetermined but generalized mitochondrial defect may frequently predispose to POI which could then be considered a form of anticipated aging in which the ovarian defect may represent the first manifestation. The determination of mtDNA content in blood may become an useful tool for the POI risk prediction.

  13. Tissue depletion of taurine accelerates skeletal muscle senescence and leads to early death in mice.

    Directory of Open Access Journals (Sweden)

    Takashi Ito

    Full Text Available Taurine (2-aminoethanesulfonic acid is found in milimolar concentrations in mammalian tissues. One of its main functions is osmoregulation; however, it also exhibits cytoprotective activity by diminishing injury caused by stress and disease. Taurine depletion is associated with several defects, many of which are found in the aging animal, suggesting that taurine might exert anti-aging actions. Therefore, in the present study, we examined the hypothesis that taurine depletion accelerates aging by reducing longevity and accelerating aging-associated tissue damage. Tissue taurine depletion in taurine transporter knockout (TauTKO mouse was found to shorten lifespan and accelerate skeletal muscle histological and functional defects, including an increase in central nuclei containing myotubes, a reduction in mitochondrial complex 1 activity and an induction in an aging biomarker, Cyclin-dependent kinase 4 inhibitor A (p16INK4a. Tissue taurine depletion also enhances unfolded protein response (UPR, which may be associated with an improvement in protein folding by taurine. Our data reveal that tissue taurine depletion affects longevity and cellular senescence; an effect possibly linked to a disturbance in protein folding.

  14. Oil depletion and terms of trade

    OpenAIRE

    Irimia-Vladu, Marina; Thompson, Henry

    2007-01-01

    A model of the international oil market model with optimal depletion and offer curves suggests importers face a backward bending offer curve. An oil tariff would then raise oil imports and lower the price of oil including the tariff. Simulations of price and extraction paths for the coming century provide insight into the future of oil depletion and terms of trade.

  15. Depletion sensitivity predicts unhealthy snack purchases

    NARCIS (Netherlands)

    Salmon, Stefanie J.; Adriaanse, Marieke A.; Fennis, Bob M.; De Vet, Emely; De Ridder, Denise T D

    2016-01-01

    The aim of the present research is to examine the relation between depletion sensitivity - a novel construct referring to the speed or ease by which one's self-control resources are drained - and snack purchase behavior. In addition, interactions between depletion sensitivity and the goal to lose we

  16. Depletion sensitivity predicts unhealthy snack purchases

    NARCIS (Netherlands)

    Salmon, Stefanie J.; Adriaanse, Marieke A.; Fennis, Bob M.; Vet, De Emely; Ridder, De Denise T.D.

    2016-01-01

    The aim of the present research is to examine the relation between depletion sensitivity - a novel construct referring to the speed or ease by which one's self-control resources are drained - and snack purchase behavior. In addition, interactions between depletion sensitivity and the goal to lose

  17. The Chemistry and Toxicology of Depleted Uranium

    Directory of Open Access Journals (Sweden)

    Sidney A. Katz

    2014-03-01

    Full Text Available Natural uranium is comprised of three radioactive isotopes: 238U, 235U, and 234U. Depleted uranium (DU is a byproduct of the processes for the enrichment of the naturally occurring 235U isotope. The world wide stock pile contains some 1½ million tons of depleted uranium. Some of it has been used to dilute weapons grade uranium (~90% 235U down to reactor grade uranium (~5% 235U, and some of it has been used for heavy tank armor and for the fabrication of armor-piercing bullets and missiles. Such weapons were used by the military in the Persian Gulf, the Balkans and elsewhere. The testing of depleted uranium weapons and their use in combat has resulted in environmental contamination and human exposure. Although the chemical and the toxicological behaviors of depleted uranium are essentially the same as those of natural uranium, the respective chemical forms and isotopic compositions in which they usually occur are different. The chemical and radiological toxicity of depleted uranium can injure biological systems. Normal functioning of the kidney, liver, lung, and heart can be adversely affected by depleted uranium intoxication. The focus of this review is on the chemical and toxicological properties of depleted and natural uranium and some of the possible consequences from long term, low dose exposure to depleted uranium in the environment.

  18. Specification for the VERA Depletion Benchmark Suite

    Energy Technology Data Exchange (ETDEWEB)

    Kim, Kang Seog [Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States)

    2015-12-17

    CASL-X-2015-1014-000 iii Consortium for Advanced Simulation of LWRs EXECUTIVE SUMMARY The CASL neutronics simulator MPACT is under development for the neutronics and T-H coupled simulation for the pressurized water reactor. MPACT includes the ORIGEN-API and internal depletion module to perform depletion calculations based upon neutron-material reaction and radioactive decay. It is a challenge to validate the depletion capability because of the insufficient measured data. One of the detoured methods to validate it is to perform a code-to-code comparison for benchmark problems. In this study a depletion benchmark suite has been developed and a detailed guideline has been provided to obtain meaningful computational outcomes which can be used in the validation of the MPACT depletion capability.

  19. Mitochondrial Dysfunction in Cancer

    Directory of Open Access Journals (Sweden)

    Michelle L Boland

    2013-12-01

    Full Text Available A mechanistic understanding of how mitochondrial dysfunction contributes to cell growth and tumorigenesis is emerging beyond Warburg as an area of research that is under-explored in terms of its significance for clinical management of cancer. Work discussed in this review focuses less on the Warburg effect and more on mitochondria and how dysfunctional mitochondria modulate cell cycle, gene expression, metabolism, cell viability and other more conventional aspects of cell growth and stress responses. There is increasing evidence that key oncogenes and tumor suppressors modulate mitochondrial dynamics through important signaling pathways and that mitochondrial mass and function vary between tumors and individuals but the sigificance of these events for cancer are not fully appreciated. We explore the interplay between key molecules involved in mitochondrial fission and fusion and in apoptosis, as well as in mitophagy, biogenesis and spatial dynamics and consider how these distinct mechanisms are coordinated in response to physiological stresses such as hypoxia and nutrient deprivation. Importantly, we examine how deregulation of these processes in cancer has knockon effects for cell proliferation and growth. Scientifically, there is also scope for defining what mitochondria dysfunction is and here we address the extent to which the functional consequences of such dysfunction can be determined and exploited for cancer diagnosis and treatment.

  20. Mitochondrial Ion Channels

    Science.gov (United States)

    O’Rourke, Brian

    2009-01-01

    In work spanning more than a century, mitochondria have been recognized for their multifunctional roles in metabolism, energy transduction, ion transport, inheritance, signaling, and cell death. Foremost among these tasks is the continuous production of ATP through oxidative phosphorylation, which requires a large electrochemical driving force for protons across the mitochondrial inner membrane. This process requires a membrane with relatively low permeability to ions to minimize energy dissipation. However, a wealth of evidence now indicates that both selective and nonselective ion channels are present in the mitochondrial inner membrane, along with several known channels on the outer membrane. Some of these channels are active under physiological conditions, and others may be activated under pathophysiological conditions to act as the major determinants of cell life and death. This review summarizes research on mitochondrial ion channels and efforts to identify their molecular correlates. Except in a few cases, our understanding of the structure of mitochondrial ion channels is limited, indicating the need for focused discovery in this area. PMID:17059356

  1. Suppression of Cpn10 increases mitochondrial fission and dysfunction in neuroblastoma cells.

    Directory of Open Access Journals (Sweden)

    So Jung Park

    Full Text Available To date, several regulatory proteins involved in mitochondrial dynamics have been identified. However, the precise mechanism coordinating these complex processes remains unclear. Mitochondrial chaperones regulate mitochondrial function and structure. Chaperonin 10 (Cpn10 interacts with heat shock protein 60 (HSP60 and functions as a co-chaperone. In this study, we found that down-regulation of Cpn10 highly promoted mitochondrial fragmentation in SK-N-MC and SH-SY5Y neuroblastoma cells. Both genetic and chemical inhibition of Drp1 suppressed the mitochondrial fragmentation induced by Cpn10 reduction. Reactive oxygen species (ROS generation in 3-NP-treated cells was markedly enhanced by Cpn10 knock down. Depletion of Cpn10 synergistically increased cell death in response to 3-NP treatment. Furthermore, inhibition of Drp1 recovered Cpn10-mediated mitochondrial dysfunction in 3-NP-treated cells. Moreover, an ROS scavenger suppressed cell death mediated by Cpn10 knockdown in 3-NP-treated cells. Taken together, these results showed that down-regulation of Cpn10 increased mitochondrial fragmentation and potentiated 3-NP-mediated mitochondrial dysfunction in neuroblastoma cells.

  2. Reversal of Cytosolic One-Carbon Flux Compensates for Loss of the Mitochondrial Folate Pathway.

    Science.gov (United States)

    Ducker, Gregory S; Chen, Li; Morscher, Raphael J; Ghergurovich, Jonathan M; Esposito, Mark; Teng, Xin; Kang, Yibin; Rabinowitz, Joshua D

    2016-06-14

    One-carbon (1C) units for purine and thymidine synthesis can be generated from serine by cytosolic or mitochondrial folate metabolism. The mitochondrial 1C pathway is consistently overexpressed in cancer. Here, we show that most but not all proliferating mammalian cell lines use the mitochondrial pathway as the default for making 1C units. Clustered regularly interspaced short palindromic repeats (CRISPR)-mediated mitochondrial pathway knockout activates cytosolic 1C-unit production. This reversal in cytosolic flux is triggered by depletion of a single metabolite, 10-formyl-tetrahydrofolate (10-formyl-THF), and enables rapid cell growth in nutrient-replete conditions. Loss of the mitochondrial pathway, however, renders cells dependent on extracellular serine to make 1C units and on extracellular glycine to make glutathione. HCT-116 colon cancer xenografts lacking mitochondrial 1C pathway activity generate the 1C units required for growth by cytosolic serine catabolism. Loss of both pathways precludes xenograft formation. Thus, either mitochondrial or cytosolic 1C metabolism can support tumorigenesis, with the mitochondrial pathway required in nutrient-poor conditions. PMID:27211901

  3. Mesencephalic complex I deficiency does not correlate with parkinsonism in mitochondrial DNA maintenance disorders.

    Science.gov (United States)

    Palin, Eino J H; Paetau, Anders; Suomalainen, Anu

    2013-08-01

    Genetic evidence from recessively inherited Parkinson's disease has indicated a clear causative role for mitochondrial dysfunction in Parkinson's disease. This role has long been discussed based on findings that toxic inhibition of mitochondrial respiratory complex I caused parkinsonism and that tissues of patients with Parkinson's disease show complex I deficiency. Disorders of mitochondrial DNA maintenance are a common cause of inherited neurodegenerative disorders, and lead to mitochondrial DNA deletions or depletion and respiratory chain defect, including complex I deficiency. However, parkinsonism associates typically with defects of catalytic domain of mitochondrial DNA polymerase gamma. Surprisingly, however, not all mutations affecting DNA polymerase gamma manifest as parkinsonism, but, for example, spacer region mutations lead to spinocerebellar ataxia and/or severe epilepsy. Furthermore, defective Twinkle helicase, a close functional companion of DNA polymerase gamma in mitochondrial DNA replication, results in infantile-onset spinocerebellar ataxia, epilepsy or adult-onset mitochondrial myopathy, but not typically parkinsonism. Here we sought for clues for this specificity in the neurological manifestations of mitochondrial DNA maintenance disorders by studying mesencephalic neuropathology of patients with DNA polymerase gamma or Twinkle defects, with or without parkinsonism. We show here that all patients with mitochondrial DNA maintenance disorders had neuronopathy in substantia nigra, most severe in DNA polymerase gamma-associated parkinsonism. The oculomotor nucleus was also affected, but less severely. In substantia nigra, all patients had a considerable decrease of respiratory chain complex I, but other respiratory chain enzymes were not affected. Complex I deficiency did not correlate with parkinsonism, age, affected gene or inheritance. We conclude that the cell number in substantia nigra correlated well with parkinsonism in DNA polymerase gamma

  4. Administrating Solr

    CERN Document Server

    Mohan, Surendra

    2013-01-01

    A fast-paced, example-based guide to learning how to administrate, monitor, and optimize Apache Solr.""Administrating Solr"" is for developers and Solr administrators who have a basic knowledge of Solr and who are looking for ways to keep their Solr server healthy and well maintained. A basic working knowledge of Apache Lucene is recommended, but this is not mandatory.

  5. Preventing mitochondrial fission impairs mitochondrial function and leads to loss of mitochondrial DNA.

    Directory of Open Access Journals (Sweden)

    Philippe A Parone

    Full Text Available Mitochondria form a highly dynamic tubular network, the morphology of which is regulated by frequent fission and fusion events. However, the role of mitochondrial fission in homeostasis of the organelle is still unknown. Here we report that preventing mitochondrial fission, by down-regulating expression of Drp1 in mammalian cells leads to a loss of mitochondrial DNA and a decrease of mitochondrial respiration coupled to an increase in the levels of cellular reactive oxygen species (ROS. At the cellular level, mitochondrial dysfunction resulting from the lack of fission leads to a drop in the levels of cellular ATP, an inhibition of cell proliferation and an increase in autophagy. In conclusion, we propose that mitochondrial fission is required for preservation of mitochondrial function and thereby for maintenance of cellular homeostasis.

  6. Administrative Circulars

    CERN Multimedia

    Département des Ressources humaines

    2004-01-01

    Administrative Circular N° 2 (Rev. 2) - May 2004 Guidelines and procedures concerning recruitment and probation period of staff members This circular has been revised. It cancels and replaces Administrative Circular N° 2 (Rev. 1) - March 2000. Administrative Circular N° 9 (Rev. 3) - May 2004 Staff members contracts This circular has been revised. It cancels and replaces Administrative Circular N° 9 (Rev. 2) - March 2000. Administrative Circular N° 26 (Rev. 4) - May 2004 Procedure governing the career evolution of staff members This circular has also been revised. It Administrative Circulars Administrative Circular N° 26 (Rev. 3) - December 2001 and brings up to date the French version (Rev. 4) published on the HR Department Web site in January 2004. Operational Circular N° 7 - May 2004 Work from home This circular has been drawn up. Operational Circular N° 8 - May 2004 Dealing with alcohol-related problems...

  7. Altering the redox state of skeletal muscle by glutathione depletion increases the exercise‐activation of PGC‐1α

    OpenAIRE

    Strobel, Natalie A.; Matsumoto, Aya; Peake, Jonathan M.; Marsh, Susan A.; Peternelj, Tina‐Tinkara; Briskey, David; Fassett, Robert G.; Coombes, Jeff S.; Wadley, Glenn D.

    2014-01-01

    Abstract We investigated the relationship between markers of mitochondrial biogenesis, cell signaling, and antioxidant enzymes by depleting skeletal muscle glutathione with diethyl maleate (DEM) which resulted in a demonstrable increase in oxidative stress during exercise. Animals were divided into six groups: (1) sedentary control rats; (2) sedentary rats + DEM; (3) exercise control rats euthanized immediately after exercise; (4) exercise rats + DEM; (5) exercise control rats euthanized 4 h ...

  8. EMRE Is a Matrix Ca(2+) Sensor that Governs Gatekeeping of the Mitochondrial Ca(2+) Uniporter.

    Science.gov (United States)

    Vais, Horia; Mallilankaraman, Karthik; Mak, Don-On Daniel; Hoff, Henry; Payne, Riley; Tanis, Jessica E; Foskett, J Kevin

    2016-01-26

    The mitochondrial uniporter (MCU) is an ion channel that mediates Ca(2+) uptake into the matrix to regulate metabolism, cell death, and cytoplasmic Ca(2+) signaling. Matrix Ca(2+) concentration is similar to that in cytoplasm, despite an enormous driving force for entry, but the mechanisms that prevent mitochondrial Ca(2+) overload are unclear. Here, we show that MCU channel activity is governed by matrix Ca(2+) concentration through EMRE. Deletion or charge neutralization of its matrix-localized acidic C terminus abolishes matrix Ca(2+) inhibition of MCU Ca(2+) currents, resulting in MCU channel activation, enhanced mitochondrial Ca(2+) uptake, and constitutively elevated matrix Ca(2+) concentration. EMRE-dependent regulation of MCU channel activity requires intermembrane space-localized MICU1, MICU2, and cytoplasmic Ca(2+). Thus, mitochondria are protected from Ca(2+) depletion and Ca(2+) overload by a unique molecular complex that involves Ca(2+) sensors on both sides of the inner mitochondrial membrane, coupled through EMRE.

  9. Doxorubicin and vincristine with methionine depletion contributed to survival in the Yoshida sarcoma bearing rats.

    Science.gov (United States)

    Nagahama, T; Goseki, N; Endo, M

    1998-01-01

    Several anti-cancer agents show increased toxicity if administered with methionine-depleting total parenteral nutrition (Met-deplete TPN). Changes in the cell cycle due to Met-deplete TPN were investigated, and then the enhancement of the anti-tumor effects of serial combinations of doxorubicin (ADM), a drug acting on late S-G2 phase and vincristine (VCR), an antimitotic drug, under Met-deplete TPN was also examined in the tumor-bearing rats. According to the fraction of labeled mitosis, within 3 to 4 days after the introduction of Met-deplete TPN in the ascites type Yoshida sarcoma (YS) -bearing rats, the cell cycle of the tumor cells showed marked delay and the fraction of labeled mitosis decreased to less than 70%. However, this delay was recovered immediately after methionine infusion, with on increase in the labeled mitotic cell population. In the experiment using solid type YS-bearing rats, ADM was administered intraperitoneally under Met-deplete TPN for 8 days, followed by intraperitoneal VCR administration with methionine-containing TPN for 3 days, and then fed on solid food and water ad libitum until death. This serial combination of Met-deplete TPN with ADM and VCR resulted in marked suppression of the tumor and prolonged survival in comparison to the control groups with a significant difference (p < 0.001) (generalized Wilcoxon test).

  10. Impaired Muscle Mitochondrial Biogenesis and Myogenesis in Spinal Muscular Atrophy

    Science.gov (United States)

    Ripolone, Michela; Ronchi, Dario; Violano, Raffaella; Vallejo, Dionis; Fagiolari, Gigliola; Barca, Emanuele; Lucchini, Valeria; Colombo, Irene; Villa, Luisa; Berardinelli, Angela; Balottin, Umberto; Morandi, Lucia; Mora, Marina; Bordoni, Andreina; Fortunato, Francesco; Corti, Stefania; Parisi, Daniela; Toscano, Antonio; Sciacco, Monica; DiMauro, Salvatore; Comi, Giacomo P.; Moggio, Maurizio

    2016-01-01

    IMPORTANCE The important depletion of mitochondrial DNA (mtDNA) and the general depression of mitochondrial respiratory chain complex levels (including complex II) have been confirmed, implying an increasing paucity of mitochondria in the muscle from patients with types I, II, and III spinal muscular atrophy (SMA-I, -II, and -III, respectively). OBJECTIVE To investigate mitochondrial dysfunction in a large series of muscle biopsy samples from patients with SMA. DESIGN, SETTING, AND PARTICIPANTS We studied quadriceps muscle samples from 24 patients with genetically documented SMA and paraspinal muscle samples from 3 patients with SMA-II undergoing surgery for scoliosis correction. Postmortem muscle samples were obtained from 1 additional patient. Age-matched controls consisted of muscle biopsy specimens from healthy children aged 1 to 3 years who had undergone analysis for suspected myopathy. Analyses were performed at the Neuromuscular Unit, Istituto di Ricovero e Cura a Carattere Scientifico Foundation Ca’ Granda Ospedale Maggiore Policlinico-Milano, from April 2011 through January 2015. EXPOSURES We used histochemical, biochemical, and molecular techniques to examine the muscle samples. MAIN OUTCOMES AND MEASURES Respiratory chain activity and mitochondrial content. RESULTS Results of histochemical analysis revealed that cytochrome-c oxidase (COX) deficiency was more evident in muscle samples from patients with SMA-I and SMA-II. Residual activities for complexes I, II, and IV in muscles from patients with SMA-I were 41%, 27%, and 30%, respectively, compared with control samples (P < .005). Muscle mtDNA content and cytrate synthase activity were also reduced in all 3 SMA types (P < .05). We linked these alterations to downregulation of peroxisome proliferator–activated receptor coactivator 1α, the transcriptional activators nuclear respiratory factor 1 and nuclear respiratory factor 2, mitochondrial transcription factor A, and their downstream targets

  11. Sealing the Mitochondrial Respirasome

    OpenAIRE

    Winge, Dennis R.

    2012-01-01

    The mitochondrial respiratory chain is organized within an array of supercomplexes that function to minimize the generation of reactive oxygen species (ROS) during electron transfer reactions. Structural models of supercomplexes are now known. Another recent advance is the discovery of non-OXPHOS complex proteins that appear to adhere to and seal the individual respiratory complexes to form stable assemblages that prevent electron leakage. This review highlights recent advances in our underst...

  12. Polar stratospheric clouds and ozone depletion

    Science.gov (United States)

    Toon, Owen B.; Turco, Richard P.

    1991-01-01

    A review is presented of investigations into the correlation between the depletion of ozone and the formation of polar stratospheric clouds (PSCs). Satellite measurements from Nimbus 7 showed that over the years the depletion from austral spring to austral spring has generally worsened. Approximately 70 percent of the ozone above Antarctica, which equals about 3 percent of the earth's ozone, is lost during September and October. Various hypotheses for ozone depletion are discussed including the theory suggesting that chlorine compounds might be responsible for the ozone hole, whereby chlorine enters the atmosphere as a component of chlorofluorocarbons produced by humans. The three types of PSCs, nitric acid trihydrate, slowly cooling water-ice, and rapidly cooling water-ice clouds act as important components of the Antarctic ozone depletion. It is indicated that destruction of the ozone will be more severe each year for the next few decades, leading to a doubling in area of the Antarctic ozone hole.

  13. Depleted UF6 programmatic environmental impact statement

    International Nuclear Information System (INIS)

    The US Department of Energy has developed a program for long-term management and use of depleted uranium hexafluoride, a product of the uranium enrichment process. As part of this effort, DOE is preparing a Programmatic Environmental Impact Statement (PEIS) for the depleted UF6 management program. This report duplicates the information available at the web site (http://www.ead.anl.gov/web/newduf6) set up as a repository for the PEIS. Options for the web site include: reviewing recent additions or changes to the web site; learning more about depleted UF6 and the PEIS; browsing the PEIS and related documents, or submitting official comments on the PEIS; downloading all or part of the PEIS documents; and adding or deleting one's name from the depleted UF6 mailing list

  14. Ecological considerations of natural and depleted uranium

    International Nuclear Information System (INIS)

    Depleted 238U is a major by-product of the nuclear fuel cycle for which increasing use is being made in counterweights, radiation shielding, and ordnance applications. This paper (1) summarizes the pertinent literature on natural and depleted uranium in the environment, (2) integrates results of a series of ecological studies conducted at Los Alamos Scientific Laboratory (LASL) in New Mexico where 70,000 kg of depleted and natural uranium has been expended to the environment over the past 34 years, and (3) synthesizes the information into an assessment of the ecological consequences of natural and depleted uranium released to the environment by various means. Results of studies of soil, plant, and animal communities exposed to this radiation and chemical environment over a third of a century provide a means of evaluating the behavior and effects of uranium in many contexts

  15. Fully Depleted Charge-Coupled Devices

    International Nuclear Information System (INIS)

    We have developed fully depleted, back-illuminated CCDs that build upon earlier research and development efforts directed towards technology development of silicon-strip detectors used in high-energy-physics experiments. The CCDs are fabricated on the same type of high-resistivity, float-zone-refined silicon that is used for strip detectors. The use of high-resistivity substrates allows for thick depletion regions, on the order of 200-300 um, with corresponding high detection efficiency for near-infrared and soft x-ray photons. We compare the fully depleted CCD to the p-i-n diode upon which it is based, and describe the use of fully depleted CCDs in astronomical and x-ray imaging applications

  16. Replicating animal mitochondrial DNA

    Directory of Open Access Journals (Sweden)

    Emily A. McKinney

    2013-01-01

    Full Text Available The field of mitochondrial DNA (mtDNA replication has been experiencing incredible progress in recent years, and yet little is certain about the mechanism(s used by animal cells to replicate this plasmid-like genome. The long-standing strand-displacement model of mammalian mtDNA replication (for which single-stranded DNA intermediates are a hallmark has been intensively challenged by a new set of data, which suggests that replication proceeds via coupled leading-and lagging-strand synthesis (resembling bacterial genome replication and/or via long stretches of RNA intermediates laid on the mtDNA lagging-strand (the so called RITOLS. The set of proteins required for mtDNA replication is small and includes the catalytic and accessory subunits of DNA polymerase y, the mtDNA helicase Twinkle, the mitochondrial single-stranded DNA-binding protein, and the mitochondrial RNA polymerase (which most likely functions as the mtDNA primase. Mutations in the genes coding for the first three proteins are associated with human diseases and premature aging, justifying the research interest in the genetic, biochemical and structural properties of the mtDNA replication machinery. Here we summarize these properties and discuss the current models of mtDNA replication in animal cells.

  17. A theoretical model of atmospheric ozone depletion

    Science.gov (United States)

    Midya, S. K.; Jana, P. K.; Lahiri, T.

    1994-01-01

    A critical study on different ozone depletion and formation processes has been made and following important results are obtained: (i) From analysis it is shown that O3 concentration will decrease very minutely with time for normal atmosphere when [O], [O2] and UV-radiation remain constant. (ii) An empirical equation is established theoretically between the variation of ozone concentration and time. (iii) Special ozone depletion processes are responsible for the dramatic decrease of O3-concentration at Antarctica.

  18. Depleted Uranium and Its Effects on Humans

    Directory of Open Access Journals (Sweden)

    Zdeněk Hon

    2015-04-01

    Full Text Available The article summarizes contemporary scientific knowledge of depleted uranium effects on human health due to its use in military conflicts. The discussion covers cases of minimal risk due to external irradiation resulting from the storage and handling of depleted uranium ammunition and, in contrast, important toxicological and radio-toxicological risks of late effects resulting from the inhalation and ingestion of dust particles produced by the burning of the core of the anti-tank ammunition.

  19. Depleted Uranium and Its Effects on Humans

    OpenAIRE

    Zdeněk Hon; Jan Österreicher; Leoš Navrátil

    2015-01-01

    The article summarizes contemporary scientific knowledge of depleted uranium effects on human health due to its use in military conflicts. The discussion covers cases of minimal risk due to external irradiation resulting from the storage and handling of depleted uranium ammunition and, in contrast, important toxicological and radio-toxicological risks of late effects resulting from the inhalation and ingestion of dust particles produced by the burning of the core of the anti-tank ammunition.

  20. Depleted Bulk Heterojunction Colloidal Quantum Dot Photovoltaics

    KAUST Repository

    Barkhouse, D. Aaron R.

    2011-05-26

    The first solution-processed depleted bulk heterojunction colloidal quantum dot solar cells are presented. The architecture allows for high absorption with full depletion, thereby breaking the photon absorption/carrier extraction compromise inherent in planar devices. A record power conversion of 5.5% under simulated AM 1.5 illumination conditions is reported. Copyright © 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  1. Development of Monte Carlo depletion code MCDEP

    Energy Technology Data Exchange (ETDEWEB)

    Kim, K. S.; Kim, K. Y.; Lee, J. C.; Ji, S. K. [KAERI, Taejon (Korea, Republic of)

    2003-07-01

    Monte Carlo neutron transport calculation has been used to obtain a reference solution in reactor physics analysis. The typical and widely-used Monte Carlo transport code is MCNP (Monte Carlo N-Particle Transport Code) developed in Los Alamos National Laboratory. The drawbacks of Monte-Carlo transport codes are the lacks of the capacities for the depletion and temperature dependent calculations. In this research we developed MCDEP (Monte Carlo Depletion Code Package) using MCNP with the capacity of the depletion calculation. This code package is the integration of MCNP and depletion module of ORIGEN-2 using the matrix exponential method. This code package enables the automatic MCNP and depletion calculations only with the initial MCNP and MCDEP inputs prepared by users. Depletion chains were simplified for the efficiency of computing time and the treatment of short-lived nuclides without cross section data. The results of MCDEP showed that the reactivity and pin power distributions for the PWR fuel pins and assemblies are consistent with those of CASMO-3 and HELIOS.

  2. Distinct nuclear gene expression profiles in cells with mtDNA depletion and homoplasmic A3243G mutation

    Energy Technology Data Exchange (ETDEWEB)

    Jahangir Tafrechi, Roshan S. [Department of Molecular Cell Biology, Leiden University Medical Center, P.O. Box 9503, 2300 RA Leiden (Netherlands); Svensson, Peter J. [Department of Toxicogenetics, Leiden University Medical Center, P.O. Box 9503, 2300 RA Leiden (Netherlands); Department of Oncology, Radiology and Clinical Immunology, University Hospital, 75185 Uppsala (Sweden); Janssen, George M.C. [Department of Molecular Cell Biology, Leiden University Medical Center, P.O. Box 9503, 2300 RA Leiden (Netherlands); Szuhai, Karoly [Department of Molecular Cell Biology, Leiden University Medical Center, P.O. Box 9503, 2300 RA Leiden (Netherlands); Maassen, J. Antonie [Department of Molecular Cell Biology, Leiden University Medical Center, P.O. Box 9503, 2300 RA Leiden (Netherlands); Raap, Anton K. [Department of Molecular Cell Biology, Leiden University Medical Center, P.O. Box 9503, 2300 RA Leiden (Netherlands)]. E-mail: A.K.Raap@lumc.nl

    2005-10-15

    The pathobiochemical pathways determining the wide variability in phenotypic expression of mitochondrial DNA (mtDNA) mutations are not well understood. Most pathogenic mtDNA mutations induce a general defect in mitochondrial respiration and thereby ATP synthesis. Yet phenotypic expression of the different mtDNA mutations shows large variations that are difficult to reconcile with ATP depletion as sole pathogenic factor, implying that additional mechanisms contribute to the phenotype. Here, we use DNA microarrays to identify changes in nuclear gene expression resulting from the presence of the A3243G diabetogenic mutation and from a depletion of mtDNA ({rho}{sup 0} cells). We find that cells respond mildly to these mitochondrial states with both general and specific changes in nuclear gene expression. This observation indicates that cells can sense the status of mtDNA. A number of genes show divergence in expression in {rho}{sup 0} cells compared to cells with the A3243G mutation, such as genes involved in oxidative phosphorylation. As a common response in A3243G and {rho}{sup 0} cells, mRNA levels for extracellular matrix genes are up-regulated, while the mRNA levels of genes involved in ubiquitin-mediated protein degradation and in ribosomal protein synthesis is down-regulated. This reduced expression is reflected at the level of cytosolic protein synthesis in both A3243G and {rho}{sup 0} cells. Our finding that mitochondrial dysfunction caused by different mutations affects nuclear gene expression in partially distinct ways suggests that multiple pathways link mitochondrial function to nuclear gene expression and contribute to the development of the different phenotypes in mitochondrial disease.

  3. Radiative characteristics of depleted uranium bomb and it is protection

    International Nuclear Information System (INIS)

    Based on the developing process of depleted uranium bombs described in the first part, the radiative characteristics and mechanism of depleted uranium bombs are analyzed emphatically. The deeper discussion on protection of depleted uranium bombs is proceeded

  4. Impaired Cerebral Mitochondrial Oxidative Phosphorylation Function in a Rat Model of Ventricular Fibrillation and Cardiopulmonary Resuscitation

    Directory of Open Access Journals (Sweden)

    Jun Jiang

    2014-01-01

    Full Text Available Postcardiac arrest brain injury significantly contributes to mortality and morbidity in patients suffering from cardiac arrest (CA. Evidence that shows that mitochondrial dysfunction appears to be a key factor in tissue damage after ischemia/reperfusion is accumulating. However, limited data are available regarding the cerebral mitochondrial dysfunction during CA and cardiopulmonary resuscitation (CPR and its relationship to the alterations of high-energy phosphate. Here, we sought to identify alterations of mitochondrial morphology and oxidative phosphorylation function as well as high-energy phosphates during CA and CPR in a rat model of ventricular fibrillation (VF. We found that impairment of mitochondrial respiration and partial depletion of adenosine triphosphate (ATP and phosphocreatine (PCr developed in the cerebral cortex and hippocampus following a prolonged cardiac arrest. Optimal CPR might ameliorate the deranged phosphorus metabolism and preserve mitochondrial function. No obvious ultrastructural abnormalities of mitochondria have been found during CA. We conclude that CA causes cerebral mitochondrial dysfunction along with decay of high-energy phosphates, which would be mitigated with CPR. This study may broaden our understanding of the pathogenic processes underlying global cerebral ischemic injury and provide a potential therapeutic strategy that aimed at preserving cerebral mitochondrial function during CA.

  5. Fusaric acid induces mitochondrial stress in human hepatocellular carcinoma (HepG2) cells.

    Science.gov (United States)

    Sheik Abdul, Naeem; Nagiah, Savania; Chuturgoon, Anil A

    2016-09-01

    Fusarium spp are common contaminants of maize and produce many mycotoxins, including the fusariotoxin fusaric acid (FA). FA is a niacin related compound, chelator of divalent cations, and mediates toxicity via oxidative stress and possible mitochondrial dysregulation. Sirtuin 3 (SIRT3) is a stress response deacetylase that maintains proper mitochondrial function. We investigated the effect of FA on SIRT3 and oxidative and mitochondrial stress pathways in the hepatocellular carcinoma (HepG2) cell line. We determined FA toxicity (24 h incubation; IC50 = 104 μg/ml) on mitochondrial output, cellular and mitochondrial stress responses, mitochondrial biogenesis and markers of cell death using spectrophotometry, luminometry, qPCR and western blots. FA caused a dose dependent decrease in metabolic activity along with significant depletion of intracellular ATP. FA induced a significant increase in lipid peroxidation, despite up-regulation of the antioxidant transcription factor, Nrf2. FA significantly decreased expression of SIRT3 mRNA with a concomitant decrease in protein expression. Lon protease was also significantly down-regulated. FA induced aberrant mitochondrial biogenesis as evidenced by significantly decreased protein expressions of: PGC-1α, p-CREB, NRF1 and HSP70. Finally, FA activated apoptosis as noted by the significantly increased activity of caspases 3/7 and also induced cellular necrosis. This study provides insight into the molecular mechanisms of FA (a neglected mycotoxin) induced hepatotoxicity. PMID:27390038

  6. Administrative Ecology

    Science.gov (United States)

    McGarity, Augustus C., III; Maulding, Wanda

    2007-01-01

    This article discusses how all four facets of administrative ecology help dispel the claims about the "impossibility" of the superintendency. These are personal ecology, professional ecology, organizational ecology, and community ecology. Using today's superintendency as an administrative platform, current literature describes a preponderance of…

  7. Increased Susceptibility to Ethylmercury-Induced Mitochondrial Dysfunction in a Subset of Autism Lymphoblastoid Cell Lines

    Directory of Open Access Journals (Sweden)

    Shannon Rose

    2015-01-01

    Full Text Available The association of autism spectrum disorders with oxidative stress, redox imbalance, and mitochondrial dysfunction has become increasingly recognized. In this study, extracellular flux analysis was used to compare mitochondrial respiration in lymphoblastoid cell lines (LCLs from individuals with autism and unaffected controls exposed to ethylmercury, an environmental toxin known to deplete glutathione and induce oxidative stress and mitochondrial dysfunction. We also tested whether pretreating the autism LCLs with N-acetyl cysteine (NAC to increase glutathione concentrations conferred protection from ethylmercury. Examination of 16 autism/control LCL pairs revealed that a subgroup (31% of autism LCLs exhibited a greater reduction in ATP-linked respiration, maximal respiratory capacity, and reserve capacity when exposed to ethylmercury, compared to control LCLs. These respiratory parameters were significantly elevated at baseline in the ethylmercury-sensitive autism subgroup as compared to control LCLs. NAC pretreatment of the sensitive subgroup reduced (normalized baseline respiratory parameters and blunted the exaggerated ethylmercury-induced reserve capacity depletion. These findings suggest that the epidemiological link between environmental mercury exposure and an increased risk of developing autism may be mediated through mitochondrial dysfunction and support the notion that a subset of individuals with autism may be vulnerable to environmental influences with detrimental effects on development through mitochondrial dysfunction.

  8. PCR-Based Analysis of Mitochondrial DNA Copy Number, Mitochondrial DNA Damage, and Nuclear DNA Damage.

    Science.gov (United States)

    Gonzalez-Hunt, Claudia P; Rooney, John P; Ryde, Ian T; Anbalagan, Charumathi; Joglekar, Rashmi; Meyer, Joel N

    2016-01-01

    Because of the role that DNA damage and depletion play in human disease, it is important to develop and improve tools to assess these endpoints. This unit describes PCR-based methods to measure nuclear and mitochondrial DNA damage and copy number. Long amplicon quantitative polymerase chain reaction (LA-QPCR) is used to detect DNA damage by measuring the number of polymerase-inhibiting lesions present based on the amount of PCR amplification; real-time PCR (RT-PCR) is used to calculate genome content. In this unit, we provide step-by-step instructions to perform these assays in Homo sapiens, Mus musculus, Rattus norvegicus, Caenorhabditis elegans, Drosophila melanogaster, Danio rerio, Oryzias latipes, Fundulus grandis, and Fundulus heteroclitus, and discuss the advantages and disadvantages of these assays. PMID:26828332

  9. Effective treatment of mitochondrial myopathy by nicotinamide riboside, a vitamin B3.

    Science.gov (United States)

    Khan, Nahid A; Auranen, Mari; Paetau, Ilse; Pirinen, Eija; Euro, Liliya; Forsström, Saara; Pasila, Lotta; Velagapudi, Vidya; Carroll, Christopher J; Auwerx, Johan; Suomalainen, Anu

    2014-06-01

    Nutrient availability is the major regulator of life and reproduction, and a complex cellular signaling network has evolved to adapt organisms to fasting. These sensor pathways monitor cellular energy metabolism, especially mitochondrial ATP production and NAD(+)/NADH ratio, as major signals for nutritional state. We hypothesized that these signals would be modified by mitochondrial respiratory chain disease, because of inefficient NADH utilization and ATP production. Oral administration of nicotinamide riboside (NR), a vitamin B3 and NAD(+) precursor, was previously shown to boost NAD(+) levels in mice and to induce mitochondrial biogenesis. Here, we treated mitochondrial myopathy mice with NR. This vitamin effectively delayed early- and late-stage disease progression, by robustly inducing mitochondrial biogenesis in skeletal muscle and brown adipose tissue, preventing mitochondrial ultrastructure abnormalities and mtDNA deletion formation. NR further stimulated mitochondrial unfolded protein response, suggesting its protective role in mitochondrial disease. These results indicate that NR and strategies boosting NAD(+) levels are a promising treatment strategy for mitochondrial myopathy. PMID:24711540

  10. Inheritance of the yeast mitochondrial genome

    DEFF Research Database (Denmark)

    Piskur, Jure

    1994-01-01

    Mitochondrion, extrachromosomal genetics, intergenic sequences, genome size, mitochondrial DNA, petite mutation, yeast......Mitochondrion, extrachromosomal genetics, intergenic sequences, genome size, mitochondrial DNA, petite mutation, yeast...

  11. Sealing the mitochondrial respirasome.

    Science.gov (United States)

    Winge, Dennis R

    2012-07-01

    The mitochondrial respiratory chain is organized within an array of supercomplexes that function to minimize the generation of reactive oxygen species (ROS) during electron transfer reactions. Structural models of supercomplexes are now known. Another recent advance is the discovery of non-OXPHOS complex proteins that appear to adhere to and seal the individual respiratory complexes to form stable assemblages that prevent electron leakage. This review highlights recent advances in our understanding of the structures of supercomplexes and the factors that mediate their stability.

  12. Depletion sensitivity predicts unhealthy snack purchases.

    Science.gov (United States)

    Salmon, Stefanie J; Adriaanse, Marieke A; Fennis, Bob M; De Vet, Emely; De Ridder, Denise T D

    2016-01-01

    The aim of the present research is to examine the relation between depletion sensitivity - a novel construct referring to the speed or ease by which one's self-control resources are drained - and snack purchase behavior. In addition, interactions between depletion sensitivity and the goal to lose weight on snack purchase behavior were explored. Participants included in the study were instructed to report every snack they bought over the course of one week. The dependent variables were the number of healthy and unhealthy snacks purchased. The results of the present study demonstrate that depletion sensitivity predicts the amount of unhealthy (but not healthy) snacks bought. The more sensitive people are to depletion, the more unhealthy snacks they buy. Moreover, there was some tentative evidence that this relation is more pronounced for people with a weak as opposed to a strong goal to lose weight, suggesting that a strong goal to lose weight may function as a motivational buffer against self-control failures. All in all, these findings provide evidence for the external validity of depletion sensitivity and the relevance of this construct in the domain of eating behavior. PMID:26321417

  13. The New MCNP6 Depletion Capability

    Energy Technology Data Exchange (ETDEWEB)

    Fensin, Michael Lorne [Los Alamos National Laboratory; James, Michael R. [Los Alamos National Laboratory; Hendricks, John S. [Los Alamos National Laboratory; Goorley, John T. [Los Alamos National Laboratory

    2012-06-19

    The first MCNP based inline Monte Carlo depletion capability was officially released from the Radiation Safety Information and Computational Center as MCNPX 2.6.0. Both the MCNP5 and MCNPX codes have historically provided a successful combinatorial geometry based, continuous energy, Monte Carlo radiation transport solution for advanced reactor modeling and simulation. However, due to separate development pathways, useful simulation capabilities were dispersed between both codes and not unified in a single technology. MCNP6, the next evolution in the MCNP suite of codes, now combines the capability of both simulation tools, as well as providing new advanced technology, in a single radiation transport code. We describe here the new capabilities of the MCNP6 depletion code dating from the official RSICC release MCNPX 2.6.0, reported previously, to the now current state of MCNP6. NEA/OECD benchmark results are also reported. The MCNP6 depletion capability enhancements beyond MCNPX 2.6.0 reported here include: (1) new performance enhancing parallel architecture that implements both shared and distributed memory constructs; (2) enhanced memory management that maximizes calculation fidelity; and (3) improved burnup physics for better nuclide prediction. MCNP6 depletion enables complete, relatively easy-to-use depletion calculations in a single Monte Carlo code. The enhancements described here help provide a powerful capability as well as dictate a path forward for future development to improve the usefulness of the technology.

  14. Malnutrition-associated liver steatosis and ATP depletion is caused by peroxisomal and mitochondrial dysfunction

    NARCIS (Netherlands)

    van Zutphen, Tim; Ciapaite, Jolita; Bloks, Vincent W.; Ackereley, Cameron; Gerding, Albert; Jurdzinski, Angelika; Allgayer de Moraes, Roberta; Zhang, Ling; Wolters, Justina C; Bischoff, Rainer; Wanders, Ronald J; Houten, Sander M; Bronte-Tinkew, Dana; Shatseva, Tatiana; Lewis, Gary F; Groen, Albert K; Reijngoud, Dirk-Jan; Bakker, Barbara M; Jonker, Johan W; Kim, Peter K; Bandsma, Robert H J

    2016-01-01

    BACKGROUND & AIMS: Severe malnutrition in young children is associated with signs of hepatic dysfunction such as steatosis and hypoalbuminemia, but its etiology is unknown. Peroxisomes and mitochondria play key roles in various hepatic metabolic functions including lipid metabolism and energy produc

  15. Palmitate induces ER calcium depletion and apoptosis in mouse podocytes subsequent to mitochondrial oxidative stress

    OpenAIRE

    Xu, S; Nam, S M; Kim, J-H; Das, R.; Choi, S-K; T.T. Nguyen; Quan, X.; Choi, S. J.; Chung, C H; Lee, E Y; Lee, I-K; Wiederkehr, A; Wollheim, C. B.; Cha, S-K; Park, K-S.

    2015-01-01

    Pathologic alterations in podocytes lead to failure of an essential component of the glomerular filtration barrier and proteinuria in chronic kidney diseases. Elevated levels of saturated free fatty acid (FFA) are harmful to various tissues, implemented in the progression of diabetes and its complications such as proteinuria in diabetic nephropathy. Here, we investigated the molecular mechanism of palmitate cytotoxicity in cultured mouse podocytes. Incubation with palmitate dose-dependently i...

  16. Biochemical diagnosis of mitochondrial disorders

    NARCIS (Netherlands)

    Rodenburg, R.J.T.

    2011-01-01

    Establishing a diagnosis in patients with a suspected mitochondrial disorder is often a challenge. Both knowledge of the clinical spectrum of mitochondrial disorders and the number of identified disease-causing molecular genetic defects are continuously expanding. The diagnostic examination of patie

  17. Muscle regeneration in mitochondrial myopathies

    DEFF Research Database (Denmark)

    Krag, T O; Hauerslev, S; Jeppesen, T D;

    2013-01-01

    Mitochondrial myopathies cover a diverse group of disorders in which ragged red and COX-negative fibers are common findings on muscle morphology. In contrast, muscle degeneration and regeneration, typically found in muscular dystrophies, are not considered characteristic features of mitochondrial...

  18. The modality effect of ego depletion: Auditory task modality reduces ego depletion.

    Science.gov (United States)

    Li, Qiong; Wang, Zhenhong

    2016-08-01

    An initial act of self-control that impairs subsequent acts of self-control is called ego depletion. The ego depletion phenomenon has been observed consistently. The modality effect refers to the effect of the presentation modality on the processing of stimuli. The modality effect was also robustly found in a large body of research. However, no study to date has examined the modality effects of ego depletion. This issue was addressed in the current study. In Experiment 1, after all participants completed a handgrip task, one group's participants completed a visual attention regulation task and the other group's participants completed an auditory attention regulation task, and then all participants again completed a handgrip task. The ego depletion phenomenon was observed in both the visual and the auditory attention regulation task. Moreover, participants who completed the visual task performed worse on the handgrip task than participants who completed the auditory task, which indicated that there was high ego depletion in the visual task condition. In Experiment 2, participants completed an initial task that either did or did not deplete self-control resources, and then they completed a second visual or auditory attention control task. The results indicated that depleted participants performed better on the auditory attention control task than the visual attention control task. These findings suggest that altering task modality may reduce ego depletion. PMID:27241617

  19. The modality effect of ego depletion: Auditory task modality reduces ego depletion.

    Science.gov (United States)

    Li, Qiong; Wang, Zhenhong

    2016-08-01

    An initial act of self-control that impairs subsequent acts of self-control is called ego depletion. The ego depletion phenomenon has been observed consistently. The modality effect refers to the effect of the presentation modality on the processing of stimuli. The modality effect was also robustly found in a large body of research. However, no study to date has examined the modality effects of ego depletion. This issue was addressed in the current study. In Experiment 1, after all participants completed a handgrip task, one group's participants completed a visual attention regulation task and the other group's participants completed an auditory attention regulation task, and then all participants again completed a handgrip task. The ego depletion phenomenon was observed in both the visual and the auditory attention regulation task. Moreover, participants who completed the visual task performed worse on the handgrip task than participants who completed the auditory task, which indicated that there was high ego depletion in the visual task condition. In Experiment 2, participants completed an initial task that either did or did not deplete self-control resources, and then they completed a second visual or auditory attention control task. The results indicated that depleted participants performed better on the auditory attention control task than the visual attention control task. These findings suggest that altering task modality may reduce ego depletion.

  20. Depleted uranium and the Gulf War syndrome

    International Nuclear Information System (INIS)

    Some military personnel involved in the 1991Gulf War have complained of continuing stress-like symptoms for which no obvious cause has been found. These symptoms have at times been attributed to the use of depleted uranium (DU) in shell casings which are believed to have caused toxic effects. Depleted uranium is natural uranium which is depleted in the rarer U-235 isotope. It is a heavy metal and in common with other heavy metals is chemically toxic. It is also slightly radioactive and could give rise to a radiological hazard if dispersed in finely divided form so that it was inhaled. In response to concerns, the possible effects of DU have been extensively studied along with other possible contributors to Gulf War sickness. This article looks at the results of some of the research that has been done on DU. (author)

  1. Ozone depletion and chlorine loading potentials

    Science.gov (United States)

    Pyle, John A.; Wuebbles, Donald J.; Solomon, Susan; Zvenigorodsky, Sergei; Connell, Peter; Ko, Malcolm K. W.; Fisher, Donald A.; Stordal, Frode; Weisenstein, Debra

    1991-01-01

    The recognition of the roles of chlorine and bromine compounds in ozone depletion has led to the regulation or their source gases. Some source gases are expected to be more damaging to the ozone layer than others, so that scientific guidance regarding their relative impacts is needed for regulatory purposes. Parameters used for this purpose include the steady-state and time-dependent chlorine loading potential (CLP) and the ozone depletion potential (ODP). Chlorine loading potentials depend upon the estimated value and accuracy of atmospheric lifetimes and are subject to significant (approximately 20-50 percent) uncertainties for many gases. Ozone depletion potentials depend on the same factors, as well as the evaluation of the release of reactive chlorine and bromine from each source gas and corresponding ozone destruction within the stratosphere.

  2. Molten-Salt Depleted-Uranium Reactor

    CERN Document Server

    Dong, Bao-Guo; Gu, Ji-Yuan

    2015-01-01

    The supercritical, reactor core melting and nuclear fuel leaking accidents have troubled fission reactors for decades, and greatly limit their extensive applications. Now these troubles are still open. Here we first show a possible perfect reactor, Molten-Salt Depleted-Uranium Reactor which is no above accident trouble. We found this reactor could be realized in practical applications in terms of all of the scientific principle, principle of operation, technology, and engineering. Our results demonstrate how these reactors can possess and realize extraordinary excellent characteristics, no prompt critical, long-term safe and stable operation with negative feedback, closed uranium-plutonium cycle chain within the vessel, normal operation only with depleted-uranium, and depleted-uranium high burnup in reality, to realize with fission nuclear energy sufficiently satisfying humanity long-term energy resource needs, as well as thoroughly solve the challenges of nuclear criticality safety, uranium resource insuffic...

  3. Plasmonic nanoprobes for stimulated emission depletion microscopy

    CERN Document Server

    Cortes, Emiliano; Sinclair, Hugo G; Guldbrand, Stina; Peveler, William J; Davies, Timothy; Parrinello, Simona; Görlitz, Frederik; Dunsby, Chris; Neil, Mark A A; Sivan, Yonatan; Parkin, Ivan P; French, Paul M; Maier, Stefan A

    2016-01-01

    Plasmonic nanoparticles influence the absorption and emission processes of nearby emitters due to local enhancements of the illuminating radiation and the photonic density of states. Here, we use the plasmon resonance of metal nanoparticles in order to enhance the stimulated depletion of excited molecules for super-resolved microscopy. We demonstrate stimulated emission depletion (STED) microscopy with gold nanorods with a long axis of only 26 nm and a width of 8 nm that provide an enhancement of the resolution compared to fluorescent-only probes without plasmonic components irradiated with the same depletion power. These novel nanoparticle-assisted STED probes represent a ~2x10^3 reduction in probe volume compared to previously used nanoparticles and we demonstrate their application to the first plasmon-assisted STED cellular imaging. We also discuss their current limitations.

  4. In vivo T cell depletion regulates resistance and morbidity in murine schistosomiasis

    Energy Technology Data Exchange (ETDEWEB)

    Phillips, S.M.; Linette, G.P.; Doughty, B.L.; Byram, J.E.; Von Lichtenberg, F.

    1987-08-01

    These studies assessed the roles of subpopulations of T lymphocytes in inducing and modulating resistance to schistosomiasis and thereby influencing subsequent morbidity. C57BL/6 mice were depleted in vivo of Lyt-1+, Lyt-2+, and L3T4+ cells by the daily administration of monoclonal antibodies. The development of protective immunity, induced by exposure to irradiated Schistosoma mansoni cercariae as expressed in depleted animals, was compared to that demonstrated in undepleted, normal, and congenitally athymic C57BL/6 mice. The development of morbidity was determined by spleen weight, portal pressure and reticuloendothelial system activity. The results indicated that depletion of specific subpopulations of T lymphocytes minimally affected the primary development of parasites; however, depletion strongly influenced the development of resistance to the parasite and subsequent morbidity due to infection. Depletion of T lymphocytes by anti-Lyt-1+ or anti-L3T4+ antibody decreased the development of resistance, antibody and delayed-type hypersensitivity directed against schistosome antigens. Morbidity due to disease was increased. Depletion of Lyt-2+ cells produced opposite changes with augmented resistance and reduced morbidity. Congenitally athymic mice developed minimal resistance and morbidity. Moreover, resistance was inversely related to the morbidity shown by a given animal. These studies indicate that the development of protective immunity to S. mansoni cercariae is regulated by discrete subpopulations of T lymphocytes. The feasibility of decreasing morbidity by increasing specific immunologically mediated resistance is suggested.

  5. Administrative Reform

    OpenAIRE

    Beh, LooSee

    2007-01-01

    This paper seeks to develop an understanding of the issues that public administrators should strive to provide in ethical practices and governance thus allowing distinctive administrative and social traditions that each country possess to flourish. Significant changes and continuities in the realm of government in contemporary China and Malaysia will be drawn upon. Recent developments have brought a sense of urgency in contrast to complacency with the status quo. This paper reviews pertinent ...

  6. Offentlig administration

    DEFF Research Database (Denmark)

    Nielsen, Elof Nellemann; Rehr, Preben René

    En undervisningsbog der henvender sig til administrationsbacheloruddannelsen. Kapitlerne er inddelt efter modulerne på uddannelsen og indeholder derfor elementer af administration, forvaltning, økonomistyring, innovation, samfundsvidenskabelige metoder og politisk styrede organisationer.......En undervisningsbog der henvender sig til administrationsbacheloruddannelsen. Kapitlerne er inddelt efter modulerne på uddannelsen og indeholder derfor elementer af administration, forvaltning, økonomistyring, innovation, samfundsvidenskabelige metoder og politisk styrede organisationer....

  7. SAT administrator

    International Nuclear Information System (INIS)

    SAT Administrator is the Information System for Nuclear Power Plant Personnel Training Program Design. It supports the design of training programs in the following phases: job analysis; task analysis; competency analysis; task competency association; definition of learning objectives to competencies; training program design; definition of test items. The general structure of the database and management software supports application of the SAT Administrator in any nuclear power installation

  8. Department of Energy depleted uranium recycle

    International Nuclear Information System (INIS)

    With its strategic supply of depleted uranium, the Department of Energy is studying reuse of the material in nuclear radiation shields, military hardware, and commercial applications. the study is expected to warrant a more detailed uranium recycle plan which would include consideration of a demonstration program and a program implementation decision. Such a program, if implemented, would become the largest nuclear material recycle program in the history of the Department of Energy. The bulk of the current inventory of depleted uranium is stored in 14-ton cylinders in the form of solid uranium hexafluoride (UF6). The radioactive 235U content has been reduced to a concentration of 0.2% to 0.4%. Present estimates indicate there are about 55,000 UF6-filled cylinders in inventory and planned operations will provide another 2,500 cylinders of depleted uranium each year. The United States government, under the auspices of the Department of Energy, considers the depleted uranium a highly-refined strategic resource of significant value. A possible utilization of a large portion of the depleted uranium inventory is as radiation shielding for spent reactor fuels and high-level radioactive waste. To this end, the Department of Energy study to-date has included a preliminary technical review to ascertain DOE chemical forms useful for commercial products. The presentation summarized the information including preliminary cost estimates. The status of commercial uranium processing is discussed. With a shrinking market, the number of chemical conversion and fabrication plants is reduced; however, the commercial capability does exist for chemical conversion of the UF6 to the metal form and for the fabrication of uranium radiation shields and other uranium products. Department of Energy facilities no longer possess a capability for depleted uranium chemical conversion

  9. Gammaspectrometric determination of depleted uranium in soil

    International Nuclear Information System (INIS)

    Full text: Three years of monitoring the content of natural radionuclides as well as radionuclides of artificial origin in all samples in the south part of the Republic of Serbia and Montenegro indicated that there was widespread, low-level contamination by depleted uranium at this region. High activity of depleted uranium was found in the soil samples taken at the points where the penetrators were found. We used high resolution gamma spectrometry measurements, because of their simplicity and accuracy. Aims of the control were to asses the increase of radioactivity above the natural levels in the immediate and near vicinity of the bomb craters, to asses the corresponding effect of changed natural radioactivity on the health of the population living in these places and finding unexploded depleted uranium bullets. The collected soil samples were cleaned of plants and stones, dried at 105 deg. C - 110 deg. C till constant weight for 24-48 h. After this, the samples were ground, sieved, and measure in cylindrical geometry. Gamma activity was determined by gamma spectrometry measurements using HP Ge detector (ORTEC), with relative efficiency of 25% and energy resolution of 1.85 keV (1332.5 keV 60Co). The analyser system conducts a peak search, energy assignment, quantification and nuclide identification in acquired spectra. Time of measurement varied from 60000 s to 250000 s. Depleted uranium was found in the soil samples from Vranje region and cape Arza (Montenegro). There are four fenced areas in Vranje region (Pljackovica, Bratoselce, Borovac and Reljan) and one in the Montenegro (cape Arza) where we have found depleted uranium penetrators. The 238U and 235U specific activities and their isotopic composition correspond to depleted uranium (238U/235U ratio from 35 to 77). (author)

  10. Review of clinical trials for mitochondrial disorders: 1997-2012.

    Science.gov (United States)

    Kerr, Douglas S

    2013-04-01

    Over the last 15 years, some 16 open and controlled clinical trials for potential treatments of mitochondrial diseases have been reported or are in progress, and are summarized and reviewed herein. These include trials of administering dichloroacetate (an activator of pyruvate dehydrogenase complex), arginine or citrulline (precursors of nitric oxide), coenzyme Q10 (CoQ10; part of the electron transport chain and an antioxidant), idebenone (a synthetic analogue of CoQ10), EPI-743 (a novel oral potent 2-electron redox cycling agent), creatine (a precursor of phosphocreatine), combined administration (of creatine, α-lipoate, and CoQ10), and exercise training (to increase muscle mitochondria). These trials have included patients with various mitochondrial disorders, a selected subcategory of mitochondrial disorders, or specific mitochondrial disorders (Leber hereditary optic neuropathy or mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes). The trial designs have varied from open-label/uncontrolled, open-label/controlled, or double-blind/placebo-controlled/crossover. Primary outcomes have ranged from single, clinically-relevant scores to multiple measures. Eight of these trials have been well-controlled, completed trials. Of these only 1 (treatment with creatine) showed a significant change in primary outcomes, but this was not reproduced in 2 subsequent trials with creatine with different patients. One trial (idebenone treatment of Leber hereditary optic neuropathy) did not show significant improvement in the primary outcome, but there was significant improvement in a subgroup of patients. Despite the paucity of benefits found so far, well-controlled clinical trials are essential building blocks in the continuing search for more effective treatment of mitochondrial disease, and current trials based on information gained from these prior experiences are in progress. Because of difficulties in recruiting sufficient mitochondrial disease patients

  11. The Chemistry and Toxicology of Depleted Uranium

    OpenAIRE

    Katz, Sidney A.

    2014-01-01

    Natural uranium is comprised of three radioactive isotopes: 238U, 235U, and 234U. Depleted uranium (DU) is a byproduct of the processes for the enrichment of the naturally occurring 235U isotope. The world wide stock pile contains some 1½ million tons of depleted uranium. Some of it has been used to dilute weapons grade uranium (~90% 235U) down to reactor grade uranium (~5% 235U), and some of it has been used for heavy tank armor and for the fabrication of armor-piercing bullets and missiles....

  12. Toxicological issues after depleted uranium weapons attacked

    International Nuclear Information System (INIS)

    Depleted Uranium (DU) is a byproduct of the uranium enrichment for producing nuclear reactor or nuclear weapon. DU is used in the military as an armor-piercing projectile due to its hardness, strength, and density. A lot of DU weapons were fired in the Gulf War, and bring about critical environmental and internal contamination. Therefore, DU becomes suddenly a hot issue. Some toxicological problems after DU weapons attacked have been reviewed, which include features of internal DU contamination. Hazard of wound contamination and inhalation with insoluble uranium, and other urgent toxicological issues. The healthy effects of implanted with depleted uranium pellets were illustrated in particular

  13. mtDNA depletion confers specific gene expression profiles in human cells grown in culture and in xenograft

    Directory of Open Access Journals (Sweden)

    Ramaswamy Krishna

    2008-11-01

    Full Text Available Abstract Background Interactions between the gene products encoded by the mitochondrial and nuclear genomes play critical roles in eukaryotic cellular function. However, the effects mitochondrial DNA (mtDNA levels have on the nuclear transcriptome have not been defined under physiological conditions. In order to address this issue, we characterized the gene expression profiles of A549 lung cancer cells and their mtDNA-depleted ρ0 counterparts grown in culture and as tumor xenografts in immune-deficient mice. Results Cultured A549 ρ0 cells were respiration-deficient and showed enhanced levels of transcripts relevant to metal homeostasis, initiation of the epithelial-mesenchymal transition, and glucuronidation pathways. Several well-established HIF-regulated transcripts showed increased or decreased abundance relative to the parental cell line. Furthermore, growth in culture versus xenograft has a significantly greater influence on expression profiles, including transcripts involved in mitochondrial structure and both aerobic and anaerobic energy metabolism. However, both in vitro and in vivo, mtDNA levels explained the majority of the variance observed in the expression of transcripts in glucuronidation, tRNA synthetase, and immune surveillance related pathways. mtDNA levels in A549 xenografts also affected the expression of genes, such as AMACR and PHYH, involved in peroxisomal lipid metabolic pathways. Conclusion We have identified mtDNA-dependent gene expression profiles that are shared in cultured cells and in xenografts. These profiles indicate that mtDNA-depleted cells could provide informative model systems for the testing the efficacy of select classes of therapeutics, such as anti-angiogenesis agents. Furthermore, mtDNA-depleted cells grown culture and in xenografts provide a powerful means to investigate possible relationships between mitochondrial activity and gene expression profiles in normal and pathological cells.

  14. [Cyclosporin A causes oxidative stress and mitochondrial dysfunction in renal tubular cells].

    Science.gov (United States)

    Pérez de Hornedo, J; de Arriba, G; Calvino, M; Benito, S; Parra, T

    2007-01-01

    Reactive oxygen species (ROS) have been implicated in cyclosporin A (CsA) nephrotoxicity. As mitochondria are one of the main sources of ROS in cells, we evaluated the role of CsA in mitochondrial structure and function in LLC-PK1 cells. We incubated cells with CsA 1 microM for 24 hours and studies were performed with flow citometry and confocal microscopy. We studied mitochondrial NAD(P)H content, superoxide anion (O2.-) production (MitoSOX Red), oxidation of cardiolipin of inner mitochondrial membrane (NAO) and mitochondrial membrane potential (DIOC2(3)). Also we analyzed the intracellular ROS synthesis (H2DCF-DA) and reduced glutation (GSH) of cells. Our results showed that CsA decreased NAD(P)H and membrane potential, and increased O2.- in mitochondria. CsA also provoked oxidation of cardiolipin. Furthermore, CsA increased intracellular ROS production and decreased GSH content. These results suggest that CsA has crucial effects in mitochondria. CsA modified mitochondrial physiology through the decrease of antioxidant mitochondrial compounds as NAD(P)H and the dissipation of mitochondrial membrane potential and increase of oxidants as O2.-. Also, CsA alters lipidic structure of inner mitochondrial membrane through the oxidation of cardiolipin. These effects trigger a chain of events that favour intracellular synthesis of ROS and depletion of GSH that can compromise cellular viability. Nephrotoxic cellular effects of CsA can be explained, at least in part, through its influence on mitochondrial functionalism.

  15. Cybrid models of Parkinson's disease show variable mitochondrial biogenesis and genotype-respiration relationships.

    Science.gov (United States)

    Keeney, Paula M; Dunham, Lisa D; Quigley, Caitlin K; Morton, Stephanie L; Bergquist, Kristen E; Bennett, James P

    2009-12-01

    Sporadic Parkinson's disease (sPD) is a nervous system-wide disease that presents with a bradykinetic movement disorder and frequently progresses to include depression and cognitive impairment. Cybrid models of sPD are based on expression of sPD platelet mitochondrial DNA (mtDNA) in neural cells and demonstrate some similarities to sPD brains. In sPD and CTL cybrids we characterized aspects of mitochondrial biogenesis, mtDNA genomics, composition of the respirasome and the relationships among isolated mitochondrial and intact cell respiration. Cybrid mtDNA levels varied and correlated with expression of PGC-1 alpha, a transcriptional co-activator regulator of mitochondrial biogenesis. Levels of mtDNA heteroplasmic mutations were asymmetrically distributed across the mitochondrial genome; numbers of heteroplasmies were more evenly distributed. Neither levels nor numbers of heteroplasmies distinguished sPD from CTL. sPD cybrid mitochondrial ETC subunit protein levels were not altered. Isolated mitochondrial complex I respiration rates showed limited correlation with whole cell complex I respiration rates in both sPD and CTL cybrids. Intact cell respiration during the normoxic-anoxic transition yielded K(m) values for oxygen that directly related to respiration rates in CTL but not in sPD cell lines. Both sPD and CTL cybrid cells are substantially heterogeneous in mitochondrial genomic and physiologic properties. Our results suggest that mtDNA depletion may occur in sPD neurons and could reflect impairment of mitochondrial biogenesis. Cybrids remain a valuable model for some aspects of sPD but their heterogeneity mitigates against a simple designation of sPD phenotype in this cell model.

  16. Cystamine induces AIF-mediated apoptosis through glutathione depletion.

    Science.gov (United States)

    Cho, Sung-Yup; Lee, Jin-Haeng; Ju, Mi-kyeong; Jeong, Eui Man; Kim, Hyo-Jun; Lim, Jisun; Lee, Seungun; Cho, Nam-Hyuk; Park, Hyun Ho; Choi, Kihang; Jeon, Ju-Hong; Kim, In-Gyu

    2015-03-01

    Cystamine and its reduced form cysteamine showed protective effects in various models of neurodegenerative disease, including Huntington's disease and Parkinson's disease. Other lines of evidence demonstrated the cytotoxic effect of cysteamine on duodenal mucosa leading to ulcer development. However, the mechanism for cystamine cytotoxicity remains poorly understood. Here, we report a new pathway in which cystamine induces apoptosis by targeting apoptosis-inducing factor (AIF). By screening of various cell lines, we observed that cystamine and cysteamine induce cell death in a cell type-specific manner. Comparison between cystamine-sensitive and cystamine-resistant cell lines revealed that cystamine cytotoxicity is not associated with unfolded protein response, reactive oxygen species generation and transglutaminase or caspase activity; rather, it is associated with the ability of cystamine to trigger AIF nuclear translocation. In cystamine-sensitive cells, cystamine suppresses the levels of intracellular glutathione by inhibiting γ-glutamylcysteine synthetase expression that triggers AIF translocation. Conversely, glutathione supplementation completely prevents cystamine-induced AIF translocation and apoptosis. In rats, cysteamine administration induces glutathione depletion and AIF translocation leading to apoptosis of duodenal epithelium. These results indicate that AIF translocation through glutathione depletion is the molecular mechanism of cystamine toxicity, and provide important implications for cystamine in the neurodegenerative disease therapeutics as well as in the regulation of AIF-mediated cell death. PMID:25549939

  17. Satellite surveillance of evaporative depletion across the Indus Basin

    Science.gov (United States)

    Bastiaanssen, Wim G. M.; Ahmad, Mobin-Ud-Din; Chemin, Yann

    2002-12-01

    The irrigated Indus Basin in Pakistan has insufficient water resources to supply all its stakeholders. Information on evaporative depletion across the Basin is an important requirement if the water resources are to be managed efficiently. This paper presents the Surface Energy Balance Algorithm for Land (SEBAL) method used to compute actual evapotranspiration for large areas based on public domain National Oceanic and Atmospheric Administration (NOAA) satellite data. Computational procedures for retrieving actual evapotranspiration from satellites have been developed over the last 20 years. The current work is among the first applications used to estimate actual evapotranspiration on an annual scale across a vast river basin system with a minimum of ground data. Only sunshine duration and wind speed are required as input data for the remote sensing flux algorithm. The results were validated in the Indus Basin by comparing results from a field-scale transient moisture flow model, in situ Bowen ratio measurements, and residual water balance analyses for an area of 3 million ha. The accuracy of assessing time-integrated actual annual evapotranspiration varied from 0% to 10% on a field scale to 5% at the regional level. Spatiotemporal information on actual evapotranspiration helps to evaluate water distribution and water use between large irrigation project areas. Wide variations in evaporative depletion between project areas and crop types were found. Satellite-based measurements can provide such information and avoid the need to rely on field databases.

  18. Interaction of TNF with angiotensin II contributes to mitochondrial oxidative stress and cardiac damage in rats.

    Directory of Open Access Journals (Sweden)

    Nithya Mariappan

    Full Text Available Recent evidence suggests that tumor necrosis factor alpha (TNF and angiotensin II (ANGII induce oxidative stress contribute to cardiovascular disease progression. Here, we examined whether an interaction between TNF and ANGII contributes to altered cardiac mitochondrial biogenesis and ATP production to cause cardiac damage in rats. Rats received intraperitoneal injections of TNF (30 µg/kg, TNF + losartan (LOS, 1 mg/kg, or vehicle for 5 days. Left ventricular (LV function was measured using echocardiography. Rats were sacrificed and LV tissues removed for gene expression, electron paramagnetic resonance and mitochondrial assays. TNF administration significantly increased expression of the NADPH oxidase subunit, gp91phox, and the angiotensin type 1 receptor (AT-1R and decreased eNOS in the LV of rats. Rats that received TNF only had increased production rates of superoxide, peroxynitrite and total reactive oxygen species (ROS in the cytosol and increased production rates of superoxide and hydrogen peroxide in mitochondria. Decreased activities of mitochondrial complexes I, II, and III and mitochondrial genes were observed in rats given TNF. In addition, TNF administration also resulted in a decrease in fractional shortening and an increase in Tei index, suggesting diastolic dysfunction. TNF administration with concomitant LOS treatment attenuated mitochondrial damage, restored cardiac function, and decreased expression of AT1-R and NADPH oxidase subunits. Mitochondrial biogenesis and function is severely impaired by TNF as evidenced by downregulation of mitochondrial genes and increased free radical production, and may contribute to cardiac damage. These defects are independent of the downregulation of mitochondrial gene expression, suggesting novel mechanisms for mitochondrial dysfunction in rats given TNF.

  19. Application of backtracking algorithm to depletion calculations

    International Nuclear Information System (INIS)

    Based on the theory of linear chain method for analytical depletion calculations, the burn-up matrix is decoupled by the divide and conquer strategy and the linear chain with Markov characteristic is formed. The density, activity and decay heat of every nuclide in the chain can be calculated by analytical solutions. Every possible reaction path of the nuclide must be considered during the linear chain establishment process. To confirm the calculation precision and efficiency, the algorithm which can cover all the reaction paths of the nuclide and search the paths automatically according to to problem description and precision restrictions should be sought. Through analysis and comparison of several kinds of searching algorithms, the backtracking algorithm was selected to search and calculate the linear chains using Depth First Search (DFS) method. The depletion program can solve the depletion problem adaptively and with high fidelity. The solution space and time complexity of the program were analyzed. The new developed depletion program was coupled with Monte Carlo program MCMG-II to calculate the benchmark burn-up problem of the first core of China Experimental Fast Reactor (CEFR). The initial verification and validation of the program was performed by the calculation. (author)

  20. Global Warming: Lessons from Ozone Depletion

    Science.gov (United States)

    Hobson, Art

    2010-01-01

    My teaching and textbook have always covered many physics-related social issues, including stratospheric ozone depletion and global warming. The ozone saga is an inspiring good-news story that's instructive for solving the similar but bigger problem of global warming. Thus, as soon as students in my physics literacy course at the University of…

  1. Mitochondrial dysfunction in heart failure.

    Science.gov (United States)

    Rosca, Mariana G; Hoppel, Charles L

    2013-09-01

    Heart failure (HF) is a complex chronic clinical syndrome. Energy deficit is considered to be a key contributor to the development of both cardiac and skeletal myopathy. In HF, several components of cardiac and skeletal muscle bioenergetics are altered, such as oxygen availability, substrate oxidation, mitochondrial ATP production, and ATP transfer to the contractile apparatus via the creatine kinase shuttle. This review focuses on alterations in mitochondrial biogenesis and respirasome organization, substrate oxidation coupled with ATP synthesis in the context of their contribution to the chronic energy deficit, and mechanical dysfunction of the cardiac and skeletal muscle in HF. We conclude that HF is associated with decreased mitochondrial biogenesis and function in both heart and skeletal muscle, supporting the concept of a systemic mitochondrial cytopathy. The sites of mitochondrial defects are located within the electron transport and phosphorylation apparatus and differ with the etiology and progression of HF in the two mitochondrial populations (subsarcolemmal and interfibrillar) of cardiac and skeletal muscle. The roles of adrenergic stimulation, the renin-angiotensin system, and cytokines are evaluated as factors responsible for the systemic energy deficit. We propose a cyclic AMP-mediated mechanism by which increased adrenergic stimulation contributes to the mitochondrial dysfunction.

  2. Administrative Reform

    DEFF Research Database (Denmark)

    Plum, Maja

    Through the example of a Danish reform of educational plans in early childhood education, the paper critically addresses administrative educational reforms promoting accountability, visibility and documentation. Drawing on Foucaultian perspectives, the relation between knowledge and governing...... of administrative technology, tracing how the humanistic values of education embed and are embedded within ‘the professional nursery teacher' as an object and subject of administrative practice. Rather than undermining the humanistic potential of education, it is argued that the technology of accounting......, implied in the reform, is analysed as a technology of accounting. A technology producing ‘the professional nursery teacher' as a reflective daily researcher, who outlives her pedagogical desire as an analytical care of the optimisation of ‘the learning child'. Thus, the paper analyses the micro physics...

  3. Lophotrochozoan mitochondrial genomes

    Energy Technology Data Exchange (ETDEWEB)

    Valles, Yvonne; Boore, Jeffrey L.

    2005-10-01

    Progress in both molecular techniques and phylogeneticmethods has challenged many of the interpretations of traditionaltaxonomy. One example is in the recognition of the animal superphylumLophotrochozoa (annelids, mollusks, echiurans, platyhelminthes,brachiopods, and other phyla), although the relationships within thisgroup and the inclusion of some phyla remain uncertain. While much ofthis progress in phylogenetic reconstruction has been based on comparingsingle gene sequences, we are beginning to see the potential of comparinglarge-scale features of genomes, such as the relative order of genes.Even though tremendous progress is being made on the sequencedetermination of whole nuclear genomes, the dataset of choice forgenome-level characters for many animals across a broad taxonomic rangeremains mitochondrial genomes. We review here what is known aboutmitochondrial genomes of the lophotrochozoans and discuss the promisethat this dataset will enable insight into theirrelationships.

  4. Respiratory active mitochondrial supercomplexes.

    Science.gov (United States)

    Acín-Pérez, Rebeca; Fernández-Silva, Patricio; Peleato, Maria Luisa; Pérez-Martos, Acisclo; Enriquez, Jose Antonio

    2008-11-21

    The structural organization of the mitochondrial respiratory complexes as four big independently moving entities connected by the mobile carriers CoQ and cytochrome c has been challenged recently. Blue native gel electrophoresis reveals the presence of high-molecular-weight bands containing several respiratory complexes and suggesting an in vivo assembly status of these structures (respirasomes). However, no functional evidence of the activity of supercomplexes as true respirasomes has been provided yet. We have observed that (1) supercomplexes are not formed when one of their component complexes is absent; (2) there is a temporal gap between the formation of the individual complexes and that of the supercomplexes; (3) some putative respirasomes contain CoQ and cytochrome c; (4) isolated respirasomes can transfer electrons from NADH to O(2), that is, they respire. Therefore, we have demonstrated the existence of a functional respirasome and propose a structural organization model that accommodates these findings.

  5. How Depleted is the MORB mantle?

    Science.gov (United States)

    Hofmann, A. W.; Hart, S. R.

    2015-12-01

    Knowledge of the degree of mantle depletion of highly incompatible elements is critically important for assessing Earth's internal heat production and Urey number. Current views of the degree of MORB source depletion are dominated by Salters and Stracke (2004), and Workman and Hart (2005). The first is based on an assessment of average MORB compositions, whereas the second considers trace element data of oceanic peridotites. Both require an independent determination of one absolute concentration, Lu (Salters & Stracke), or Nd (Workman & Hart). Both use parent-daughter ratios Lu/Hf, Sm/Nd, and Rb/Sr calculated from MORB isotopes combined with continental-crust extraction models, as well as "canonical" trace element ratios, to boot-strap the full range of trace element abundances. We show that the single most important factor in determining the ultimate degree of incompatible element depletion in the MORB source lies in the assumptions about the timing of continent extraction, exemplified by continuous extraction versus simple two-stage models. Continued crust extraction generates additional, recent mantle depletion, without affecting the isotopic composition of the residual mantle significantly. Previous emphasis on chemical compositions of MORB and/or peridotites has tended to obscure this. We will explore the effect of different continent extraction models on the degree of U, Th, and K depletion in the MORB source. Given the uncertainties of the two most popular models, the uncertainties of U and Th in DMM are at least ±50%, and this impacts the constraints on the terrestrial Urey ratio. Salters, F.J.M. and Stracke, A., 2004, Geochem. Geophys. Geosyst. 5, Q05004. Workman, R.K. and Hart, S.R., 2005, EPSL 231, 53-72.

  6. A role for mitochondrial phosphoenolpyruvate carboxykinase (PEPCK-M) in the regulation of hepatic gluconeogenesis.

    Science.gov (United States)

    Stark, Romana; Guebre-Egziabher, Fitsum; Zhao, Xiaojian; Feriod, Colleen; Dong, Jianying; Alves, Tiago C; Ioja, Simona; Pongratz, Rebecca L; Bhanot, Sanjay; Roden, Michael; Cline, Gary W; Shulman, Gerald I; Kibbey, Richard G

    2014-03-14

    Synthesis of phosphoenolpyruvate (PEP) from oxaloacetate is an absolute requirement for gluconeogenesis from mitochondrial substrates. Generally, this reaction has solely been attributed to the cytosolic isoform of PEPCK (PEPCK-C), although loss of the mitochondrial isoform (PEPCK-M) has never been assessed. Despite catalyzing the same reaction, to date the only significant role reported in mammals for the mitochondrial isoform is as a glucose sensor necessary for insulin secretion. We hypothesized that this nutrient-sensing mitochondrial GTP-dependent pathway contributes importantly to gluconeogenesis. PEPCK-M was acutely silenced in gluconeogenic tissues of rats using antisense oligonucleotides both in vivo and in isolated hepatocytes. Silencing PEPCK-M lowers plasma glucose, insulin, and triglycerides, reduces white adipose, and depletes hepatic glycogen, but raises lactate. There is a switch of gluconeogenic substrate preference to glycerol that quantitatively accounts for a third of glucose production. In contrast to the severe mitochondrial deficiency characteristic of PEPCK-C knock-out livers, hepatocytes from PEPCK-M-deficient livers maintained normal oxidative function. Consistent with its predicted role, gluconeogenesis rates from hepatocytes lacking PEPCK-M are severely reduced for lactate, alanine, and glutamine, but not for pyruvate and glycerol. Thus, PEPCK-M has a direct role in fasted and fed glucose homeostasis, and this mitochondrial GTP-dependent pathway should be reconsidered for its involvement in both normal and diabetic metabolism. PMID:24497630

  7. Mitochondrial oxidative stress and dysfunction induced by isoniazid: study on isolated rat liver and brain mitochondria.

    Science.gov (United States)

    Ahadpour, Morteza; Eskandari, Mohammad Reza; Mashayekhi, Vida; Haj Mohammad Ebrahim Tehrani, Kamaleddin; Jafarian, Iman; Naserzadeh, Parvaneh; Hosseini, Mir-Jamal

    2016-01-01

    Isoniazid (INH or isonicotinic hydrazide) is used for the treatment and prophylaxis of tuberculosis. Liver and brain are two important target organs in INH toxicity. However, the exact mechanisms behind the INH hepatotoxicity or neurotoxicity have not yet been completely understood. Considering the mitochondria as one of the possible molecular targets for INH toxicity, the aim of this study was to evaluate the mechanisms of INH mitochondrial toxicity on isolated mitochondria. Mitochondria were isolated by differential ultracentrifugation from male Sprague-Dawley rats and incubated with different concentrations of INH (25-2000 μM) for the investigation of mitochondrial parameters. The results indicated that INH could interact with mitochondrial respiratory chain and inhibit its activity. Our results showed an elevation in mitochondrial reactive oxygen species (ROS) formation, lipid peroxidation and mitochondrial membrane potential collapse after exposure of isolated liver mitochondria in INH. However, different results were obtained in brain mitochondria. Noteworthy, significant glutathione oxidation, adenosine triphosphate (ATP) depletion and lipid peroxidation were observed in higher concentration of INH, as compared to liver mitochondria. In conclusion, our results suggest that INH may initiate its toxicity in liver mitochondria through interaction with electron transfer chain, lipid peroxidation, mitochondrial membrane potential decline and cytochrome c expulsion which ultimately lead to cell death signaling.

  8. The potato tuber mitochondrial proteome

    DEFF Research Database (Denmark)

    Møller, Ian Max; Salvato, Fernanda; Havelund, Jesper;

    We are testing the hypothesis that oxidized peptides are released from stressed mitochondria and contribute to retrograde signalling (Møller IM & Sweetlove LJ 2010 Trends Plant Sci 15, 370-374). However, there is a large gap between the number of experimentally verified mitochondrial proteins (~450......) and in silico-predicted mitochondrial proteins (2000-3000). Thus, before starting to look for oxidized peptides, we wanted to expand the current compendium of plant mitochondrial proteins while obtaining what could be termed the "baseline proteome" from our model organelle, the potato tuber mitochondrion. Its...

  9. The Protection of Polysaccharide from the Brown Seaweed Sargassum graminifolium against Ethylene Glycol-Induced Mitochondrial Damage

    Directory of Open Access Journals (Sweden)

    Wen-Hui Wu

    2013-03-01

    Full Text Available The aim of the present study is to evaluate the protective effect of polysaccharide from the Brown Seaweed Sargassum graminifolium (SGP on ethylene glycol-induced kidney damage and the mechanism of SGP-mediated protection. Mitochondrial lipid peroxidation, mitochondrial swelling, the activity of succinate dehydrogenase (SDH, ATPases and mitochondrial antioxidant enzymes was observed in hyperoxaluric rats. Administration of SGP (25, 100 and 400 mg·kg−1, intragastrically increased the activities of antioxidant enzymes, SDH and Na+/K+-ATPases, Ca2+-ATPases, Mg2+-ATPases, also decreased mitochondrial lipid peroxidation and mitochondrial swelling. SGP exhibited a protective effect by improving antioxidant enzymes and restoring mitochondrial dysfunction in the kidney of hyperoxaluric rats. It may be used as a promising therapeutic agent to provide superior renal protection.

  10. Mitochondrial Stress: A Bridge between Mitochondrial Dysfunction and Metabolic Diseases?

    OpenAIRE

    Hu, Fang; Liu, Feng

    2011-01-01

    Under pathophysiological conditions such as obesity, excessive oxidation of nutrients may induce mitochondrial stress, leading to mitochondrial unfolded protein response (UPRmt) and initiation of a retrograde stress signaling pathway. Defects in the UPRmt and the retrograde signaling pathways may disrupt the integrity and homeostasis of the mitochondria, resulting endoplasmic reticulum stress and insulin resistance. Improving the capacity of mitochondria to reduce stress may be an effective a...

  11. Effect of β-alanine treatment on mitochondrial taurine level and 5-taurinomethyluridine content

    OpenAIRE

    Jong Chian; Ito Takashi; Mozaffari Mahmood; Azuma Junichi; Schaffer Stephen

    2010-01-01

    Abstract Background The β-amino acid, taurine, is a nutritional requirement in some species. In these species, the depletion of intracellular stores of taurine leads to the development of severe organ dysfunction. The basis underlying these defects is poorly understood, although there is some suggestion that oxidative stress may contribute to the abnormalities. Recent studies indicate that taurine is required for normal mitochondrial protein synthesis and normal electron transport chain activ...

  12. Increased uncoupling protein 3 content does not affect mitochondrial function in human skeletal muscle in vivo

    OpenAIRE

    Hesselink, M.K.C.; Greenhaff, P L; Constantin-Teodosu, D.; Hultman, E; Saris, W. H. M.; Nieuwlaat, R.; Schaart, G.; Kornips, C.F.P.; P. Schrauwen

    2003-01-01

    Phosphocreatine (PCr) resynthesis rate following intense anoxic contraction can be used as a sensitive index of in vivo mitochondrial function. We examined the effect of a diet-induced increase in uncoupling protein 3 (UCP3) expression on postexercise PCr resynthesis in skeletal muscle. Nine healthy male volunteers undertook 20 one-legged maximal voluntary contractions with limb blood flow occluded to deplete muscle PCr stores. Exercise was performed following 7 days consumption of low-fat (L...

  13. Database Administrator

    Science.gov (United States)

    Moore, Pam

    2010-01-01

    The Internet and electronic commerce (e-commerce) generate lots of data. Data must be stored, organized, and managed. Database administrators, or DBAs, work with database software to find ways to do this. They identify user needs, set up computer databases, and test systems. They ensure that systems perform as they should and add people to the…

  14. Administrative IT

    Science.gov (United States)

    Grayson, Katherine, Ed.

    2006-01-01

    When it comes to Administrative IT solutions and processes, best practices range across the spectrum. Enterprise resource planning (ERP), student information systems (SIS), and tech support are prominent and continuing areas of focus. But widespread change can also be accomplished via the implementation of campuswide document imaging and sharing,…

  15. Translating the basic knowledge of mitochondrial functions to metabolic therapy: role of L-carnitine.

    Science.gov (United States)

    Marcovina, Santica M; Sirtori, Cesare; Peracino, Andrea; Gheorghiade, Mihai; Borum, Peggy; Remuzzi, Giuseppe; Ardehali, Hossein

    2013-02-01

    Mitochondria play important roles in human physiological processes, and therefore, their dysfunction can lead to a constellation of metabolic and nonmetabolic abnormalities such as a defect in mitochondrial gene expression, imbalance in fuel and energy homeostasis, impairment in oxidative phosphorylation, enhancement of insulin resistance, and abnormalities in fatty acid metabolism. As a consequence, mitochondrial dysfunction contributes to the pathophysiology of insulin resistance, obesity, diabetes, vascular disease, and chronic heart failure. The increased knowledge on mitochondria and their role in cellular metabolism is providing new evidence that these disorders may benefit from mitochondrial-targeted therapies. We review the current knowledge of the contribution of mitochondrial dysfunction to chronic diseases, the outcomes of experimental studies on mitochondrial-targeted therapies, and explore the potential of metabolic modulators in the treatment of selected chronic conditions. As an example of such modulators, we evaluate the efficacy of the administration of L-carnitine and its analogues acetyl and propionyl L-carnitine in several chronic diseases. L-carnitine is intrinsically involved in mitochondrial metabolism and function as it plays a key role in fatty acid oxidation and energy metabolism. In addition to the transportation of free fatty acids across the inner mitochondrial membrane, L-carnitine modulates their oxidation rate and is involved in the regulation of vital cellular functions such as apoptosis. Thus, L-carnitine and its derivatives show promise in the treatment of chronic conditions and diseases associated with mitochondrial dysfunction but further translational studies are needed to fully explore their potential. PMID:23138103

  16. A worldwide view of groundwater depletion

    Science.gov (United States)

    van Beek, L. P.; Wada, Y.; van Kempen, C.; Reckman, J. W.; Vasak, S.; Bierkens, M. F.

    2010-12-01

    During the last decades, global water demand has increased two-fold due to increasing population, expanding irrigated area and economic development. Globally such demand can be met by surface water availability (i.e., water in rivers, lakes and reservoirs) but regional variations are large and the absence of sufficient rainfall and run-off increasingly encourages the use of groundwater resources, particularly in the (semi-)arid regions of the world. Excessive abstraction for irrigation frequently leads to overexploitation, i.e. if groundwater abstraction exceeds the natural groundwater recharge over extensive areas and prolonged times, persistent groundwater depletion may occur. Observations and various regional studies have revealed that groundwater depletion is a substantial issue in regions such as Northwest India, Northeast Pakistan, Central USA, Northeast China and Iran. Here we provide a global overview of groundwater depletion from the year 1960 to 2000 at a spatial resolution of 0.5 degree by assessing groundwater recharge with the global hydrological model PCR-GLOBWB and subtracting estimates of groundwater abstraction obtained from IGRAC-GGIS database. PCR-GLOBWB was forced by the CRU climate dataset downscaled to daily time steps using ERA40 re-analysis data. PCR-GLOBWB simulates daily global groundwater recharge (0.5 degree) while considering sub-grid variability of each grid cell (e.g., short and tall vegetation, different soil types, fraction of saturated soil). Country statistics of groundwater abstraction were downscaled to 0.5 degree by using water demand (i.e., agriculture, industry and domestic) as a proxy. To limit problems related to increased capture of discharge and increased recharge due to groundwater pumping, we restricted our analysis to sub-humid to arid areas. The uncertainty in the resulting estimates was assessed by a Monte Carlo analysis of 100 realizations of groundwater recharge and 100 realizations of groundwater abstraction

  17. Health and environmental impact of depleted uranium

    International Nuclear Information System (INIS)

    Depleted Uranium (DU) is 'nuclear waste' produced from the enrichment process and is mostly made up of 238U and is depleted in the fissionable isotope 235U compared to natural uranium (NU). Depleted uranium has about 60% of the radioactivity of natural uranium. Depleted uranium and natural uranium are identical in terms of the chemical toxicity. Uranium's high density gives depleted uranium shells increased range and penetrative power. This density, combined with uranium's pyrophoric nature, results in a high-energy kinetic weapon that can punch and burn through armour plating. Striking a hard target, depleted uranium munitions create extremely high temperatures. The uranium immediately burns and vaporizes into an aerosol, which is easily diffused in the environment. People can inhale the micro-particles of uranium oxide in an aerosol and absorb them mainly from lung. Depleted uranium has both aspects of radiological toxicity and chemical toxicity. The possible synergistic effect of both kinds of toxicities is also pointed out. Animal and cellular studies have been reported the carcinogenic, neurotoxic, immuno-toxic and some other effects of depleted uranium including the damage on reproductive system and foetus. In addition, the health effects of micro/ nano-particles, similar in size of depleted uranium aerosols produced by uranium weapons, have been reported. Aerosolized DU dust can easily spread over the battlefield spreading over civilian areas, sometimes even crossing international borders. Therefore, not only the military personnel but also the civilians can be exposed. The contamination continues after the cessation of hostilities. Taking these aspects into account, DU weapon is illegal under international humanitarian laws and is considered as one of the inhumane weapons of 'indiscriminate destruction'. The international society is now discussing the prohibition of DU weapons based on 'precautionary principle'. The 1991 Gulf War is reportedly the first

  18. Role of mitochondrial function in cell death and body metabolism.

    Science.gov (United States)

    Lee, Myung-Shik

    2016-01-01

    Mitochondria are the key players in apoptosis and necrosis. Mitochondrial DNA (mtDNA)-depleted r0 cells were resistant to diverse apoptosis inducers such as TNF-alpha, TNFSF10, staurosporine and p53. Apoptosis resistance was accompanied by the absence of mitochondrial potential loss or cytochrome c translocation. r0 cells were also resistant to necrosis induced by reactive oxygen species (ROS) donors due to upregulation of antioxidant enzymes such as manganese superoxide dismutase. Mitochondria also has a close relationship with autophagy that plays a critical role in the turnover of senescent organelles or dysfunctional proteins and may be included in 'cell death' category. It was demonstrated that autophagy deficiency in insulin target tissues such as skeletal muscle induces mitochondrial stress response, which leads to the induction of FGF21 as a 'mitokine' and affects the whole body metabolism. These results show that mitochondria are not simply the power plants of cells generating ATP, but are closely related to several types of cell death and autophagy. Mitochondria affect various pathophysiological events related to diverse disorders such as cancer, metabolic disorders and aging. PMID:27100503

  19. The hexameric structure of the human mitochondrial replicative helicase Twinkle

    Science.gov (United States)

    Fernández-Millán, Pablo; Lázaro, Melisa; Cansız-Arda, Şirin; Gerhold, Joachim M.; Rajala, Nina; Schmitz, Claus-A.; Silva-Espiña, Cristina; Gil, David; Bernadó, Pau; Valle, Mikel; Spelbrink, Johannes N.; Solà, Maria

    2015-01-01

    The mitochondrial replicative helicase Twinkle is involved in strand separation at the replication fork of mitochondrial DNA (mtDNA). Twinkle malfunction is associated with rare diseases that include late onset mitochondrial myopathies, neuromuscular disorders and fatal infantile mtDNA depletion syndrome. We examined its 3D structure by electron microscopy (EM) and small angle X-ray scattering (SAXS) and built the corresponding atomic models, which gave insight into the first molecular architecture of a full-length SF4 helicase that includes an N-terminal zinc-binding domain (ZBD), an intermediate RNA polymerase domain (RPD) and a RecA-like hexamerization C-terminal domain (CTD). The EM model of Twinkle reveals a hexameric two-layered ring comprising the ZBDs and RPDs in one layer and the CTDs in another. In the hexamer, contacts in trans with adjacent subunits occur between ZBDs and RPDs, and between RPDs and CTDs. The ZBDs show important structural heterogeneity. In solution, the scattering data are compatible with a mixture of extended hexa- and heptameric models in variable conformations. Overall, our structural data show a complex network of dynamic interactions that reconciles with the structural flexibility required for helicase activity. PMID:25824949

  20. Genetic counseling in mitochondrial disease.

    Science.gov (United States)

    Vento, Jodie M; Pappa, Belen

    2013-04-01

    Mitochondrial diseases are a genetically and clinically diverse group of disorders that arise as a result of dysfunction of the mitochondria. Mitochondrial disorders can be caused by alterations in nuclear DNA and/or mitochondrial DNA. Although some mitochondrial syndromes have been described clearly in the literature many others present as challenging clinical cases with multisystemic involvement at variable ages of onset. Given the clinical variability and genetic heterogeneity of these conditions, patients and their families often experience a lengthy and complicated diagnostic process. The diagnostic journey may be characterized by heightened levels of uncertainty due to the delayed diagnosis and the absence of a clear prognosis, among other factors. Uncertainty surrounding issues of family planning and genetic testing may also affect the patient. The role of the genetic counselor is particularly important to help explain these complexities and support the patient and family's ability to achieve effective coping strategies in dealing with increased levels of uncertainty.

  1. Bioenergetic roles of mitochondrial fusion.

    Science.gov (United States)

    Silva Ramos, Eduardo; Larsson, Nils-Göran; Mourier, Arnaud

    2016-08-01

    Mitochondria are bioenergetic hotspots, producing the bulk of ATP by the oxidative phosphorylation process. Mitochondria are also structurally dynamic and undergo coordinated fusion and fission to maintain their function. Recent studies of the mitochondrial fusion machinery have provided new evidence in detailing their role in mitochondrial metabolism. Remarkably, mitofusin 2, in addition to its role in fusion, is important for maintaining coenzyme Q levels and may be an integral player in the mevalonate synthesis pathway. Here, we review the bioenergetic roles of mitochondrial dynamics and emphasize the importance of the in vitro growth conditions when evaluating mitochondrial respiration. This article is part of a Special Issue entitled 'EBEC 2016: 19th European Bioenergetics Conference, Riva del Garda, Italy, July 2-6, 2016,' edited by Prof. Paolo Bernardi. PMID:27060252

  2. The assembly of mitochondrial complex I : a product of nuclear-mitochondrial synergy

    NARCIS (Netherlands)

    Vogel, Rutger Oscar

    2007-01-01

    Mitochondria are essential to cellular energy production. Embedded in the mitochondrial inner membrane, the engine of the mitochondrial powerhouse is formed by the five enzymatic complexes of the oxidative phosphorylation (OXPHOS) system. Dysfunction of this system results in mitochondrial disease,

  3. Mitochondrial dysfunction and organophosphorus compounds

    Energy Technology Data Exchange (ETDEWEB)

    Karami-Mohajeri, Somayyeh [Department of Toxicology and Pharmacology, Faculty of Pharmacy, and Pharmaceutical Sciences Research Center, Tehran University of Medical Sciences, Tehran (Iran, Islamic Republic of); Department of Toxicology and Pharmacology, Faculty of Pharmacy, and Pharmaceutical Sciences Research Center, Kerman University of Medical Sciences, Kerman (Iran, Islamic Republic of); Abdollahi, Mohammad, E-mail: Mohammad.Abdollahi@UToronto.Ca [Department of Toxicology and Pharmacology, Faculty of Pharmacy, and Pharmaceutical Sciences Research Center, Tehran University of Medical Sciences, Tehran (Iran, Islamic Republic of)

    2013-07-01

    Organophosphorous (OPs) pesticides are the most widely used pesticides in the agriculture and home. However, many acute or chronic poisoning reports about OPs have been published in the recent years. Mitochondria as a site of cellular oxygen consumption and energy production can be a target for OPs poisoning as a non-cholinergic mechanism of toxicity of OPs. In the present review, we have reviewed and criticized all the evidences about the mitochondrial dysfunctions as a mechanism of toxicity of OPs. For this purpose, all biochemical, molecular, and morphological data were retrieved from various studies. Some toxicities of OPs are arisen from dysfunction of mitochondrial oxidative phosphorylation through alteration of complexes I, II, III, IV and V activities and disruption of mitochondrial membrane. Reductions of adenosine triphosphate (ATP) synthesis or induction of its hydrolysis can impair the cellular energy. The OPs disrupt cellular and mitochondrial antioxidant defense, reactive oxygen species generation, and calcium uptake and promote oxidative and genotoxic damage triggering cell death via cytochrome C released from mitochondria and consequent activation of caspases. The mitochondrial dysfunction induced by OPs can be restored by use of antioxidants such as vitamin E and C, alpha-tocopherol, electron donors, and through increasing the cytosolic ATP level. However, to elucidate many aspect of mitochondrial toxicity of Ops, further studies should be performed. - Highlights: • As a non-cholinergic mechanism of toxicity, mitochondria is a target for OPs. • OPs affect action of complexes I, II, III, IV and V in the mitochondria. • OPs reduce mitochondrial ATP. • OPs promote oxidative and genotoxic damage via release of cytochrome C from mitochondria. • OP-induced mitochondrial dysfunction can be restored by increasing the cytosolic ATP.

  4. Mitochondrial transplantation for therapeutic use

    OpenAIRE

    McCully, James Donald; Levitsky, Sidney; del Nido, Pedro J.; Cowan, Douglas Burr

    2016-01-01

    Mitochondria play a key role in the homeostasis of the vast majority of the body’s cells. In the myocardium where mitochondria constitute 30 % of the total myocardial cell volume, temporary attenuation or obstruction of blood flow and as a result oxygen delivery to myocardial cells (ischemia) severely alters mitochondrial structure and function. These alterations in mitochondrial structure and function occur during ischemia and continue after blood flow and oxygen delivery to the myocardium i...

  5. Mitochondrial dysfunction and organophosphorus compounds

    International Nuclear Information System (INIS)

    Organophosphorous (OPs) pesticides are the most widely used pesticides in the agriculture and home. However, many acute or chronic poisoning reports about OPs have been published in the recent years. Mitochondria as a site of cellular oxygen consumption and energy production can be a target for OPs poisoning as a non-cholinergic mechanism of toxicity of OPs. In the present review, we have reviewed and criticized all the evidences about the mitochondrial dysfunctions as a mechanism of toxicity of OPs. For this purpose, all biochemical, molecular, and morphological data were retrieved from various studies. Some toxicities of OPs are arisen from dysfunction of mitochondrial oxidative phosphorylation through alteration of complexes I, II, III, IV and V activities and disruption of mitochondrial membrane. Reductions of adenosine triphosphate (ATP) synthesis or induction of its hydrolysis can impair the cellular energy. The OPs disrupt cellular and mitochondrial antioxidant defense, reactive oxygen species generation, and calcium uptake and promote oxidative and genotoxic damage triggering cell death via cytochrome C released from mitochondria and consequent activation of caspases. The mitochondrial dysfunction induced by OPs can be restored by use of antioxidants such as vitamin E and C, alpha-tocopherol, electron donors, and through increasing the cytosolic ATP level. However, to elucidate many aspect of mitochondrial toxicity of Ops, further studies should be performed. - Highlights: • As a non-cholinergic mechanism of toxicity, mitochondria is a target for OPs. • OPs affect action of complexes I, II, III, IV and V in the mitochondria. • OPs reduce mitochondrial ATP. • OPs promote oxidative and genotoxic damage via release of cytochrome C from mitochondria. • OP-induced mitochondrial dysfunction can be restored by increasing the cytosolic ATP

  6. Mitochondrial Dysfunction in Neurodegenerative Diseases

    OpenAIRE

    Johri, Ashu; Beal, M. Flint

    2012-01-01

    Neurodegenerative diseases are a large group of disabling disorders of the nervous system, characterized by the relative selective death of neuronal subtypes. In most cases, there is overwhelming evidence of impaired mitochondrial function as a causative factor in these diseases. More recently, evidence has emerged for impaired mitochondrial dynamics (shape, size, fission-fusion, distribution, movement etc.) in neurodegenerative diseases such as Parkinson's disease, Huntington's disease, amyo...

  7. A mitochondrially targeted compound delays aging in yeast through a mechanism linking mitochondrial membrane lipid metabolism to mitochondrial redox biology

    Directory of Open Access Journals (Sweden)

    Michelle T. Burstein

    2014-01-01

    Full Text Available A recent study revealed a mechanism of delaying aging in yeast by a natural compound which specifically impacts mitochondrial redox processes. In this mechanism, exogenously added lithocholic bile acid enters yeast cells, accumulates mainly in the inner mitochondrial membrane, and elicits an age-related remodeling of phospholipid synthesis and movement within both mitochondrial membranes. Such remodeling of mitochondrial phospholipid dynamics progresses with the chronological age of a yeast cell and ultimately causes significant changes in mitochondrial membrane lipidome. These changes in the composition of membrane phospholipids alter mitochondrial abundance and morphology, thereby triggering changes in the age-related chronology of such longevity-defining redox processes as mitochondrial respiration, the maintenance of mitochondrial membrane potential, the preservation of cellular homeostasis of mitochondrially produced reactive oxygen species, and the coupling of electron transport to ATP synthesis.

  8. Elemental depletions in the Magellanic Clouds and the evolution of depletions with metallicity

    CERN Document Server

    Tchernyshyov, Kirill; Seale, Jonathan; Fox, Andrew; Friedman, Scott D; Dwek, Eli; Galliano, Frédéric; Sembach, Kenneth

    2015-01-01

    We present a study of the composition of gas and dust in the Large and Small Magellanic Clouds (LMC and SMC, together -- the MCs) as measured by UV absorption spectroscopy. We have measured P II and Fe II along 85 sightlines toward the MCs using archival FUSE observations. For 16 of those sightlines, we have measured Si II, Cr II, and Zn II from new HST COS observations. We have combined these measurements with H I and H$_2$ column densities and reference stellar abundances from the literature to derive gas-phase abundances, depletions, and gas-to-dust ratios (GDRs). 80 of our 84 P measurements and 13 of our 16 Zn measurements are depleted by more than 0.1 decades, suggesting that P and Zn abundances are not accurate metallicity indicators at and above the metallicity of the SMC. The maximum P and Zn depletions are the same in the MW, LMC, and SMC. Si, Cr, and Fe are systematically less depleted in the SMC than in the MW or LMC. The minimum Si depletion in the SMC is consistent with zero. Our depletion-derive...

  9. Mitochondrial Complex I Inhibitors and Forced Oxidative Phosphorylation Synergize in Inducing Cancer Cell Death

    Directory of Open Access Journals (Sweden)

    Roberta Palorini

    2013-01-01

    Full Text Available Cancer cells generally rely mostly on glycolysis rather than oxidative phosphorylation (OXPHOS for ATP production. In fact, they are particularly sensitive to glycolysis inhibition and glucose depletion. On the other hand mitochondrial dysfunctions, involved in the onset of the Warburg effect, are sometimes also associated with the resistance to apoptosis that characterizes cancer cells. Therefore, combined treatments targeting both glycolysis and mitochondria function, exploiting peculiar tumor features, might be lethal for cancer cells. In this study, we show that glucose deprivation and mitochondrial Complex I inhibitors synergize in inducing cancer cell death. In particular, our results reveal that low doses of Complex I inhibitors, ineffective on immortalized cells and in high glucose growth, become specifically cytotoxic on cancer cells deprived of glucose. Importantly, the cytotoxic effect of the inhibitors on cancer cells is strongly enhanced by forskolin, a PKA pathway activator, that we have previously shown to stimulate OXPHOS. Taken together, we demonstrate that induction in cancer cells of a switch from a glycolytic to a more respirative metabolism, obtained by glucose depletion or mitochondrial activity stimulation, strongly increases their sensitivity to low doses of mitochondrial Complex I inhibitors. Our findings might be a valuable approach to eradicate cancer cells.

  10. Mitochondrial efficiency and insulin resistance.

    Science.gov (United States)

    Crescenzo, Raffaella; Bianco, Francesca; Mazzoli, Arianna; Giacco, Antonia; Liverini, Giovanna; Iossa, Susanna

    2014-01-01

    Insulin resistance, "a relative impairment in the ability of insulin to exert its effects on glucose, protein and lipid metabolism in target tissues," has many detrimental effects on metabolism and is strongly correlated to deposition of lipids in non-adipose tissues. Mitochondria are the main cellular sites devoted to ATP production and fatty acid oxidation. Therefore, a role for mitochondrial dysfunction in the onset of skeletal muscle insulin resistance has been proposed and many studies have dealt with possible alteration in mitochondrial function in obesity and diabetes, both in humans and animal models. Data reporting evidence of mitochondrial dysfunction in type two diabetes mellitus are numerous, even though the issue that this reduced mitochondrial function is causal in the development of the disease is not yet solved, also because a variety of parameters have been used in the studies carried out on this subject. By assessing the alterations in mitochondrial efficiency as well as the impact of this parameter on metabolic homeostasis of skeletal muscle cells, we have obtained results that allow us to suggest that an increase in mitochondrial efficiency precedes and therefore can contribute to the development of high-fat-induced insulin resistance in skeletal muscle. PMID:25601841

  11. Mitochondrial Metabolism in Aging Heart.

    Science.gov (United States)

    Lesnefsky, Edward J; Chen, Qun; Hoppel, Charles L

    2016-05-13

    Altered mitochondrial metabolism is the underlying basis for the increased sensitivity in the aged heart to stress. The aged heart exhibits impaired metabolic flexibility, with a decreased capacity to oxidize fatty acids and enhanced dependence on glucose metabolism. Aging impairs mitochondrial oxidative phosphorylation, with a greater role played by the mitochondria located between the myofibrils, the interfibrillar mitochondria. With aging, there is a decrease in activity of complexes III and IV, which account for the decrease in respiration. Furthermore, aging decreases mitochondrial content among the myofibrils. The end result is that in the interfibrillar area, there is ≈50% decrease in mitochondrial function, affecting all substrates. The defective mitochondria persist in the aged heart, leading to enhanced oxidant production and oxidative injury and the activation of oxidant signaling for cell death. Aging defects in mitochondria represent new therapeutic targets, whether by manipulation of the mitochondrial proteome, modulation of electron transport, activation of biogenesis or mitophagy, or the regulation of mitochondrial fission and fusion. These mechanisms provide new ways to attenuate cardiac disease in elders by preemptive treatment of age-related defects, in contrast to the treatment of disease-induced dysfunction. PMID:27174952

  12. Mitochondrial Epigenetics and Environmental Exposure.

    Science.gov (United States)

    Lambertini, Luca; Byun, Hyang-Min

    2016-09-01

    The rising toll of chronic and debilitating diseases brought about by the exposure to an ever expanding number of environmental pollutants and socio-economic factors is calling for action. The understanding of the molecular mechanisms behind the effects of environmental exposures can lead to the development of biomarkers that can support the public health fields of both early diagnosis and intervention to limit the burden of environmental diseases. The study of mitochondrial epigenetics carries high hopes to provide important biomarkers of exposure and disease. Mitochondria are in fact on the frontline of the cellular response to the environment. Modifications of the epigenetic factors regulating the mitochondrial activity are emerging as informative tools that can effectively report on the effects of the environment on the phenotype. Here, we will discuss the emerging field of mitochondrial epigenetics. This review describes the main epigenetic phenomena that modify the activity of the mitochondrial DNA including DNA methylation, long and short non-coding RNAs. We will discuss the unique pattern of mitochondrial DNA methylation, describe the challenges of correctly measuring it, and report on the existing studies that have analysed the correlation between environmental exposures and mitochondrial DNA methylation. Finally, we provide a brief account of the therapeutic approaches targeting mitochondria currently under consideration. PMID:27344144

  13. Mitochondrial dysfunction in Parkinson's disease.

    Science.gov (United States)

    Hu, Qingsong; Wang, Guanghui

    2016-01-01

    Parkinson's disease (PD) is the second most common neurodegenerative disease, which is characterized by loss of dopaminergic (DA) neurons in the substantia nigra pars compacta and the formation of Lewy bodies and Lewy neurites in surviving DA neurons in most cases. Although the cause of PD is still unclear, the remarkable advances have been made in understanding the possible causative mechanisms of PD pathogenesis. Numerous studies showed that dysfunction of mitochondria may play key roles in DA neuronal loss. Both genetic and environmental factors that are associated with PD contribute to mitochondrial dysfunction and PD pathogenesis. The induction of PD by neurotoxins that inhibit mitochondrial complex I provides direct evidence linking mitochondrial dysfunction to PD. Decrease of mitochondrial complex I activity is present in PD brain and in neurotoxin- or genetic factor-induced PD cellular and animal models. Moreover, PINK1 and parkin, two autosomal recessive PD gene products, have important roles in mitophagy, a cellular process to clear damaged mitochondria. PINK1 activates parkin to ubiquitinate outer mitochondrial membrane proteins to induce a selective degradation of damaged mitochondria by autophagy. In this review, we summarize the factors associated with PD and recent advances in understanding mitochondrial dysfunction in PD. PMID:27453777

  14. CFTR activity and mitochondrial function

    Directory of Open Access Journals (Sweden)

    Angel Gabriel Valdivieso

    2013-01-01

    Full Text Available Cystic Fibrosis (CF is a frequent and lethal autosomal recessive disease, caused by mutations in the gene encoding the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR. Before the discovery of the CFTR gene, several hypotheses attempted to explain the etiology of this disease, including the possible role of a chloride channel, diverse alterations in mitochondrial functions, the overexpression of the lysosomal enzyme α-glucosidase and a deficiency in the cytosolic enzyme glucose 6-phosphate dehydrogenase. Because of the diverse mitochondrial changes found, some authors proposed that the affected gene should codify for a mitochondrial protein. Later, the CFTR cloning and the demonstration of its chloride channel activity turned the mitochondrial, lysosomal and cytosolic hypotheses obsolete. However, in recent years, using new approaches, several investigators reported similar or new alterations of mitochondrial functions in Cystic Fibrosis, thus rediscovering a possible role of mitochondria in this disease. Here, we review these CFTR-driven mitochondrial defects, including differential gene expression, alterations in oxidative phosphorylation, calcium homeostasis, oxidative stress, apoptosis and innate immune response, which might explain some characteristics of the complex CF phenotype and reveals potential new targets for therapy.

  15. MOLECULAR NEUROGENETICS OF MITOCHONDRIAL DISEASES

    Directory of Open Access Journals (Sweden)

    E. Cardaioli

    2012-01-01

    Full Text Available Mitochondrial diseases are an expanding group of clinically heterogeneous disorders associated with mitochondrial DNA (mtDNA mutations or nuclear gene defects. Whatever the mechanism, the final common step in mitochondrial disorders is a defect of energy production resulting from respiratory chain impairment. The complexity of the biochemical and genetic features of the respiratory chain accounts for the extraordinarily wide range of clinical presentations of mitochondrial disorders. In general, organs with high aerobic demand, such as skeletal muscle, brain and heart, are the most affected. However, virtually any organ or tissue in the body may be affected and the disorders can be multisystemic (mitochondrial encephalomyopathiesor confined to a single tissue. Moreover, mitochondrial diseases can be sporadic or transmitted by mendelian (nuclear genes or maternal inheritance (mutations in mtDNA. Precise diagnosis is often a challenge; we go through the traditional steps of the diagnostic process, starting with study of inheritance in the family, clinical manifestations in the individual,electrophysiology and imaging techniques at organ level, down to biochemistry, pathology and molecular genetics at tissue, cell and DNA level, respectively. In fact the ultimate goal is to reach, whenever possible, a definitive molecular diagnosis, which can permit rational therapeutic approach and a genetic counseling.

  16. The depletion of the stratospheric ozone layer

    International Nuclear Information System (INIS)

    The protection of the Earth's ozone layer is of the highest importance to mankind. The dangers of its destruction are by now well known. The depletion of that layer has reached record levels. The Antarctic ozone hole covered this year a record area. The ozone layer is predicted to begin recovery in the next one or two decades and should be restored to pre-1980 levels by 2050. This is the achievement of the regime established by the 1985 Vienna Convention for the Protection of the Ozone Layer and the 1987 Montreal Protocol on Substances that Deplete the Ozone Layer. The regime established by these two agreements has been revised, and made more effective in London (1990), Copenhagen (1992), Vienna (1995), and Beijing (1999)

  17. The ultimate disposition of depleted uranium

    Energy Technology Data Exchange (ETDEWEB)

    Lemons, T.R. [Uranium Enrichment Organization, Oak Ridge, TN (United States)

    1991-12-31

    Depleted uranium (DU) is produced as a by-product of the uranium enrichment process. Over 340,000 MTU of DU in the form of UF{sub 6} have been accumulated at the US government gaseous diffusion plants and the stockpile continues to grow. An overview of issues and objectives associated with the inventory management and the ultimate disposition of this material is presented.

  18. Ecological and corrosion behavior of depleted uranium

    Directory of Open Access Journals (Sweden)

    Stojanović Mirjana D.

    2015-01-01

    Full Text Available Environmental pollution with radionuclides, particularly uranium and its decay products is a serious global problem. The current scientific studies estimated that the contamination originating from TENORM, caused by nuclear and non-nuclear technologies, has significantly increased natural level of radioactivity in the last thirty years. During the last decades all the more were talking about the "new pollutant" - depleted uranium (DU, which has been used in anti-tank penetrators because of its high density, penetration and pyrophoric properties. It is estimated that during the Gulf War, the war in Bosnia and Yugoslavia and during the invasion of Iraq, 1.4 million missiles with depleted uranium was fired. During the NATO aggression against the ex Yugoslavia in 1999., 112 locations in Kosovo and Metohija, 12 locations in southern Serbia and two locations in Montenegro were bombed. On this occasion, approximately 10 tons of depleted uranium were entered into the environment, mainly on land, where the degree of contamination ranged from 200 Bq / kg to 235 000 Bq/kg, which is up to 1000 times higher than the natural level. Fourteen years ago there was very little information about the behavior of ecological systems damaged by DU penetrators fired. Today, unfortunately, we are increasingly faced with the ―invisible threat" of depleted uranium, which has a strong radioactive and hemotoxic impact on human health. Present paper provides a detailed overview of the current understanding of corrosion and corrosion behavior of DU and environmental factors that control corrosion, together with indicators of environmental impact in order to highlight areas that need further attention in developing remediation programs.

  19. Molten-Salt Depleted-Uranium Reactor

    OpenAIRE

    Dong, Bao-Guo; Dong, Pei; Gu, Ji-Yuan

    2015-01-01

    The supercritical, reactor core melting and nuclear fuel leaking accidents have troubled fission reactors for decades, and greatly limit their extensive applications. Now these troubles are still open. Here we first show a possible perfect reactor, Molten-Salt Depleted-Uranium Reactor which is no above accident trouble. We found this reactor could be realized in practical applications in terms of all of the scientific principle, principle of operation, technology, and engineering. Our results...

  20. Ecological and corrosion behavior of depleted uranium

    OpenAIRE

    Stojanović Mirjana D.; Lačnjevac Časlav M.; Mihajlović Marija L.; Petrović Marija V.; Šoštarić Tanja D.; Petrović Jelena T.; Lopičić Zorica R.

    2015-01-01

    Environmental pollution with radionuclides, particularly uranium and its decay products is a serious global problem. The current scientific studies estimated that the contamination originating from TENORM, caused by nuclear and non-nuclear technologies, has significantly increased natural level of radioactivity in the last thirty years. During the last decades all the more were talking about the "new pollutant" - depleted uranium (DU), which has been used i...

  1. Educational software on the ozone layer Depletion

    OpenAIRE

    Psomiadis, Ploutarchos; Chalkidis, Anthimos; Saridaki, Anna; Tampakis, Constantine (Konstantinos); Skordoulis, Constantine

    2007-01-01

    This paper describes the design and the formative evaluation of educational software concerning the ‘Depletion of the Ozone Layer’ designed for the students of the Faculty of Primary Education (pre-service teachers) of the National and Kapodistrian University of Athens. The selection of the topic was based on: i) environmental criteria (importance of the phenomenon, complexity of the phenomenon), ii) societal criteria (local interest, human activities effects), iii) pedagogical cr...

  2. The ultimate disposition of depleted uranium

    Energy Technology Data Exchange (ETDEWEB)

    1990-12-01

    Significant amounts of the depleted uranium (DU) created by past uranium enrichment activities have been sold, disposed of commercially, or utilized by defense programs. In recent years, however, the demand for DU has become quite small compared to quantities available, and within the US Department of Energy (DOE) there is concern for any risks and/or cost liabilities that might be associated with the ever-growing inventory of this material. As a result, Martin Marietta Energy Systems, Inc. (Energy Systems), was asked to review options and to develop a comprehensive plan for inventory management and the ultimate disposition of DU accumulated at the gaseous diffusion plants (GDPs). An Energy Systems task team, under the chairmanship of T. R. Lemons, was formed in late 1989 to provide advice and guidance for this task. This report reviews options and recommends actions and objectives in the management of working inventories of partially depleted feed (PDF) materials and for the ultimate disposition of fully depleted uranium (FDU). Actions that should be considered are as follows. (1) Inspect UF{sub 6} cylinders on a semiannual basis. (2) Upgrade cylinder maintenance and storage yards. (3) Convert FDU to U{sub 3}O{sub 8} for long-term storage or disposal. This will include provisions for partial recovery of costs to offset those associated with DU inventory management and the ultimate disposal of FDU. Another recommendation is to drop the term tails'' in favor of depleted uranium'' or DU'' because the tails'' label implies that it is waste.'' 13 refs.

  3. Novel basophil- or eosinophil-depleted mouse models for functional analyses of allergic inflammation.

    Directory of Open Access Journals (Sweden)

    Kunie Matsuoka

    Full Text Available Basophils and eosinophils play important roles in various host defense mechanisms but also act as harmful effectors in allergic disorders. We generated novel basophil- and eosinophil-depletion mouse models by introducing the human diphtheria toxin (DT receptor gene under the control of the mouse CD203c and the eosinophil peroxidase promoter, respectively, to study the critical roles of these cells in the immunological response. These mice exhibited selective depletion of the target cells upon DT administration. In the basophil-depletion model, DT administration attenuated a drop in body temperature in IgG-mediated systemic anaphylaxis in a dose-dependent manner and almost completely abolished the development of ear swelling in IgE-mediated chronic allergic inflammation (IgE-CAI, a typical skin swelling reaction with massive eosinophil infiltration. In contrast, in the eosinophil-depletion model, DT administration ameliorated the ear swelling in IgE-CAI whether DT was administered before, simultaneously, or after, antigen challenge, with significantly lower numbers of eosinophils infiltrating into the swelling site. These results confirm that basophils and eosinophils act as the initiator and the effector, respectively, in IgE-CAI. In addition, antibody array analysis suggested that eotaxin-2 is a principal chemokine that attracts proinflammatory cells, leading to chronic allergic inflammation. Thus, the two mouse models established in this study are potentially useful and powerful tools for studying the in vivo roles of basophils and eosinophils. The combination of basophil- and eosinophil-depletion mouse models provides a new approach to understanding the complicated mechanism of allergic inflammation in conditions such as atopic dermatitis and asthma.

  4. Barium depletion in hollow cathode emitters

    Energy Technology Data Exchange (ETDEWEB)

    Polk, James E., E-mail: james.e.polk@jpl.nasa.gov; Mikellides, Ioannis G.; Katz, Ira [Jet Propulsion Laboratory, California Institute of Technology, Pasadena, California 91109 (United States); Capece, Angela M. [Graduate Aerospace Laboratories, California Institute of Technology, Pasadena, California 91125 (United States)

    2016-01-14

    Dispenser hollow cathodes rely on a consumable supply of Ba released by BaO-CaO-Al{sub 2}O{sub 3} source material in the pores of a tungsten matrix to maintain a low work function surface. The examination of cathode emitters from long duration tests shows deposits of tungsten at the downstream end that appear to block the flow of Ba from the interior. In addition, a numerical model of Ba transport in the cathode plasma indicates that the Ba partial pressure in the insert may exceed the equilibrium vapor pressure of the dominant Ba-producing reaction, and it was postulated previously that this would suppress Ba loss in the upstream part of the emitter. New measurements of the Ba depletion depth from a cathode insert operated for 8200 h reveal that Ba loss is confined to a narrow region near the downstream end, confirming this hypothesis. The Ba transport model was modified to predict the depletion depth with time. A comparison of the calculated and measured depletion depths gives excellent qualitative agreement, and quantitative agreement was obtained assuming an insert temperature 70 °C lower than measured beginning-of-life values.

  5. Understanding the haling power depletion (HPD) method

    International Nuclear Information System (INIS)

    The Pennsylvania State Univ. (PSU) is using the university version of the Studsvik Scandpower Code System (CMS) for research and education purposes. Preparations have been made to incorporate the CMS into the PSU Nuclear Engineering graduate class 'Nuclear Fuel Management' course. The information presented in this paper was developed during the preparation of the material for the course. The Haling Power Depletion (HPD) was presented in the course for the first time. The HPD method has been criticized as not valid by many in the field even though it has been successfully applied at PSU for the past 20 years. It was noticed that the radial power distribution (RPD) for low leakage cores during depletion remained similar to that of the HPD during most of the cycle. Thus, the Haling Power Depletion (HPD) may be used conveniently mainly for low leakage cores. Studies were then made to better understand the HPD and the results are presented in this paper. Many different core configurations can be computed quickly with the HPD without using Burnable Poisons (BP) to produce several excellent low leakage core configurations that are viable for power production. Once the HPD core configuration is chosen for further analysis, techniques are available for establishing the BP design to prevent violating any of the safety constraints in such HPD calculated cores. In summary, in this paper it has been shown that the HPD method can be used for guiding the design for the low leakage core. (authors)

  6. Barium depletion in hollow cathode emitters

    International Nuclear Information System (INIS)

    Dispenser hollow cathodes rely on a consumable supply of Ba released by BaO-CaO-Al2O3 source material in the pores of a tungsten matrix to maintain a low work function surface. The examination of cathode emitters from long duration tests shows deposits of tungsten at the downstream end that appear to block the flow of Ba from the interior. In addition, a numerical model of Ba transport in the cathode plasma indicates that the Ba partial pressure in the insert may exceed the equilibrium vapor pressure of the dominant Ba-producing reaction, and it was postulated previously that this would suppress Ba loss in the upstream part of the emitter. New measurements of the Ba depletion depth from a cathode insert operated for 8200 h reveal that Ba loss is confined to a narrow region near the downstream end, confirming this hypothesis. The Ba transport model was modified to predict the depletion depth with time. A comparison of the calculated and measured depletion depths gives excellent qualitative agreement, and quantitative agreement was obtained assuming an insert temperature 70 °C lower than measured beginning-of-life values

  7. Insulin fails to enhance mTOR phosphorylation, mitochondrial protein synthesis, and ATP production in human skeletal muscle without amino acid replacement

    OpenAIRE

    Barazzoni, Rocco; Short, Kevin R.; Asmann, Yan; Coenen-Schimke, Jill M.; Robinson, Matthew M.; Sreekumaran Nair, K.

    2012-01-01

    Systemic insulin administration causes hypoaminoacidemia by inhibiting protein degradation, which may in turn inhibit muscle protein synthesis (PS). Insulin enhances muscle mitochondrial PS and ATP production when hypoaminoacidemia is prevented by exogenous amino acid (AA) replacement. We determined whether insulin would stimulate mitochondrial PS and ATP production in the absence of AA replacement. Using l-[1,2-13C]leucine as a tracer, we measured the fractional synthetic rate of mitochondri...

  8. Mitochondrial drug targets in neurodegenerative diseases.

    Science.gov (United States)

    Lee, Jiyoun

    2016-02-01

    Growing evidence suggests that mitochondrial dysfunction is the main culprit in neurodegenerative diseases. Given the fact that mitochondria participate in diverse cellular processes, including energetics, metabolism, and death, the consequences of mitochondrial dysfunction in neuronal cells are inevitable. In fact, new strategies targeting mitochondrial dysfunction are emerging as potential alternatives to current treatment options for neurodegenerative diseases. In this review, we focus on mitochondrial proteins that are directly associated with mitochondrial dysfunction. We also examine recently identified small molecule modulators of these mitochondrial targets and assess their potential in research and therapeutic applications.

  9. Formation and Regulation of Mitochondrial Membranes

    Directory of Open Access Journals (Sweden)

    Laila Cigana Schenkel

    2014-01-01

    Full Text Available Mitochondrial membrane phospholipids are essential for the mitochondrial architecture, the activity of respiratory proteins, and the transport of proteins into the mitochondria. The accumulation of phospholipids within mitochondria depends on a coordinate synthesis, degradation, and trafficking of phospholipids between the endoplasmic reticulum (ER and mitochondria as well as intramitochondrial lipid trafficking. Several studies highlight the contribution of dietary fatty acids to the remodeling of phospholipids and mitochondrial membrane homeostasis. Understanding the role of phospholipids in the mitochondrial membrane and their metabolism will shed light on the molecular mechanisms involved in the regulation of mitochondrial function and in the mitochondrial-related diseases.

  10. Depletions at Browns Park National Wildlife Refuge [Draft

    Data.gov (United States)

    US Fish and Wildlife Service, Department of the Interior — Estimated depletion associated with the operation of Spitzie Marsh in Browns Park National Wildlife Refuge. Attached are the methods used to estimate depletion....

  11. Depletion interaction measured by colloidal probe atomic force microscopy

    NARCIS (Netherlands)

    Wijting, W.K.; Knoben, W.; Besseling, N.A.M.; Leermakers, F.A.M.; Cohen Stuart, M.A.

    2004-01-01

    We investigated the depletion interaction between stearylated silica surfaces in cyclohexane in the presence of dissolved polydimethylsiloxane by means of colloidal probe atomic force microscopy. We found that the range of the depletion interaction decreases with increasing concentration. Furthermor

  12. Lithium Depletion in Fully Convective Pre-Main Sequence Stars

    CERN Document Server

    Bildsten, L; Matzner, C D; Ushomirsky, G; Bildsten, Lars; Brown, Edward F.; Matzner, Christopher D.; Ushomirsky, Greg

    1996-01-01

    We present an analytic calculation of the thermonuclear depletion of lithium in contracting, fully convective, pre-main sequence stars of mass M 0.08 M_sun) and for constraining the masses of lithium depleted stars.

  13. Administrative decisions

    International Nuclear Information System (INIS)

    This article reviews relevant administrative decisions that have been taken in various countries during the last semester of 1999 and the first one of 2000. In Argentina, an inter-ministerial commission has been settled to examine the prospects of completing the construction of the Atucha-2 unit. In Sweden, an agreement has been signed between Sydkraft, Vattenfall and the Swedish government on a compensation plan for the early shutdown of the Barsebaeck unit 1. In Switzerland, the government of the canton of Bern has rejected a constitutional initiative requesting the shutdown of the Muehleberg nuclear power plant. (A.C.)

  14. Effects of Long-Term Rice Bran Extract Supplementation on Survival, Cognition and Brain Mitochondrial Function in Aged NMRI Mice.

    Science.gov (United States)

    Hagl, Stephanie; Asseburg, Heike; Heinrich, Martina; Sus, Nadine; Blumrich, Eva-Maria; Dringen, Ralf; Frank, Jan; Eckert, Gunter P

    2016-09-01

    Aging represents a major risk factor for the development of neurodegenerative diseases like Alzheimer's disease (AD). As mitochondrial dysfunction plays an important role in brain aging and occurs early in the development of AD, the prevention of mitochondrial dysfunction might help to slow brain aging and the development of neurodegenerative diseases. Rice bran extract (RBE) contains high concentrations of vitamin E congeners and γ-oryzanol. We have previously shown that RBE increased mitochondrial function and protected from mitochondrial dysfunction in vitro and in short-term in vivo feeding studies. To mimic the use of RBE as food additive, we have now investigated the effects of a long-term (6 months) feeding of RBE on survival, behavior and brain mitochondrial function in aged NMRI mice. RBE administration significantly increased survival and performance of aged NMRI mice in the passive avoidance and Y-maze test. Brain mitochondrial dysfunction found in aged mice was ameliorated after RBE administration. Furthermore, data from mRNA and protein expression studies revealed an up-regulation of mitochondrial proteins in RBE-fed mice, suggesting an increase in mitochondrial content which is mediated by a peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1α)-dependent mechanism. Our findings suggest that a long-term treatment with a nutraceutical containing RBE could be useful for slowing down brain aging and thereby delaying or even preventing AD. PMID:27350374

  15. Changes in liver mitochondrial plasticity induced by brain tumor

    Directory of Open Access Journals (Sweden)

    Debien Emilie

    2006-10-01

    Full Text Available Abstract Background Accumulating data suggest that liver is a major target organ of systemic effects observed in the presence of a cancer. In this study, we investigated the consequences of the presence of chemically induced brain tumors in rats on biophysical parameters accounting for the dynamics of water in liver mitochondria. Methods Tumors of the central nervous system were induced by intraveinous administration of ethylnitrosourea (ENU to pregnant females on the 19th day of gestation. The mitochondrial crude fraction was isolated from the liver of each animal and the dynamic parameters of total water and its macromolecule-associated fraction (structured water, H2Ost were calculated from Nuclear Magnetic Resonance (NMR measurements. Results The presence of a malignant brain tumor induced a loss of water structural order that implicated changes in the physical properties of the hydration shells of liver mitochondria macromolecules. This feature was linked to an increase in the membrane cholesterol content, a way to limit water penetration into the bilayer and then to reduce membrane permeability. As expected, these alterations in mitochondrial plasticity affected ionic exchanges and led to abnormal features of mitochondrial biogenesis and caspase activation. Conclusion This study enlightens the sensitivity of the structured water phase in the liver mitochondria machinery to external conditions such as tumor development at a distant site. The profound metabolic and functional changes led to abnormal features of ion transport, mitochondrial biogenesis and caspase activation.

  16. Cell-permeable succinate prodrugs bypass mitochondrial complex I deficiency.

    Science.gov (United States)

    Ehinger, Johannes K; Piel, Sarah; Ford, Rhonan; Karlsson, Michael; Sjövall, Fredrik; Frostner, Eleonor Åsander; Morota, Saori; Taylor, Robert W; Turnbull, Doug M; Cornell, Clive; Moss, Steven J; Metzsch, Carsten; Hansson, Magnus J; Fliri, Hans; Elmér, Eskil

    2016-01-01

    Mitochondrial complex I (CI) deficiency is the most prevalent defect in the respiratory chain in paediatric mitochondrial disease. This heterogeneous group of diseases includes serious or fatal neurological presentations such as Leigh syndrome and there are very limited evidence-based treatment options available. Here we describe that cell membrane-permeable prodrugs of the complex II substrate succinate increase ATP-linked mitochondrial respiration in CI-deficient human blood cells, fibroblasts and heart fibres. Lactate accumulation in platelets due to rotenone-induced CI inhibition is reversed and rotenone-induced increase in lactate:pyruvate ratio in white blood cells is alleviated. Metabolomic analyses demonstrate delivery and metabolism of [(13)C]succinate. In Leigh syndrome patient fibroblasts, with a recessive NDUFS2 mutation, respiration and spare respiratory capacity are increased by prodrug administration. We conclude that prodrug-delivered succinate bypasses CI and supports electron transport, membrane potential and ATP production. This strategy offers a potential future therapy for metabolic decompensation due to mitochondrial CI dysfunction. PMID:27502960

  17. Autism and Intellectual Disability Associated with Mitochondrial Disease and Hyperlactacidemia

    Directory of Open Access Journals (Sweden)

    José Guevara-Campos

    2015-02-01

    Full Text Available Autism spectrum disorder (ASD with intellectual disability (ID is a life-long debilitating condition, which is characterized by cognitive function impairment and other neurological signs. Children with ASD-ID typically attain motor skills with a significant delay. A sub-group of ASD-IDs has been linked to hyperlactacidemia and alterations in mitochondrial respiratory chain activity. The objective of this report is to describe the clinical features of patients with these comorbidities in order to shed light on difficult diagnostic and therapeutic approaches in such patients. We reported the different clinical features of children with ID associated with hyperlactacidemia and deficiencies in mitochondrial respiratory chain complex II–IV activity whose clinical presentations are commonly associated with the classic spectrum of mitochondrial diseases. We concluded that patients with ASD and ID presenting with persistent hyperlactacidemia should be evaluated for mitochondrial disorders. Administration of carnitine, coenzyme Q10, and folic acid is partially beneficial, although more studies are needed to assess the efficacy of this vitamin/cofactor treatment combination.

  18. Overview of mitochondrial bioenergetics.

    Science.gov (United States)

    Madeira, Vitor M C

    2012-01-01

    Bioenergetic Science started in seventh century with the pioneer works by Joseph Priestley and Antoine Lavoisier on photosynthesis and respiration, respectively. New developments were implemented by Pasteur in 1860s with the description of fermentations associated to microorganisms, further documented by Buchner brothers who discovered that fermentations also occurred in cell extracts in the absence of living cells. In the beginning of twentieth century, Harden and Young demonstrated that orthophosphate and other heat-resistant compounds (cozymase), later identified as NAD, ADP, and metal ions, were mandatory in the fermentation of glucose. The full glycolysis pathway has been detailed in 1940s with the contributions of Embden, Meyeroff, Parnas, Warburg, among others. Studies on the citric acid cycle started in 1910 (Thunberg) and were elucidated by Krebs et al. in the 1940s. Mitochondrial bioenergetics gained emphasis in the late 1940s and 1950s with the works of Lenhinger, Racker, Chance, Boyer, Ernster, and Slater, among others. The prevalent "chemical coupling hypothesis" of energy conservation in oxidative phosphorylation was challenged and replaced by the "chemiosmotic hypothesis" originally formulated in 1960s by Mitchell and later substantiated and extended to energy conservation in bacteria and chloroplasts, besides mitochondria, with clear-cut identification of molecular proton pumps. After identification of most reactive mechanisms, emphasis has been directed to structure resolution of molecular complex clusters, e.g., cytochrome c oxidase, complex III, complex II, ATP synthase, photosystem I, photosynthetic water splitting center, and energy collecting antennæ of several photosynthetic systems. Modern trends concern to the reactivity of radical and other active species in association with bioenergetic activities. A promising trend concentrates on the cell redox status quantified in terms of redox potentials. In spite of significant development and

  19. Implications of altered glutathione metabolism in aspirin-induced oxidative stress and mitochondrial dysfunction in HepG2 cells.

    Directory of Open Access Journals (Sweden)

    Haider Raza

    Full Text Available We have previously reported that acetylsalicylic acid (aspirin, ASA induces cell cycle arrest, oxidative stress and mitochondrial dysfunction in HepG2 cells. In the present study, we have further elucidated that altered glutathione (GSH-redox metabolism in HepG2 cells play a critical role in ASA-induced cytotoxicity. Using selected doses and time point for ASA toxicity, we have demonstrated that when GSH synthesis is inhibited in HepG2 cells by buthionine sulfoximine (BSO, prior to ASA treatment, cytotoxicity of the drug is augmented. On the other hand, when GSH-depleted cells were treated with N-acetyl cysteine (NAC, cytotoxicity/apoptosis caused by ASA was attenuated with a significant recovery in oxidative stress, GSH homeostasis, DNA fragmentation and some of the mitochondrial functions. NAC treatment, however, had no significant effects on the drug-induced inhibition of mitochondrial aconitase activity and ATP synthesis in GSH-depleted cells. Our results have confirmed that aspirin increases apoptosis by increased reactive oxygen species production, loss of mitochondrial membrane potential and inhibition of mitochondrial respiratory functions. These effects were further amplified when GSH-depleted cells were treated with ASA. We have also shown that some of the effects of aspirin might be associated with reduced GSH homeostasis, as treatment of cells with NAC attenuated the effects of BSO and aspirin. Our results strongly suggest that GSH dependent redox homeostasis in HepG2 cells is critical in preserving mitochondrial functions and preventing oxidative stress associated complications caused by aspirin treatment.

  20. Children's Models of the Ozone Layer and Ozone Depletion.

    Science.gov (United States)

    Christidou, Vasilia; Koulaidis, Vasilis

    1996-01-01

    The views of 40 primary students on ozone and its depletion were recorded through individual, semi-structured interviews. The data analysis resulted in the formation of a limited number of models concerning the distribution and role of ozone in the atmosphere, the depletion process, and the consequences of ozone depletion. Identifies five target…

  1. 26 CFR 1.642(e)-1 - Depreciation and depletion.

    Science.gov (United States)

    2010-04-01

    ... 26 Internal Revenue 8 2010-04-01 2010-04-01 false Depreciation and depletion. 1.642(e)-1 Section 1... (CONTINUED) INCOME TAXES Estates, Trusts, and Beneficiaries § 1.642(e)-1 Depreciation and depletion. An estate or trust is allowed the deductions for depreciation and depletion, but only to the extent...

  2. Hsp90 inhibition decreases mitochondrial protein turnover.

    Directory of Open Access Journals (Sweden)

    Daciana H Margineantu

    Full Text Available BACKGROUND: Cells treated with hsp90 inhibitors exhibit pleiotropic changes, including an expansion of the mitochondrial compartment, accompanied by mitochondrial fragmentation and condensed mitochondrial morphology, with ultimate compromise of mitochondrial integrity and apoptosis. FINDINGS: We identified several mitochondrial oxidative phosphorylation complex subunits, including several encoded by mtDNA, that are upregulated by hsp90 inhibitors, without corresponding changes in mRNA abundance. Post-transcriptional accumulation of mitochondrial proteins observed with hsp90 inhibitors is also seen in cells treated with proteasome inhibitors. Detailed studies of the OSCP subunit of mitochondrial F1F0-ATPase revealed the presence of mono- and polyubiquitinated OSCP in mitochondrial fractions. We demonstrate that processed OSCP undergoes retrotranslocation to a trypsin-sensitive form associated with the outer mitochondrial membrane. Inhibition of proteasome or hsp90 function results in accumulation of both correctly targeted and retrotranslocated mitochondrial OSCP. CONCLUSIONS: Cytosolic turnover of mitochondrial proteins demonstrates a novel connection between mitochondrial and cytosolic compartments through the ubiquitin-proteasome system. Analogous to defective protein folding in the endoplasmic reticulum, a mitochondrial unfolded protein response may play a role in the apoptotic effects of hsp90 and proteasome inhibitors.

  3. The depletion of plasma prolactin by pantethine in oestrogen-primed hyperprolactinaemic rats.

    Science.gov (United States)

    Jeitner, T M; Oliver, J R

    1990-03-01

    Pantethine was investigated for its potential to deplete prolactin in the plasma and pituitary cells of oestrogen-primed hyperprolactinaemic rats. This compound has been used in the past to deliver cysteamine systemically, through its congener pantetheine, a metabolic precursor for cysteamine. Cysteamine itself, specifically reduces plasma and pituitary prolactin. The addition of pantethine (2-10 mmol/l) to the media of isolated pituitary cells over 4 h did not appreciably alter the intracellular content of immunoreactive prolactin. Moreover, oral administration of pantethine at 0.5 and 1.0 g/kg body weight did not influence the concentration of immunoreactive plasma prolactin. However, the concentration of plasma prolactin fell by 48 and 67%, when pantethine was injected i.p. at 0.5 and 1.0 g/kg body weight, after 4 h. Intravenous administration of pantethine resulted in even greater losses of prolactin, in the order of 50 and 81% depletion for 0.5 and 1.0 g/kg body weight respectively and within 2 h of administration. However, cysteamine was found to be more efficacious than pantethine on a molar basis with regard to depleting the plasma concentration of prolactin in hyperprolactinaemic rats. PMID:2332716

  4. A modern depleted uranium manufacturing facility

    Energy Technology Data Exchange (ETDEWEB)

    Zagula, T.A.

    1995-07-01

    The Specific Manufacturing Capabilities (SMC) Project located at the Idaho National Engineering Laboratory (INEL) and operated by Lockheed Martin Idaho Technologies Co. (LMIT) for the Department of Energy (DOE) manufactures depleted uranium for use in the U.S. Army MIA2 Abrams Heavy Tank Armor Program. Since 1986, SMC has fabricated more than 12 million pounds of depleted uranium (DU) products in a multitude of shapes and sizes with varying metallurgical properties while maintaining security, environmental, health and safety requirements. During initial facility design in the early 1980`s, emphasis on employee safety, radiation control and environmental consciousness was gaining momentum throughout the DOE complex. This fact coupled with security and production requirements forced design efforts to focus on incorporating automation, local containment and computerized material accountability at all work stations. The result was a fully automated production facility engineered to manufacture DU armor packages with virtually no human contact while maintaining security, traceability and quality requirements. This hands off approach to handling depleted uranium resulted in minimal radiation exposures and employee injuries. Construction of the manufacturing facility was complete in early 1986 with the first armor package certified in October 1986. Rolling facility construction was completed in 1987 with the first certified plate produced in the fall of 1988. Since 1988 the rolling and manufacturing facilities have delivered more than 2600 armor packages on schedule with 100% final product quality acceptance. During this period there was an annual average of only 2.2 lost time incidents and a single individual maximum radiation exposure of 150 mrem. SMC is an example of designing and operating a facility that meets regulatory requirements with respect to national security, radiation control and personnel safety while achieving production schedules and product quality.

  5. Weight loss by Ppc-1, a novel small molecule mitochondrial uncoupler derived from slime mold.

    Science.gov (United States)

    Suzuki, Toshiyuki; Kikuchi, Haruhisa; Ogura, Masato; Homma, Miwako K; Oshima, Yoshiteru; Homma, Yoshimi

    2015-01-01

    Mitochondria play a key role in diverse processes including ATP synthesis and apoptosis. Mitochondrial function can be studied using inhibitors of respiration, and new agents are valuable for discovering novel mechanisms involved in mitochondrial regulation. Here, we screened small molecules derived from slime molds and other microorganisms for their effects on mitochondrial oxygen consumption. We identified Ppc-1 as a novel molecule which stimulates oxygen consumption without adverse effects on ATP production. The kinetic behavior of Ppc-1 suggests its function as a mitochondrial uncoupler. Serial administration of Ppc-1 into mice suppressed weight gain with no abnormal effects on liver or kidney tissues, and no evidence of tumor formation. Serum fatty acid levels were significantly elevated in mice treated with Ppc-1, while body fat content remained low. After a single administration, Ppc-1 distributes into various tissues of individual animals at low levels. Ppc-1 stimulates adipocytes in culture to release fatty acids, which might explain the elevated serum fatty acids in Ppc-1-treated mice. The results suggest that Ppc-1 is a unique mitochondrial regulator which will be a valuable tool for mitochondrial research as well as the development of new drugs to treat obesity. PMID:25668511

  6. Weight loss by Ppc-1, a novel small molecule mitochondrial uncoupler derived from slime mold.

    Directory of Open Access Journals (Sweden)

    Toshiyuki Suzuki

    Full Text Available Mitochondria play a key role in diverse processes including ATP synthesis and apoptosis. Mitochondrial function can be studied using inhibitors of respiration, and new agents are valuable for discovering novel mechanisms involved in mitochondrial regulation. Here, we screened small molecules derived from slime molds and other microorganisms for their effects on mitochondrial oxygen consumption. We identified Ppc-1 as a novel molecule which stimulates oxygen consumption without adverse effects on ATP production. The kinetic behavior of Ppc-1 suggests its function as a mitochondrial uncoupler. Serial administration of Ppc-1 into mice suppressed weight gain with no abnormal effects on liver or kidney tissues, and no evidence of tumor formation. Serum fatty acid levels were significantly elevated in mice treated with Ppc-1, while body fat content remained low. After a single administration, Ppc-1 distributes into various tissues of individual animals at low levels. Ppc-1 stimulates adipocytes in culture to release fatty acids, which might explain the elevated serum fatty acids in Ppc-1-treated mice. The results suggest that Ppc-1 is a unique mitochondrial regulator which will be a valuable tool for mitochondrial research as well as the development of new drugs to treat obesity.

  7. RESERVOIR CAPACITY DEPLETION ON ACCOUNT OF SEDIMENTATION

    Institute of Scientific and Technical Information of China (English)

    Prabhata K.SWAMEE

    2001-01-01

    Capacity depletion is an important information required for planning of multipurpose reservoirs. It is a complex phenomenon involving diverse fields like surface hydrology, sediment transport, varied flow hydraulics and soil consolidation. Proper assessment of capacity reduction is helpful in ascertaining the life of the reservoir and the project benefits for cost/benefit analysis. In this study dimensionally consistent equations for deposition volume and the trap efficiency have been obtained. Methods of obtaining the parameters involved these equations have also been indicated. It was found that there is good agreement with the field data. It is hoped that the equations are useful to design engineer.

  8. Depleted Uranium Penetrators : Hazards and Safety

    OpenAIRE

    Rao, S S; T. Balakrishna Bhat

    1997-01-01

    The depleted uranium (DU) alloy is a state-of-the-art material for kinetic energy penetrators due to its superior ballistic performance. Several countries use DU penetrators in their main battle tanks. There is no gamma radiation hazard to the crew members from stowage of DO rounds. Open air firing can result in environmental contamination and associated hazards due to airborne particles containing essentially U/sub 3/0/sub 8/ and UO/sub 2/. Inhalation of polluted air only through resp...

  9. Uranium: myths and realities the depleted uranium

    International Nuclear Information System (INIS)

    Uranium is an element whose name causes worry. The uranium properties are very unknown for people. However the element plays an important roll in the Earth as responsible of numerous natural phenomena, which are vital for life evolution. An example of the low knowledge about uranium has been the Balkan syndrome. A relation between cancers and the use of depleted uranium in ammunition in the Balkan War has been pretended to be established. From the beginning, this hypothesis could have been discarded as it has been confirmed and stated in recent reports of UNEP Commissions who have studied this matter. (Author)

  10. Capstone Depleted Uranium Aerosols: Generation and Characterization

    Energy Technology Data Exchange (ETDEWEB)

    Parkhurst, MaryAnn; Szrom, Fran; Guilmette, Ray; Holmes, Tom; Cheng, Yung-Sung; Kenoyer, Judson L.; Collins, John W.; Sanderson, T. Ellory; Fliszar, Richard W.; Gold, Kenneth; Beckman, John C.; Long, Julie

    2004-10-19

    In a study designed to provide an improved scientific basis for assessing possible health effects from inhaling depleted uranium (DU) aerosols, a series of DU penetrators was fired at an Abrams tank and a Bradley fighting vehicle. A robust sampling system was designed to collect aerosols in this difficult environment and continuously monitor the sampler flow rates. Aerosols collected were analyzed for uranium concentration and particle size distribution as a function of time. They were also analyzed for uranium oxide phases, particle morphology, and dissolution in vitro. The resulting data provide input useful in human health risk assessments.

  11. Scientific assessment of ozone depletion: 1991

    Science.gov (United States)

    1991-01-01

    Over the past few years, there have been highly significant advances in the understanding of the impact of human activities on the Earth's stratospheric ozone layer and the influence of changes in chemical composition of the radiative balance of the climate system. Specifically, since the last international scientific review (1989), there have been five major advances: (1) global ozone decreases; (2) polar ozone; (3) ozone and industrial halocarbons; (4) ozone and climate relations; and (5) ozone depletion potentials (ODP's) and global warming potentials (GWP's). These topics and others are discussed.

  12. The Time of Shipbuilding Order Depletion

    Institute of Scientific and Technical Information of China (English)

    Reporter Xing Dan

    2012-01-01

    In 2012, shipbuilding market is facing even colder weather. Depletion of orders, deals that can only ensure cost recovery ndustry which has already bankruptcy of ship yards one after another are also torturing this had many uncertainties. Some shipbuilding enterprises are trying to survive by cutting off parts of their business, some enterprises are leaving like the horses migrating on the African grassland, only those horses that have fights with crocodiles will reach the fertile land and enjoy the next warm spring. the business. It is survived the fierce

  13. ADMINISTRATIVE CIRCULARS

    CERN Multimedia

    Division des ressources humaines

    2000-01-01

    N° 2 (Rev. 1) - March 2000Guidelines and procedures concerning recruitment and probation period of staff membersN° 9 (Rev. 2) - March 2000Staff members contractsN° 16 (Rev. 2) - January 2000TrainingN° 30 (Rev. 1) - January 2000Indemnities and reimbursements upon taking up appointment and termination of contractN° 32 - February 2000Principles and procedures governing complaints of harassmentThese circular have been amended (No 2, N° 9, N° 16 and N° 30) or drawn up (N° 32).Copies are available in the Divisional Secretariats.Note:\tAdministrative and operational circulars, as well as the lists of those in force, are available for consultation in the server SRV4_Home in the Appletalk zone NOVELL (as GUEST or using your Novell username and password), volume PE Division Data Disk.The Word files are available in the folder COM, folder Public, folder ADM.CIRC.docHuman Resources DivisionTel. 74128

  14. Mitochondrial DNA and Cancer Epidemiology Workshop

    Science.gov (United States)

    A workshop to review the state-of-the science in the mitochondrial DNA field and its use in cancer epidemiology, and to develop a concept for a research initiative on mitochondrial DNA and cancer epidemiology.

  15. Nanodelivery System for Mitochondrial Targeting

    Science.gov (United States)

    Yoong, Sia Lee; Pastorin, Giorgia

    2014-02-01

    Mitochondria are indispensable in cellular functions such as energy production and death execution. They are emerging as intriguing therapeutic target as their dysregulation was found to be monumental in diseases such as neurodegenerative disease, obesity, and cancer etc. Despite tremendous interest being focused on therapeutically intervening mitochondrial function, few mito-active drugs were successfully developed, particularly due to challenges in delivering active compound to this organelle. In this review, effort in utilizing nanotechnology for targeted mitochondrial delivery of compound is expounded based on the nature of the nanomaterial used. The advantage and potential offered are discussed alongside the limitation. Finally the review is concluded with perspectives of the application of nanocarrier in mitochondrial medicine, given the unresolved concern on potential complications.

  16. Cilostazol promotes mitochondrial biogenesis in human umbilical vein endothelial cells through activating the expression of PGC-1α

    Energy Technology Data Exchange (ETDEWEB)

    Zuo, Luning [Shandong University, 44 Wenhua Xi Road, Jinan, Shandong 250012 (China); Department of Cardiology, Yantaishan Hospital, Yantai, Shandong 264001 (China); Li, Qiang; Sun, Bei; Xu, Zhiying [Department of Cardiology, Yantaishan Hospital, Yantai, Shandong 264001 (China); Ge, Zhiming, E-mail: zhimingge2000@hotmail.com [Department of Cardiology, Qilu Hospital, Shandong University, 44 Wenhua Xi Road, Jinan, Shandong 250012 (China)

    2013-03-29

    Highlights: ► First time to show that cilostazol promotes the expressions of PGC-1α. ► First time to show that cilostazol stimulates mitochondrial biogenesis in HUVECs. ► PKA/CREB pathway mediates the effect of cilostazol on PGC-1α expression. ► Suggesting the roles of cilostazol in mitochondrial dysfunction related disease. -- Abstract: Mitochondrial dysfunction is frequently observed in vascular diseases. Cilostazol is a drug approved by the US Food and Drug Administration for the treatment of intermittent claudication. Cilostazol increases intracellular cyclic adenosine monophosphate (cAMP) levels through inhibition of type III phosphodiesterase. The effects of cilostazol in mitochondrial biogenesis in human umbilical vein endothelial cells (HUVECs) were investigated in this study. Cilostazol treated HUVECs displayed increased levels of ATP, mitochondrial DNA/nuclear DNA ratio, expressions of cytochrome B, and mitochondrial mass, suggesting an enhanced mitochondrial biogenesis induced by cilostazol. The promoted mitochondrial biogenesis could be abolished by Protein kinase A (PKA) specific inhibitor H-89, implying that PKA pathway played a critical role in increased mitochondrial biogenesis after cilostazol treatment. Indeed, expression levels of peroxisome proliferator activator receptor gamma-coactivator 1α (PGC-1α), NRF 1 and mitochondrial transcription factor A (TFAM) were significantly increased in HUVECs after incubation with cilostazol at both mRNA levels and protein levels. Importantly, knockdown of PGC-1α could abolish cilostazol-induced mitochondrial biogenesis. Enhanced expression of p-CREB and PGC-1α induced by cilostazol could be inhibited by H-89. Moreover, the increased expression of PGC-1α induced by cilostazol could be inhibited by downregulation of CREB using CREB siRNA at both mRNA and protein levels. All the results indicated that cilostazol promoted mitochondrial biogenesis through activating the expression of PGC-1α in

  17. An Atypical Mitochondrial Carrier That Mediates Drug Action in Trypanosoma brucei.

    Science.gov (United States)

    de Macêdo, Juan P; Schumann Burkard, Gabriela; Niemann, Moritz; Barrett, Michael P; Vial, Henri; Mäser, Pascal; Roditi, Isabel; Schneider, André; Bütikofer, Peter

    2015-05-01

    Elucidating the mechanism of action of trypanocidal compounds is an important step in the development of more efficient drugs against Trypanosoma brucei. In a screening approach using an RNAi library in T. brucei bloodstream forms, we identified a member of the mitochondrial carrier family, TbMCP14, as a prime candidate mediating the action of a group of anti-parasitic choline analogs. Depletion of TbMCP14 by inducible RNAi in both bloodstream and procyclic forms increased resistance of parasites towards the compounds by 7-fold and 3-fold, respectively, compared to uninduced cells. In addition, down-regulation of TbMCP14 protected bloodstream form mitochondria from a drug-induced decrease in mitochondrial membrane potential. Conversely, over-expression of the carrier in procyclic forms increased parasite susceptibility more than 13-fold. Metabolomic analyses of parasites over-expressing TbMCP14 showed increased levels of the proline metabolite, pyrroline-5-carboxylate, suggesting a possible involvement of TbMCP14 in energy production. The generation of TbMCP14 knock-out parasites showed that the carrier is not essential for survival of T. brucei bloodstream forms, but reduced parasite proliferation under standard culture conditions. In contrast, depletion of TbMCP14 in procyclic forms resulted in growth arrest, followed by parasite death. The time point at which parasite proliferation stopped was dependent on the major energy source, i.e. glucose versus proline, in the culture medium. Together with our findings that proline-dependent ATP production in crude mitochondria from TbMCP14-depleted trypanosomes was reduced compared to control mitochondria, the study demonstrates that TbMCP14 is involved in energy production in T. brucei. Since TbMCP14 belongs to a trypanosomatid-specific clade of mitochondrial carrier family proteins showing very poor similarity to mitochondrial carriers of mammals, it may represent an interesting target for drug action or targeting. PMID

  18. An Atypical Mitochondrial Carrier That Mediates Drug Action in Trypanosoma brucei.

    Directory of Open Access Journals (Sweden)

    Juan P de Macêdo

    2015-05-01

    Full Text Available Elucidating the mechanism of action of trypanocidal compounds is an important step in the development of more efficient drugs against Trypanosoma brucei. In a screening approach using an RNAi library in T. brucei bloodstream forms, we identified a member of the mitochondrial carrier family, TbMCP14, as a prime candidate mediating the action of a group of anti-parasitic choline analogs. Depletion of TbMCP14 by inducible RNAi in both bloodstream and procyclic forms increased resistance of parasites towards the compounds by 7-fold and 3-fold, respectively, compared to uninduced cells. In addition, down-regulation of TbMCP14 protected bloodstream form mitochondria from a drug-induced decrease in mitochondrial membrane potential. Conversely, over-expression of the carrier in procyclic forms increased parasite susceptibility more than 13-fold. Metabolomic analyses of parasites over-expressing TbMCP14 showed increased levels of the proline metabolite, pyrroline-5-carboxylate, suggesting a possible involvement of TbMCP14 in energy production. The generation of TbMCP14 knock-out parasites showed that the carrier is not essential for survival of T. brucei bloodstream forms, but reduced parasite proliferation under standard culture conditions. In contrast, depletion of TbMCP14 in procyclic forms resulted in growth arrest, followed by parasite death. The time point at which parasite proliferation stopped was dependent on the major energy source, i.e. glucose versus proline, in the culture medium. Together with our findings that proline-dependent ATP production in crude mitochondria from TbMCP14-depleted trypanosomes was reduced compared to control mitochondria, the study demonstrates that TbMCP14 is involved in energy production in T. brucei. Since TbMCP14 belongs to a trypanosomatid-specific clade of mitochondrial carrier family proteins showing very poor similarity to mitochondrial carriers of mammals, it may represent an interesting target for drug

  19. Selective Mitochondrial Targeting Exerts Anxiolytic Effects In Vivo.

    Science.gov (United States)

    Nussbaumer, Markus; Asara, John M; Teplytska, Larysa; Murphy, Michael P; Logan, Angela; Turck, Christoph W; Filiou, Michaela D

    2016-06-01

    Current treatment strategies for anxiety disorders are predominantly symptom-based. However, a third of anxiety patients remain unresponsive to anxiolytics highlighting the need for more effective, mechanism-based therapeutic approaches. We have previously compared high vs low anxiety mice and identified changes in mitochondrial pathways, including oxidative phosphorylation and oxidative stress. In this work, we show that selective pharmacological targeting of these mitochondrial pathways exerts anxiolytic effects in vivo. We treated high anxiety-related behavior (HAB) mice with MitoQ, an antioxidant that selectively targets mitochondria. MitoQ administration resulted in decreased anxiety-related behavior in HAB mice. This anxiolytic effect was specific for high anxiety as MitoQ treatment did not affect the anxiety phenotype of C57BL/6N and DBA/2J mouse strains. We furthermore investigated the molecular underpinnings of the MitoQ-driven anxiolytic effect and found that MitoQ treatment alters the brain metabolome and that the response to MitoQ treatment is characterized by distinct molecular signatures. These results indicate that a mechanism-driven approach based on selective mitochondrial targeting has the potential to attenuate the high anxiety phenotype in vivo, thus paving the way for translational implementation as long-term MitoQ administration is well-tolerated with no reported side effects in mice and humans. PMID:26567514

  20. Unexplained gastrointestinal symptoms: Think mitochondrial disease

    OpenAIRE

    Chapman, TP; Hadley, G.; Fratter, C; Cullen, SN; Bax, BE; Bain, MD; Sapsford, RA; Poulton, J; Travis, SP

    2014-01-01

    Defects in mitochondrial function are increasingly recognised as central to the pathogenesis of many diseases, both inherited and acquired. Many of these mitochondrial defects arise from abnormalities in mitochondrial DNA and can result in multisystem disease, with gastrointestinal involvement common. Moreover, mitochondrial disease may present with a range of non-specific symptoms, and thus can be easily misdiagnosed, or even considered to be non-organic.We describe the clinical, histopathol...

  1. Unexplained gastrointestinal symptoms: think mitochondrial disease.

    OpenAIRE

    Chapman, TP; Hadley, G.; Fratter, C; Cullen, SN; Bax, BE; Bain, MD; Sapsford, RA; Poulton, J; Travis, SP

    2014-01-01

    Defects in mitochondrial function are increasingly recognised as central to the pathogenesis of many diseases, both inherited and acquired. Many of these mitochondrial defects arise from abnormalities in mitochondrial DNA and can result in multisystem disease, with gastrointestinal involvement common. Moreover, mitochondrial disease may present with a range of non-specific symptoms, and thus can be easily misdiagnosed, or even considered to be non-organic. We describe the clinical, histopatho...

  2. Platelet mitochondrial membrane potential in Parkinson's disease

    OpenAIRE

    Antony, P.M.; Boyd, O.; Trefois, C.; Ammerlaan, W; Ostaszewski, M.; Baumuratov, A.S.; Longhino, L.; Antunes, L; Koopman, W.J.H.; Balling, R; Diederich, N.J.

    2014-01-01

    OBJECTIVE: Mitochondrial dysfunction is a hallmark of idiopathic Parkinson's disease (IPD), which has been reported not to be restricted to striatal neurons. However, studies that analyzed mitochondrial function at the level of selected enzymatic activities in peripheral tissues have produced conflicting data. We considered the electron transport chain as a complex system with mitochondrial membrane potential as an integrative indicator for mitochondrial fitness. METHODS: Twenty-five IPD pati...

  3. Unexplained gastrointestinal symptoms: think mitochondrial disease.

    OpenAIRE

    Chapman, TP; Hadley, G.; Fratter, C; Cullen, SN; Bax, BE; Bain, MD; Sapsford, RA; Poulton, J; Travis, SP

    2014-01-01

    Defects in mitochondrial function are increasingly recognised as central to the pathogenesis of many diseases, both inherited and acquired. Many of these mitochondrial defects arise from abnormalities in mitochondrial DNA and can result in multisystem disease, with gastrointestinal involvement common. Moreover, mitochondrial disease may present with a range of non-specific symptoms, and thus can be easily misdiagnosed, or even considered to be non-organic.We describe the clinical, histopathol...

  4. Ethics of mitochondrial therapy for deafness.

    Science.gov (United States)

    Legge, Michael; Fitzgerald, Ruth P

    2014-11-07

    Mitochondrial therapy may provide the relief to many families with inherited mitochondrial diseases. However, it also has the potential for use in non-fatal disorders such as inherited mitochondrial deafness, providing an option for correction of the deafness using assisted reproductive technology. In this paper we discuss the potential for use in correcting mitochondrial deafness and consider some of the issues for the deaf community.

  5. Mitochondrial Cardiomyopathy: Pathophysiology, Diagnosis, and Management

    OpenAIRE

    Meyers, Deborah E.; Basha, Haseeb Ilias; Koenig, Mary Kay

    2013-01-01

    Mitochondrial disease is a heterogeneous group of multisystemic diseases that develop consequent to mutations in nuclear or mitochondrial DNA. The prevalence of inherited mitochondrial disease has been estimated to be greater than 1 in 5,000 births; however, the diagnosis and treatment of this disease are not taught in most adult-cardiology curricula. Because mitochondrial diseases often occur as a syndrome with resultant multiorgan dysfunction, they might not immediately appear to be specifi...

  6. Mitochondrial myopathy and myoclonic epilepsy

    Directory of Open Access Journals (Sweden)

    Walter O. Arruda

    1990-03-01

    Full Text Available The authors describe a family (mother, son and two daughters with mitochondrial myopathy. The mother was asymptomatic. Two daughters had lactic acidosis and myoclonic epilepsy, mild dementia, ataxia, weakness and sensory neuropathy. The son suffered one acute hemiplegic episode due to an ischemic infarct in the right temporal region. All the patients studied had hypertension. EEG disclosed photomyoclonic response in the proband patient. Muscle biopsy disclosed ragged-red fibers and abnormal mitochondria by electron microscopy. Biochemical analysis showed a defect of cytochrome C oxidase in mitochondria isolated from skeletal muscle. Several clinical and genetic aspects of the mitochondrial encephalomyopathies are discussed.

  7. Halocarbon ozone depletion and global warming potentials

    Science.gov (United States)

    Cox, Richard A.; Wuebbles, D.; Atkinson, R.; Connell, Peter S.; Dorn, H. P.; Derudder, A.; Derwent, Richard G.; Fehsenfeld, F. C.; Fisher, D.; Isaksen, Ivar S. A.

    1990-01-01

    Concern over the global environmental consequences of fully halogenated chlorofluorocarbons (CFCs) has created a need to determine the potential impacts of other halogenated organic compounds on stratospheric ozone and climate. The CFCs, which do not contain an H atom, are not oxidized or photolyzed in the troposphere. These compounds are transported into the stratosphere where they decompose and can lead to chlorine catalyzed ozone depletion. The hydrochlorofluorocarbons (HCFCs or HFCs), in particular those proposed as substitutes for CFCs, contain at least one hydrogen atom in the molecule, which confers on these compounds a much greater sensitivity toward oxidation by hydroxyl radicals in the troposphere, resulting in much shorter atmospheric lifetimes than CFCs, and consequently lower potential for depleting ozone. The available information is reviewed which relates to the lifetime of these compounds (HCFCs and HFCs) in the troposphere, and up-to-date assessments are reported of the potential relative effects of CFCs, HCFCs, HFCs, and halons on stratospheric ozone and global climate (through 'greenhouse' global warming).

  8. Bone marrow scintigraphy in hemopoietic depletion states

    International Nuclear Information System (INIS)

    Bone marrow scintigraphy was performed in 29 patients with hemopoietic depletion states of various etiology. Two tracers were used for visualization, viz., sup(99m)Tc-sulfur-colloid and 111InCl3;some patients were examined using both indicators. 111InCl3 is bound to transferrin and is adsorbed on the surface of reticulocytes and erythroblasts. A scintillation camera PHO GAMMA SEARLE IV fitted with a moving table and computer CLINCOM were used to obtain whole-body images. The comparison of all scans and marrow puncture smears was done. In patients with aplastic anemia with both hyperplastic or hypoplastic marrow good correlation of bone marrow scans and sternal puncture smears was found. In several cases the scintigraphic examination helped to establish the diagnosis of marrow depletion. A peculiar disadvantage of the imaging method with either sup(99m)Tc-sulfur-colloid or 111InCl3 is that it shows the disorders in erythropoietic and reticuloendothelial cells whereas the defects in myelopoietic cell series and platelet precursors are not provable. According to literature data, great attention is paid to the prognostic value of scintigraphic examination in aplastic anemia. (author)

  9. Molecular beam depletion: a new approach

    CERN Document Server

    Dorado, Manuel

    2014-01-01

    During the last years some interesting experimental results have been reported for experiments in N20, N0 , N0 dimer , H2 , Toluene and BaFCH3 cluster. The main result consists in the observation of molecular beam depletion when the molecules of a pulsed beam interact with a static electric or magnetic field and an oscillating field (RF). In these cases, and as a main difference, instead of using four fields as in the original technique developed by I.I. Rabi and others, only two fields, those which configure the resonant unit, are used. That is, without using the nonhomogeneous magnetic fields. The depletion explanation for I.I. Rabi and others is based in the interaction between the molecular electric or magnetic dipole moment and the non-homogeneous fields. But, obviously, the change in the molecules trajectories observed on these new experiments has to be explained without considering the force provided by the field gradient because it happens without using non-homogeneous fields. In this paper a theoreti...

  10. Mitochondrial transcription factor A regulation of mitochondrial degeneration in experimental diabetic neuropathy.

    Science.gov (United States)

    Chandrasekaran, Krish; Anjaneyulu, Muragundla; Inoue, Tatsuya; Choi, Joungil; Sagi, Avinash Rao; Chen, Chen; Ide, Tamomi; Russell, James W

    2015-07-15

    Oxidative stress-induced mitochondrial dysfunction and mitochondrial DNA (mtDNA) damage in peripheral neurons is considered to be important in the development of diabetic neuropathy. Mitochondrial transcription factor A (TFAM) wraps mtDNA and promotes mtDNA replication and transcription. We studied whether overexpression of TFAM reverses experimental peripheral diabetic neuropathy using TFAM transgenic mice (TFAM Tg) that express human TFAM (hTFAM). Levels of mouse mtDNA and the total TFAM (mouse TFAM + hTFAM) in the dorsal root ganglion (DRG) increased by approximately twofold in the TFAM Tg mice compared with control (WT) mice. WT and TFAM Tg mice were made diabetic by the administration of streptozotocin. Neuropathy end points were motor and sensory nerve conduction velocities, mechanical allodynia, thermal nociception, and intraepidermal nerve fiber density (IENFD). In the DRG neurons, mtDNA copy number and damage to mtDNA were quantified by qPCR, and TFAM levels were measured by Western blot. Mice with 16-wk duration of diabetes developed motor and sensory nerve conduction deficits, behavioral deficits, and intraepidermal nerve fiber loss. All of these changes were mostly prevented in diabetic TFAM Tg mice and were independent of changes in blood parameters. Mice with 16 wk of diabetes had a 40% decrease in mtDNA copy number compared with nondiabetic mice (P diabetic TFAM Tg mice reached the same level as that of WT nondiabetic mice. In comparison, there was upregulation of mtDNA and TFAM in 6-wk diabetic mice, suggesting that TFAM activation could be a therapeutic strategy to treat peripheral neuropathy.

  11. Mitochondrial dysfunction in the striatum of aged chronic mouse model of Parkinson's disease

    Directory of Open Access Journals (Sweden)

    Gaurav Patki

    2009-12-01

    Full Text Available Mitochondrial oxidative stress and dysfunction has been implicated as a possible mechanism for the onset and progression of Parkinson-like neurodegeneration. However, long-term mitochondrial defects in chronic animal neurodegenerative models have not been demonstrated. In this study, we investigated the function of striatal mitochondria 6 weeks after the induction of a chronic 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP mouse model of Parkinson’s disease (MPD. Although severe depression of mitochondrial respiration was observed immediately after acute administrations of MPTP, we failed to detect a significant mitochondrial inhibition in presence of striatal dopamine deficit 6 weeks after the chronic MPD induction in young adult mice. In contrast, when aged mice were chronically treated with MPTP and at 6 weeks post-treatment, these animals suffered an inhibition of the basal (state 4 and ADP-stimulated (state 3 respiration and a fall in ATP level in the striatal mitochondria. The aged chronic MPD also brought about a sustained diminution of striatal anti-oxidant enzyme levels including that of superoxide dismutases and cytochrome c. The mitochondrial deficits in the striatum of aged chronic MPD 6 weeks after treatment were further correlated with significant losses of striatal dopamine, tyrosine hydroxylase, dopamine uptake transporter, and with impaired movement when tested on a challenging beam. Our findings suggest that MPTP may trigger the neurodegenerative process by obstructing the mitochondrial function; however, striatal mitochondria in young animals may potentially rejuvenate, whereas mitochondrial dysfunction is sustained in the aged chronic MPD. Therefore, the aged chronic MPD may serve as a suitable investigative model for further elucidating the integral relationship between mitochondrial dysfunction and neurodegenerative disorder, and for assessing the therapeutic efficacy of mitochondrial protective agents as potential

  12. GSH depletion enhances adenoviral bax-induced apoptosis in lung cancer cells.

    Science.gov (United States)

    Honda, Tsuyoshi; Coppola, Simona; Ghibelli, Lina; Cho, Song H; Kagawa, Shunsuke; Spurgers, Kevin B; Brisbay, Shawn M; Roth, Jack A; Meyn, Raymond E; Fang, Bingliang; McDonnell, Timothy J

    2004-04-01

    The utility of dominant acting proapoptotic molecules to induce cell death in cancer cells is being evaluated in preclinical studies and clinical trials. We recently developed a binary adenoviral expression system to enable the efficient gene transfer of Bax and other proapoptotic molecules. Using this system, overexpression of Bax protein in four non-small-cell lung cancer (NSCLC) cell lines, H1299, A549, H226 and H322, was evaluated. The H322 line exhibited significant resistance to Bax-induced cell death compared to the other cell lines. H322 cells had the highest level of glutathione (GSH). GSH levels were significantly decreased following buthionine sulfoximine treatment and this coincided with enhanced apoptosis induction by Ad-Bax in H322 cells. GSH depletion enhanced Bax protein translocation to mitochondrial membranes. These findings suggest that the redox status may be a determinant of Bax-mediated cell death and that manipulation of intracellular thiols may sensitize cells to apoptosis by facilitating Bax insertion into mitochondrial membranes. PMID:15002033

  13. Natural Compounds Modulating Mitochondrial Functions

    Directory of Open Access Journals (Sweden)

    Lara Gibellini

    2015-01-01

    Full Text Available Mitochondria are organelles responsible for several crucial cell functions, including respiration, oxidative phosphorylation, and regulation of apoptosis; they are also the main intracellular source of reactive oxygen species (ROS. In the last years, a particular interest has been devoted to studying the effects on mitochondria of natural compounds of vegetal origin, quercetin (Qu, resveratrol (RSV, and curcumin (Cur being the most studied molecules. All these natural compounds modulate mitochondrial functions by inhibiting organelle enzymes or metabolic pathways (such as oxidative phosphorylation, by altering the production of mitochondrial ROS and by modulating the activity of transcription factors which regulate the expression of mitochondrial proteins. While Qu displays both pro- and antioxidant activities, RSV and Cur are strong antioxidant, as they efficiently scavenge mitochondrial ROS and upregulate antioxidant transcriptional programmes in cells. All the three compounds display a proapoptotic activity, mediated by the capability to directly cause the release of cytochrome c from mitochondria or indirectly by upregulating the expression of proapoptotic proteins of Bcl-2 family and downregulating antiapoptotic proteins. Interestingly, these effects are particularly evident on proliferating cancer cells and can have important therapeutic implications.

  14. Historical Perspective on Mitochondrial Medicine

    Science.gov (United States)

    DiMauro, Salvatore; Garone, Caterina

    2010-01-01

    In this review, we trace the origins and follow the development of mitochondrial medicine from the premolecular era (1962-1988) based on clinical clues, muscle morphology, and biochemistry into the molecular era that started in 1988 and is still advancing at a brisk pace. We have tried to stress conceptual advances, such as endosymbiosis,…

  15. Coenzyme Q and Mitochondrial Disease

    Science.gov (United States)

    Quinzii, Catarina M.; Hirano, Michio

    2010-01-01

    Coenzyme Q[subscript 10] (CoQ[subscript 10]) is an essential electron carrier in the mitochondrial respiratory chain and an important antioxidant. Deficiency of CoQ[subscript 10] is a clinically and molecularly heterogeneous syndrome, which, to date, has been found to be autosomal recessive in inheritance and generally responsive to CoQ[subscript…

  16. Mitochondrial dysfunction and Huntington disease

    Institute of Scientific and Technical Information of China (English)

    2006-01-01

    Huntington disease (HD) is a chronic autosomal-dominant neurodegenerative disease. The gene coding Huntingtin has been identified, but the pathogenic mechanisms of the disease are still not fully understood. This paper reviews the involvement of mitochondrial dysfunction in pathogenesis of HD.

  17. Vacancy Formation Enthalpy in Polycrystalline Depleted Uranium

    Science.gov (United States)

    Lund, K. R.; Lynn, K. G.; Weber, M. H.; Okuniewski, M. A.

    2013-06-01

    Positron Annihilation Spectroscopy was performed as a function of temperature and beam energy on polycrystalline depleted uranium (DU) foil. Samples were run with varying heat profiles all starting at room temperature. While collecting Doppler-Broadening data, the temperature of the sample was cycled several times. The first heat cycle shows an increasing S-parameter near temperatures of 400K to 500K much lower than the first phase transition of 941K indicating increasing vacancies possibly due to oxygen diffusion from the bulk to the surface. Vacancy formation enthalpies were calculated fitting a model to the data to be 1.6± 0.16 eV. Results are compared to previous work [3,4].

  18. Depleted Uranium Penetrators : Hazards and Safety

    Directory of Open Access Journals (Sweden)

    S. S. Rao

    1997-01-01

    Full Text Available The depleted uranium (DU alloy is a state-of-the-art material for kinetic energy penetrators due to its superior ballistic performance. Several countries use DU penetrators in their main battle tanks. There is no gamma radiation hazard to the crew members from stowage of DO rounds. Open air firing can result in environmental contamination and associated hazards due to airborne particles containing essentially U/sub 3/0/sub 8/ and UO/sub 2/. Inhalation of polluted air only through respirators or nose masks and refraining form ingestion of water or food materials from contaminated environment are safety measures for avoiding exposure to uranium and its toxicity. Infusion of sodium bicarbonate helps in urinary excretion of uranium that may have entered the body.

  19. Assessment of exposure to depleted uranium

    International Nuclear Information System (INIS)

    In most circumstances, measurement of uranium excreted in urine at known times after exposure is potentially the most sensitive method for determining the amount of depleted uranium (DU) incorporated. The problems associated with this approach are that natural uranium is always present in urine because of the ingestion of natural uranium in food and drink, and that the uncertainties in the intakes as assessed from excretion measurements can be quite large, because many assumptions concerning the exposure characteristics (time pattern of exposure, route of intake, chemical form, solubility, biokinetics within the body) must be made. Applying currently available methods and instruments for the measurement of uranium in urine samples, DU incorporations of levels relevant with respect to potential health hazards can be detected reliably, even a long time after exposure. (author)

  20. Arctic Ozone Depletion from UARS MLS Measurements

    Science.gov (United States)

    Manney, G. L.

    1995-01-01

    Microwave Limb Sounder (MLS) measurements of ozone during four Arctic winters are compared. The evolution of ozone in the lower stratosphere is related to temperature, chlorine monoxide (also measured by MLS), and the evolution of the polar vortex. Lagrangian transport calculations using winds from the United Kingdom Meteorological Office's Stratosphere-Troposphere Data Assimilation system are used to estimate to what extent the evolution of lower stratospheric ozone is controlled by dynamics. Observations, along with calculations of the expected dynamical behavior, show evidence for chemical ozone depletion throughout most of the Arctic lower stratospheric vortex during the 1992-93 middle and late winter, and during all of the 1994-95 winter that was observed by MLS. Both of these winters were unusually cold and had unusually cold and had unusually strong Arctic polar vortices compared to meteorological data over the past 17 years.

  1. ROLE OF HOSPITAL ADMINISTRATION

    OpenAIRE

    UDAYSINH R. MANEPATIL

    2013-01-01

    Hospital administration is the management of the hospital as a business. The administration is made up of medical and health services managers (sometimes called health care executives and health care administrators) and assistant administrators. Administrations range in size and the duties of the administrator depends on the size of the administration.

  2. Mitochondrial rejuvenation after induced pluripotency.

    Directory of Open Access Journals (Sweden)

    Steven T Suhr

    Full Text Available BACKGROUND: As stem cells of the early embryo mature and differentiate into all tissues, the mitochondrial complement undergoes dramatic functional improvement. Mitochondrial activity is low to minimize generation of DNA-damaging reactive oxygen species during pre-implantation development and increases following implantation and differentiation to meet higher metabolic demands. It has recently been reported that when the stem cell type known as induced pluripotent stem cells (IPSCs are re-differentiated for several weeks in vitro, the mitochondrial complement progressively re-acquires properties approximating input fibroblasts, suggesting that despite the observation that IPSC conversion "resets" some parameters of cellular aging such as telomere length, it may have little impact on other age-affected cellular systems such as mitochondria in IPSC-derived cells. METHODOLOGY/PRINCIPAL FINDINGS: We have examined the properties of mitochondria in two fibroblast lines, corresponding IPSCs, and fibroblasts re-derived from IPSCs using biochemical methods and electron microscopy, and found a dramatic improvement in the quality and function of the mitochondrial complement of the re-derived fibroblasts compared to input fibroblasts. This observation likely stems from two aspects of our experimental design: 1 that the input cell lines used were of advanced cellular age and contained an inefficient mitochondrial complement, and 2 the re-derived fibroblasts were produced using an extensive differentiation regimen that may more closely mimic the degree of growth and maturation found in a developing mammal. CONCLUSIONS/SIGNIFICANCE: These results - coupled with earlier data from our laboratory - suggest that IPSC conversion not only resets the "biological clock", but can also rejuvenate the energetic capacity of derived cells.

  3. Emerging Mitochondrial Therapeutic Targets in Optic Neuropathies.

    Science.gov (United States)

    Lopez Sanchez, M I G; Crowston, J G; Mackey, D A; Trounce, I A

    2016-09-01

    Optic neuropathies are an important cause of blindness worldwide. The study of the most common inherited mitochondrial optic neuropathies, Leber hereditary optic neuropathy (LHON) and autosomal dominant optic atrophy (ADOA) has highlighted a fundamental role for mitochondrial function in the survival of the affected neuron-the retinal ganglion cell. A picture is now emerging that links mitochondrial dysfunction to optic nerve disease and other neurodegenerative processes. Insights gained from the peculiar susceptibility of retinal ganglion cells to mitochondrial dysfunction are likely to inform therapeutic development for glaucoma and other common neurodegenerative diseases of aging. Despite it being a fast-evolving field of research, a lack of access to human ocular tissues and limited animal models of mitochondrial disease have prevented direct retinal ganglion cell experimentation and delayed the development of efficient therapeutic strategies to prevent vision loss. Currently, there are no approved treatments for mitochondrial disease, including optic neuropathies caused by primary or secondary mitochondrial dysfunction. Recent advances in eye research have provided important insights into the molecular mechanisms that mediate pathogenesis, and new therapeutic strategies including gene correction approaches are currently being investigated. Here, we review the general principles of mitochondrial biology relevant to retinal ganglion cell function and provide an overview of the major optic neuropathies with mitochondrial involvement, LHON and ADOA, whilst highlighting the emerging link between mitochondrial dysfunction and glaucoma. The pharmacological strategies currently being trialed to improve mitochondrial dysfunction in these optic neuropathies are discussed in addition to emerging therapeutic approaches to preserve retinal ganglion cell function.

  4. N-Methyl-3,4-methylenedioxyamphetamine-induced hepatotoxicity in rats: Oxidative stress after acute and chronic administration

    Directory of Open Access Journals (Sweden)

    Ninković Milica

    2004-01-01

    Full Text Available Background. The underlying mechanisms of N-Methyl-3,4-methylenedioxyamphetamine-MDMA-induced hepatotoxicity are still unknown. The aim of this study was to evaluate hepatic oxido-reductive status in the rats liver after the single and repeated administration of MDMA. Methods. MDMA was dissolved in distilled water and administered in the doses of 5 mg, 10 mg, 20 mg, and 40 mg/kg. The animals from the acute experiment were treated per os with the single dose of the appropriate solution, through the orogastric tube. The animals from the chronic experiment were treated per os, with the doses of 5, 10, or 20 mg/kg of MDMA every day during 14 days. The control groups were treated with water only. Eight hours after the last dose, the animals were sacrificed, dissected their livers were rapidly removed, frozen and stored at -70°C until the moment of analysis. The parameters of oxidative stress in the crude mitochondrial fractions of the livers were analyzed. Results. Superoxide dismutase (SOD activity increased in the livers of the animals that were treated with single doses of MDMA. Chronically treated animals showed the increased SOD activity only after the highest dose (20 mg/kg. The content of reduced glutathione decreased in both groups, but the depletion was much more expressed after the single administration. Lipid peroxidation index increased in dose-dependent manner in both groups, being much higher after the single administration. Conclusion. The increased index of lipid peroxidation and the decreased reduced glutathione levels suggested that MDMA application induced the state of oxidative stress in the liver. These changes were much more expressed after the single administration of MDMA.

  5. Catastrophic NAD+ depletion in activated T lymphocytes through Nampt inhibition reduces demyelination and disability in EAE.

    Science.gov (United States)

    Bruzzone, Santina; Fruscione, Floriana; Morando, Sara; Ferrando, Tiziana; Poggi, Alessandro; Garuti, Anna; D'Urso, Agustina; Selmo, Martina; Benvenuto, Federica; Cea, Michele; Zoppoli, Gabriele; Moran, Eva; Soncini, Debora; Ballestrero, Alberto; Sordat, Bernard; Patrone, Franco; Mostoslavsky, Raul; Uccelli, Antonio; Nencioni, Alessio

    2009-11-19

    Nicotinamide phosphoribosyltransferase (Nampt) inhibitors such as FK866 are potent inhibitors of NAD(+) synthesis that show promise for the treatment of different forms of cancer. Based on Nampt upregulation in activated T lymphocytes and on preliminary reports of lymphopenia in FK866 treated patients, we have investigated FK866 for its capacity to interfere with T lymphocyte function and survival. Intracellular pyridine nucleotides, ATP, mitochondrial function, viability, proliferation, activation markers and cytokine secretion were assessed in resting and in activated human T lymphocytes. In addition, we used experimental autoimmune encephalomyelitis (EAE) as a model of T-cell mediated autoimmune disease to assess FK866 efficacy in vivo. We show that activated, but not resting, T lymphocytes undergo massive NAD(+) depletion upon FK866-mediated Nampt inhibition. As a consequence, impaired proliferation, reduced IFN-gamma and TNF-alpha production, and finally autophagic cell demise result. We demonstrate that upregulation of the NAD(+)-degrading enzyme poly-(ADP-ribose)-polymerase (PARP) by activated T cells enhances their susceptibility to NAD(+) depletion. In addition, we relate defective IFN-gamma and TNF-alpha production in response to FK866 to impaired Sirt6 activity. Finally, we show that FK866 strikingly reduces the neurological damage and the clinical manifestations of EAE. In conclusion, Nampt inhibitors (and possibly Sirt6 inhibitors) could be used to modulate T cell-mediated immune responses and thereby be beneficial in immune-mediated disorders.

  6. Catastrophic NAD+ depletion in activated T lymphocytes through Nampt inhibition reduces demyelination and disability in EAE.

    Directory of Open Access Journals (Sweden)

    Santina Bruzzone

    Full Text Available Nicotinamide phosphoribosyltransferase (Nampt inhibitors such as FK866 are potent inhibitors of NAD(+ synthesis that show promise for the treatment of different forms of cancer. Based on Nampt upregulation in activated T lymphocytes and on preliminary reports of lymphopenia in FK866 treated patients, we have investigated FK866 for its capacity to interfere with T lymphocyte function and survival. Intracellular pyridine nucleotides, ATP, mitochondrial function, viability, proliferation, activation markers and cytokine secretion were assessed in resting and in activated human T lymphocytes. In addition, we used experimental autoimmune encephalomyelitis (EAE as a model of T-cell mediated autoimmune disease to assess FK866 efficacy in vivo. We show that activated, but not resting, T lymphocytes undergo massive NAD(+ depletion upon FK866-mediated Nampt inhibition. As a consequence, impaired proliferation, reduced IFN-gamma and TNF-alpha production, and finally autophagic cell demise result. We demonstrate that upregulation of the NAD(+-degrading enzyme poly-(ADP-ribose-polymerase (PARP by activated T cells enhances their susceptibility to NAD(+ depletion. In addition, we relate defective IFN-gamma and TNF-alpha production in response to FK866 to impaired Sirt6 activity. Finally, we show that FK866 strikingly reduces the neurological damage and the clinical manifestations of EAE. In conclusion, Nampt inhibitors (and possibly Sirt6 inhibitors could be used to modulate T cell-mediated immune responses and thereby be beneficial in immune-mediated disorders.

  7. Catastrophic NAD+ Depletion in Activated T Lymphocytes through Nampt Inhibition Reduces Demyelination and Disability in EAE

    Science.gov (United States)

    Ferrando, Tiziana; Poggi, Alessandro; Garuti, Anna; D'Urso, Agustina; Selmo, Martina; Benvenuto, Federica; Cea, Michele; Zoppoli, Gabriele; Moran, Eva; Soncini, Debora; Ballestrero, Alberto; Sordat, Bernard; Patrone, Franco; Mostoslavsky, Raul; Uccelli, Antonio; Nencioni, Alessio

    2009-01-01

    Nicotinamide phosphoribosyltransferase (Nampt) inhibitors such as FK866 are potent inhibitors of NAD+ synthesis that show promise for the treatment of different forms of cancer. Based on Nampt upregulation in activated T lymphocytes and on preliminary reports of lymphopenia in FK866 treated patients, we have investigated FK866 for its capacity to interfere with T lymphocyte function and survival. Intracellular pyridine nucleotides, ATP, mitochondrial function, viability, proliferation, activation markers and cytokine secretion were assessed in resting and in activated human T lymphocytes. In addition, we used experimental autoimmune encephalomyelitis (EAE) as a model of T-cell mediated autoimmune disease to assess FK866 efficacy in vivo. We show that activated, but not resting, T lymphocytes undergo massive NAD+ depletion upon FK866-mediated Nampt inhibition. As a consequence, impaired proliferation, reduced IFN-γ and TNF-α production, and finally autophagic cell demise result. We demonstrate that upregulation of the NAD+-degrading enzyme poly-(ADP-ribose)-polymerase (PARP) by activated T cells enhances their susceptibility to NAD+ depletion. In addition, we relate defective IFN-γ and TNF-α production in response to FK866 to impaired Sirt6 activity. Finally, we show that FK866 strikingly reduces the neurological damage and the clinical manifestations of EAE. In conclusion, Nampt inhibitors (and possibly Sirt6 inhibitors) could be used to modulate T cell-mediated immune responses and thereby be beneficial in immune-mediated disorders. PMID:19936064

  8. Persurf, a new method to improve surfactant delivery: a study in surfactant depleted rats.

    Directory of Open Access Journals (Sweden)

    Wolfram Burkhardt

    Full Text Available PURPOSE: Exogenous surfactant is not very effective in adults with ARDS, since surfactant does not reach atelectatic alveoli. Perfluorocarbons (PFC can recruit atelectatic areas but do not replace impaired endogenous surfactant. A surfactant-PFC-mixture could combine benefits of both therapies. The aim of the proof-of-principal-study was to produce a PFC-in-surfactant emulsion (Persurf and to test in surfactant depleted Wistar rats whether Persurf achieves I. a more homogenous pulmonary distribution and II. a more homogenous recruitment of alveoli when compared with surfactant or PFC alone. METHODS: Three different PFC were mixed with surfactant and phospholipid concentration in the emulsion was measured. After surfactant depletion, animals either received 30 ml/kg of PF5080, 100 mg/kg of stained (green dye Curosurf™ or 30 ml/kg of Persurf. Lungs were fixated after 1 hour of ventilation and alveolar aeration and surfactant distribution was estimated by a stereological approach. RESULTS: Persurf contained 3 mg/ml phospholipids and was stable for more than 48 hours. Persurf-administration improved oxygenation. Histological evaluation revealed a more homogenous surfactant distribution and alveolar inflation when compared with surfactant treated animals. CONCLUSIONS: In surfactant depleted rats administration of PFC-in-surfactant emulsion leads to a more homogenous distribution and aeration of the lung than surfactant alone.

  9. Quercetin protects against aluminium induced oxidative stress and promotes mitochondrial biogenesis via activation of the PGC-1α signaling pathway.

    Science.gov (United States)

    Sharma, Deep Raj; Sunkaria, Aditya; Wani, Willayat Yousuf; Sharma, Reeta Kumari; Verma, Deepika; Priyanka, Kumari; Bal, Amanjit; Gill, Kiran Dip

    2015-12-01

    The present investigation was carried out to elucidate a possible molecular mechanism related to the protective effect of quercetin administration against aluminium-induced oxidative stress on various mitochondrial respiratory complex subunits with special emphasis on the role of PGC-1α and its downstream targets, i.e. NRF-1, NRF-2 and Tfam in mitochondrial biogenesis. Aluminium lactate (10mg/kg b.wt./day) was administered intragastrically to rats, which were pre-treated with quercetin 6h before aluminium (10mg/kg b.wt./day, intragastrically) for 12 weeks. We found a decrease in ROS levels, mitochondrial DNA oxidation and citrate synthase activity in the hippocampus (HC) and corpus striatum (CS) regions of rat brain treated with quercetin. Besides this an increase in the mRNA levels of the mitochondrial encoded subunits - ND1, ND2, ND3, Cyt b, COX1, COX3 and ATPase6 along with increased expression of nuclear encoded subunits COX4, COX5A and COX5B of electron transport chain (ETC). In quercetin treated group an increase in the mitochondrial DNA copy number and mitochondrial content in both the regions of rat brain was observed. The PGC-1α was up regulated in quercetin treated rats along with NRF-1, NRF-2 and Tfam, which act downstream from PGC-1α. Electron microscopy results revealed a significant decrease in the mitochondrial cross-section area, mitochondrial perimeter length and increase in mitochondrial number in case of quercetin treated rats as compared to aluminium treated ones. Therefore it seems quercetin increases mitochondrial biogenesis and makes it an almost ideal flavanoid to control or limit the damage that has been associated with the defective mitochondrial function seen in many neurodegenerative diseases.

  10. Effect of greenhouse gas emissions on stratospheric ozone depletion

    OpenAIRE

    Velders GJM; LLO

    1997-01-01

    The depletion of the ozone layer is caused mainly by the increase in emissions of chlorine- and bromine-containing compounds like CFCs, halons, carbon tetrachloride, methyl chloroform and methyl bromide. Emissions of greenhouse gases can affect the depletion of the ozone layer through atmospheric interaction. We studied the interactions in the atmosphere between the greenhouse effect and stratospheric ozone depletion from the point of view of past and future emissions of the anthropogenic com...

  11. The MOD depleted uranium program independent review board : closure report

    OpenAIRE

    B. Smith

    2007-01-01

    This closure report was prepared by the MOD’s Depleted Uranium Independent Review Board (IRB; see Appendix A for membership) and summarises the review board’s general observations in respect of MOD’s depleted uranium research programme and the associated independent review process. The report starts by providing an introduction to MOD’s research programme on the health and environmental consequences of depleted uranium (DU), membership of the IRB, the operation of the review...

  12. Control of Single Molecule Fluorescence Dynamics by Stimulated Emission Depletion

    OpenAIRE

    Marsh, R J; Osborne, M A; Bain, A. J.

    2003-01-01

    The feasibility of manipulating the single molecule absorption-emission cycle using picosecond stimulated emission depletion (STED) is investigated using a stochastic computer simulation. In the simulation the molecule is subjected to repeated excitation and depletion events using time delayed pairs of excitation (PUMP) and depletion (DUMP) pulses derived from a high repetition rate pulsed laser system. The model is used to demonstrate that a significant and even substantial reduction in the ...

  13. A Novel Depletion-Mode MOS Gated Emitter Shorted Thyristor

    Institute of Scientific and Technical Information of China (English)

    张鹤鸣; 戴显英; 张义门; 马晓华; 林大松

    2000-01-01

    A Novel MOS-gated thyristor, depletion-mode MOS gated emitter shorted thyristor (DMST),and its two structures are proposed. In DMST,the channel of depletion-mode MOS makes the thyristor emitter-based junction inherently short. The operation of the device is controlled by the interruption and recovery of the depletion-mode MOS P channel. The perfect properties have been demonstrated by 2-D numerical simulations and the tests on the fabricated chips.

  14. Depletion curves of galaxy number counts behind cluster lenses

    OpenAIRE

    Mayen, C.; Soucail, G.

    1999-01-01

    When the logarithmic slope of the galaxy counts is lower than 0.4 (this is the case in all filters at high magnitude), the magnification bias due to the lens makes the number density of objects decrease. Consequently, the radial distribution shows a typical depletion curve. We present simulations of depletion curves obtained for a variety of different lens models and we show how the model parameters affect the depletion area.

  15. Mantle depletion and metasomatism recorded in orthopyroxene in highly depleted peridotites

    DEFF Research Database (Denmark)

    Scott, James; Liu, Jingao; Pearson, D. Graham;

    2016-01-01

    Although trace element concentrations in clinopyroxene serve as a useful tool for assessing the depletion and enrichment history of mantle peridotites, this is not applicable for peridotites in which the clinopyroxene component has been consumed (~ 25% partial melting). Orthopyroxene persists.......6), high spinel Cr# (commonly > 45) and low orthopyroxene Al2O3 (generally compositions shows that all samples, even the most refractory, have undergone metasomatism by small volume light rare earth element-bearing agents. Measured...

  16. The depletion potential in one, two and three dimensions

    Indian Academy of Sciences (India)

    R Roth; P-M König

    2005-06-01

    We study the behavior of the depletion potential in binary mixtures of hard particles in one, two, and three dimensions within the framework of a general theory for depletion potential using density functional theory. By doing so we extend earlier studies of the depletion potential in three dimensions to the cases of = 1 and 2 about which little is known, despite their importance for experiments. We also verify scaling relations between depletion potentials in sphere–sphere and wall–sphere geometries in = 3 and in disk–disk and wall–disk geometries in = 2, which originate from geometrical considerations.

  17. Development of heavy concrete mixed with depleted uranium

    International Nuclear Information System (INIS)

    Compressive strength and shielding performance tests of heavy weight concrete mixed with depleted Uranium (Depleted Uranium Concrete) were carried out. The depleted uranium pellets (φ 8 mm, height 9.5 mm) were mixed into cement paste instead of coarse aggregate. Specimens with nominal specific gravity of 3.2 - 5.4 were manufactured. The results of the compression strength test showed that compressive strength of more than 30 MPa was obtained with the specimens having the nominal specific gravity of more than 5 and it was confirmed from the shielding performance tests that Depleted Uranium Concrete has shielding corresponding to its nominal specific gravity. (author)

  18. Research on using depleted uranium as nuclear fuel for HWR

    International Nuclear Information System (INIS)

    The purpose of our work is to find a way for application of depleted uranium in CANDU reactor by using MOX nuclear fuel of depleted U and Pu instead of natural uranium. From preliminary evaluation and calculation, it was shown that MOX nuclear fuel consisting of depleted uranium enrichment tailings (0.25% 235U) and plutonium (their ratio 99.5%:0.5%) could replace natural uranium in CANDU reactor to sustain chain reaction. The prospects of application of depleted uranium in nuclear energy field are also discussed

  19. Regret causes ego-depletion and finding benefits in the regrettable events alleviates ego-depletion.

    Science.gov (United States)

    Gao, Hongmei; Zhang, Yan; Wang, Fang; Xu, Yan; Hong, Ying-Yi; Jiang, Jiang

    2014-01-01

    This study tested the hypotheses that experiencing regret would result in ego-depletion, while finding benefits (i.e., "silver linings") in the regret-eliciting events counteracted the ego-depletion effect. Using a modified gambling paradigm (Experiments 1, 2, and 4) and a retrospective method (Experiments 3 and 5), five experiments were conducted to induce regret. Results revealed that experiencing regret undermined performance on subsequent tasks, including a paper-and-pencil calculation task (Experiment 1), a Stroop task (Experiment 2), and a mental arithmetic task (Experiment 3). Furthermore, finding benefits in the regret-eliciting events improved subsequent performance (Experiments 4 and 5), and this improvement was mediated by participants' perceived vitality (Experiment 4). This study extended the depletion model of self-regulation by considering emotions with self-conscious components (in our case, regret). Moreover, it provided a comprehensive understanding of how people felt and performed after experiencing regret and after finding benefits in the events that caused the regret. PMID:24940811

  20. Nitric oxide inhibits capacitative Ca2+ entry by suppression of mitochondrial Ca2+ handling

    Science.gov (United States)

    Thyagarajan, Baskaran; Malli, Roland; Schmidt, Kurt; Graier, Wolfgang F; Groschner, Klaus

    2002-01-01

    Nitric oxide (NO) is a key modulator of cellular Ca2+ signalling and a determinant of mitochondrial function. Here, we demonstrate that NO governs capacitative Ca2+ entry (CCE) into HEK293 cells by impairment of mitochondrial Ca2+ handling. Authentic NO as well as the NO donors 1-[2-(carboxylato)pyrrolidin-1-yl]diazem-1-ium-1,2-diolate (ProliNO) and 2-(N,N-diethylamino)-diazenolate-2-oxide (DEANO) suppressed CCE activated by thapsigargin (TG)-induced store depletion. Threshold concentrations for inhibition of CCE by ProliNO and DEANO were 0.3 and 1 μM, respectively. NO-induced inhibition of CCE was not mimicked by peroxynitrite (100 μM), the peroxynitrite donor 3-morpholino-sydnonimine (SIN-1, 100 μM) or 8-bromoguanosine 3′,5′-cyclic monophosphate (8-BrcGMP, 1 mM). In addition, the guanylyl cyclase inhibitor 1H-[1,2,4] oxadiazole[4,3-a] quinoxalin-1-one (ODQ, 30 μM) failed to antagonize the inhibitory action of NO on CCE. DEANO (1–10 μM) suppressed mitochondrial respiration as evident from inhibition of cellular oxygen consumption. Experiments using fluorescent dyes to monitor mitochondrial membrane potential and mitochondrial Ca2+ levels, respectively, indicated that DEANO (10 μM) depolarized mitochondria and suppressed mitochondrial Ca2+ sequestration. The inhibitory effect of DEANO on Ca2+ uptake into mitochondria was confirmed by recording mitochondrial Ca2+ during agonist stimulation in HEK293 cells expressing ratiometric-pericam in mitochondria. DEANO (10 μM) failed to inhibit Ba2+ entry into TG-stimulated cells when extracellular Ca2+ was buffered below 1 μM, while clear inhibition of Ba2+ entry into store depleted cells was observed when extracellular Ca2+ levels were above 10 μM. Moreover, buffering of intracellular Ca2+ by use of N,N′-[1,2-ethanediylbis(oxy-2,1-phenylene)] bis [N-[25-[(acetyloxy) methoxy]-2-oxoethyl

  1. Administrative Appeals and ADR in Danish Administrative Law

    DEFF Research Database (Denmark)

    Conradsen, Inger Marie; Gøtze, Michael

    2014-01-01

    Administrative Appeals, review, administrative tribunals, ombudsman, alternative dispute resolution......Administrative Appeals, review, administrative tribunals, ombudsman, alternative dispute resolution...

  2. A reaction-diffusion model of ROS-induced ROS release in a mitochondrial network.

    Directory of Open Access Journals (Sweden)

    Lufang Zhou

    2010-01-01

    Full Text Available Loss of mitochondrial function is a fundamental determinant of cell injury and death. In heart cells under metabolic stress, we have previously described how the abrupt collapse or oscillation of the mitochondrial energy state is synchronized across the mitochondrial network by local interactions dependent upon reactive oxygen species (ROS. Here, we develop a mathematical model of ROS-induced ROS release (RIRR based on reaction-diffusion (RD-RIRR in one- and two-dimensional mitochondrial networks. The nodes of the RD-RIRR network are comprised of models of individual mitochondria that include a mechanism of ROS-dependent oscillation based on the interplay between ROS production, transport, and scavenging; and incorporating the tricarboxylic acid (TCA cycle, oxidative phosphorylation, and Ca(2+ handling. Local mitochondrial interaction is mediated by superoxide (O2.- diffusion and the O2.(--dependent activation of an inner membrane anion channel (IMAC. In a 2D network composed of 500 mitochondria, model simulations reveal DeltaPsi(m depolarization waves similar to those observed when isolated guinea pig cardiomyocytes are subjected to a localized laser-flash or antioxidant depletion. The sensitivity of the propagation rate of the depolarization wave to O(2.- diffusion, production, and scavenging in the reaction-diffusion model is similar to that observed experimentally. In addition, we present novel experimental evidence, obtained in permeabilized cardiomyocytes, confirming that DeltaPsi(m depolarization is mediated specifically by O2.-. The present work demonstrates that the observed emergent macroscopic properties of the mitochondrial network can be reproduced in a reaction-diffusion model of RIRR. Moreover, the findings have uncovered a novel aspect of the synchronization mechanism, which is that clusters of mitochondria that are oscillating can entrain mitochondria that would otherwise display stable dynamics. The work identifies the

  3. Mitochondrial plasticity in pathophysiological conditions

    OpenAIRE

    Padrão, Ana Isabel Martins Novais

    2013-01-01

    Both skeletal and cardiac muscles daily burn tremendous amounts of ATP to meet the energy requirements for contraction. So, it is not surprising that the maintenance of mitochondrial morphology, number, distribution and functionality in striated muscle are important for muscle homeostasis. In these tissues mitochondria present the added dimension of two populations, the intermyofibrillar (IMF) and the subsarcolemmal (SS) mitochondria, being IMF the most abundant one. In the present thesis, th...

  4. Decommissioning plan depleted uranium manufacturing facility

    International Nuclear Information System (INIS)

    Aerojet Ordnance Tennessee, Inc. (Aerojet) is decommissioning its California depleted uranium (DU) manufacturing facility. Aerojet has conducted manufacturing and research and development activities at the facility since 1977 under a State of California Source Materials License. The decontamination is being performed by a contractor selector for technical competence through competitive bid. Since the facility will be released for uncontrolled use it will be decontaminated to levels as low as reasonably achievable (ALARA). In order to fully apply the principles of ALARA, and ensure the decontamination is in full compliance with appropriate guides, Aerojet has retained Rogers and Associaties Engineering Corporation (RAE) to assist in the decommissioning. RAE has assisted in characterizing the facility and preparing contract bid documents and technical specifications to obtain a qualified decontamination contractor. RAE will monitor the decontamination work effort to assure the contractor's performance complies with the contract specifications and the decontamination plan. The specifications require a thorough cleaning and decontamination of the facility, not just sufficient cleaning to meet the numeric cleanup criteria

  5. Supercontinuum Stimulated Emission Depletion Fluorescence Lifetime Imaging

    Energy Technology Data Exchange (ETDEWEB)

    Lesoine, Michael; Bose, Sayantan; Petrich, Jacob; Smith, Emily

    2012-06-13

    Supercontinuum (SC) stimulated emission depletion (STED) fluorescence lifetime imaging is demonstrated by using time-correlated single-photon counting (TCSPC) detection. The spatial resolution of the developed STED instrument was measured by imaging monodispersed 40-nm fluorescent beads and then determining their fwhm, and was 36 ± 9 and 40 ± 10 nm in the X and Y coordinates, respectively. The same beads measured by confocal microscopy were 450 ± 50 and 430 ± 30 nm, which is larger than the diffraction limit of light due to underfilling the microscope objective. Underfilling the objective and time gating the signal were necessary to achieve the stated STED spatial resolution. The same fluorescence lifetime (2.0 ± 0.1 ns) was measured for the fluorescent beads by using confocal or STED lifetime imaging. The instrument has been applied to study Alexa Fluor 594-phalloidin labeled F-actin-rich projections with dimensions smaller than the diffraction limit of light in cultured cells. Fluorescence lifetimes of the actin-rich projections range from 2.2 to 2.9 ns as measured by STED lifetime imaging.

  6. Thermal stress depletes energy reserves in Drosophila.

    Science.gov (United States)

    Klepsatel, Peter; Gáliková, Martina; Xu, Yanjun; Kühnlein, Ronald P

    2016-01-01

    Understanding how environmental temperature affects metabolic and physiological functions is of crucial importance to assess the impacts of climate change on organisms. Here, we used different laboratory strains and a wild-caught population of the fruit fly Drosophila melanogaster to examine the effect of temperature on the body energy reserves of an ectothermic organism. We found that permanent ambient temperature elevation or transient thermal stress causes significant depletion of body fat stores. Surprisingly, transient thermal stress induces a lasting "memory effect" on body fat storage, which also reduces survivorship of the flies upon food deprivation later after stress exposure. Functional analyses revealed that an intact heat-shock response is essential to protect flies from temperature-dependent body fat decline. Moreover, we found that the temperature-dependent body fat reduction is caused at least in part by apoptosis of fat body cells, which might irreversibly compromise the fat storage capacity of the flies. Altogether, our results provide evidence that thermal stress has a significant negative impact on organismal energy reserves, which in turn might affect individual fitness. PMID:27641694

  7. Levels of depleted uranium in Kosovo soils

    Energy Technology Data Exchange (ETDEWEB)

    Sansone, U.; Stellato, L.; Jia, G.; Rosamilia, S.; Gaudino, S.; Barbizzi, S.; Belli, M

    2001-07-01

    The United Nations Environment Programme has performed a field survey at 11 sites located in Kosovo, where depleted uranium (DU) ammunitions were used by the North Atlantic Treaty Organization (NATO) during the last Balkans conflict (1999). Soil sampling was performed to assess the spread of DU ground contamination around and within the NATO target sites and the migration of DU along the soil profile. The {sup 234}U/{sup 238}U and {sup 235}U/{sup 238}U activity concentration ratios have been used as an indicator of natural against anthropogenic sources of uranium. The results show that levels of {sup 238}U activity concentrations in soils above 100 Bq.kg{sup -1} can be considered a 'tracer' of the presence of DU in soils. The results also indicate that detectable ground surface contamination by DU is limited to areas within a few metres from localised points of concentrated contamination caused by penetrator impacts. Vertical distribution of DU along the soil profile is measurable up to a depth of 10-20 cm. This latter aspect is of particular relevance for the potential risk of future contamination of groundwater. (author)

  8. Levels of depleted uranium in Kosovo soils

    International Nuclear Information System (INIS)

    The United Nations Environment Programme has performed a field survey at 11 sites located in Kosovo, where depleted uranium (DU) ammunitions were used by the North Atlantic Treaty Organization (NATO) during the last Balkans conflict (1999). Soil sampling was performed to assess the spread of DU ground contamination around and within the NATO target sites and the migration of DU along the soil profile. The 234U/238U and 235U/238U activity concentration ratios have been used as an indicator of natural against anthropogenic sources of uranium. The results show that levels of 238U activity concentrations in soils above 100 Bq.kg-1 can be considered a 'tracer' of the presence of DU in soils. The results also indicate that detectable ground surface contamination by DU is limited to areas within a few metres from localised points of concentrated contamination caused by penetrator impacts. Vertical distribution of DU along the soil profile is measurable up to a depth of 10-20 cm. This latter aspect is of particular relevance for the potential risk of future contamination of groundwater. (author)

  9. Nitrogen chemistry and depletion in starless cores

    CERN Document Server

    Hily-Blant, Pierre; forêts, G Pineau Des; Flower, David

    2010-01-01

    We investigated the chemistry of nitrogen--containing species, principally isotopomers of CN, HCN, and HNC, in a sample of pre-protostellar cores. We used the IRAM 30 m telescope to measure the emission in rotational and hyperfine transitions of CN, HCN, 13CN, H13CN, HN13C, and HC15N, in L 1544, L 183, Oph D, L 1517B, L 310. The observations were made along axial cuts through the dust emission peak, at a number of regularly--spaced offset positions. The observations were reduced and analyzed to obtain the column densities, using the measurements of the less abundant isotopic variants in order to minimize the consequences of finite optical depths in the lines. The observations were compared with the predictions of a free--fall gravitational collapse model, which incorporates a non-equilibrium treatment of the relevant chemistry. We found that CN, HCN, and HNC remain present in the gas phase at densities well above that at which CO depletes on to grains. The CN:HCN and the HNC:HCN abundance ratios are larger th...

  10. Thermal stress depletes energy reserves in Drosophila

    Science.gov (United States)

    Klepsatel, Peter; Gáliková, Martina; Xu, Yanjun; Kühnlein, Ronald P.

    2016-01-01

    Understanding how environmental temperature affects metabolic and physiological functions is of crucial importance to assess the impacts of climate change on organisms. Here, we used different laboratory strains and a wild-caught population of the fruit fly Drosophila melanogaster to examine the effect of temperature on the body energy reserves of an ectothermic organism. We found that permanent ambient temperature elevation or transient thermal stress causes significant depletion of body fat stores. Surprisingly, transient thermal stress induces a lasting “memory effect” on body fat storage, which also reduces survivorship of the flies upon food deprivation later after stress exposure. Functional analyses revealed that an intact heat-shock response is essential to protect flies from temperature-dependent body fat decline. Moreover, we found that the temperature-dependent body fat reduction is caused at least in part by apoptosis of fat body cells, which might irreversibly compromise the fat storage capacity of the flies. Altogether, our results provide evidence that thermal stress has a significant negative impact on organismal energy reserves, which in turn might affect individual fitness. PMID:27641694

  11. Plectin isoform P1b and P1d deficiencies differentially affect mitochondrial morphology and function in skeletal muscle

    Science.gov (United States)

    Winter, Lilli; Kuznetsov, Andrey V.; Grimm, Michael; Zeöld, Anikó; Fischer, Irmgard; Wiche, Gerhard

    2015-01-01

    Plectin, a versatile 500-kDa cytolinker protein, is essential for muscle fiber integrity and function. The most common disease caused by mutations in the human plectin gene, epidermolysis bullosa simplex with muscular dystrophy (EBS-MD), is characterized by severe skin blistering and progressive muscular dystrophy. Besides displaying pathological desmin-positive protein aggregates and degenerative changes in the myofibrillar apparatus, skeletal muscle specimens of EBS-MD patients and plectin-deficient mice are characterized by massive mitochondrial alterations. In this study, we demonstrate that structural and functional alterations of mitochondria are a primary aftermath of plectin deficiency in muscle, contributing to myofiber degeneration. We found that in skeletal muscle of conditional plectin knockout mice (MCK-Cre/cKO), mitochondrial content was reduced, and mitochondria were aggregated in sarcoplasmic and subsarcolemmal regions and were no longer associated with Z-disks. Additionally, decreased mitochondrial citrate synthase activity, respiratory function and altered adenosine diphosphate kinetics were characteristic of plectin-deficient muscles. To analyze a mechanistic link between plectin deficiency and mitochondrial alterations, we comparatively assessed mitochondrial morphology and function in whole muscle and teased muscle fibers of wild-type, MCK-Cre/cKO and plectin isoform-specific knockout mice that were lacking just one isoform (either P1b or P1d) while expressing all others. Monitoring morphological alterations of mitochondria, an isoform P1b-specific phenotype affecting the mitochondrial fusion–fission machinery and manifesting with upregulated mitochondrial fusion-associated protein mitofusin-2 could be identified. Our results show that the depletion of distinct plectin isoforms affects mitochondrial network organization and function in different ways. PMID:26019234

  12. Observed and simulated depletion layers with southward IMF

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    N. C. Maynard

    2004-06-01

    Full Text Available We present observations from the Polar satellite that confirm the existence of two types of depletion layers predicted under southward interplanetary magnetic field (IMF conditions in magnetohydrodynamic simulations. The first depletion type occurs along the stagnation line when IMF BX and/or dipole tilt are/is present. Magnetic merging occurred away from the equator (Maynard et al., 2003 and flux pile-ups developed while the field lines drape to the high-latitude merging sites. This high-shear type of depletion is consistent with the depletion layer model suggested by Zwan and Wolf (1976 for low-shear northward IMF conditions. Expected sites for depletion layers are associated with places where IMF tubes of force first impinge upon the magnetopause. The second depletion type develops poleward of the cusp. Under strongly driven conditions, magnetic fields from Region 1 current closure over the lobes (Siscoe et al., 2002c cause the high-latitude magnetopause to bulge outward, creating a shoulder above the cusp. These shoulders present the initial obstacle with which the IMF interacts. Flow is impeded, causing local flux pile-ups and low-shear depletion layers to form poleward of the cusps. Merging at the high-shear dayside magnetopause is consequently delayed. In both low- and high-shear cases, we show that the depletion layer structure is part of a slow mode wave standing in front of the magnetopause. As suggested by Southwood and Kivelson (1995, the depletions are rarefactions on the magnetopause side of slow-mode density compressions. While highly sheared magnetic fields are often used as proxies for ongoing local magnetic merging, depletion layers are prohibited at merging locations. Therefore, the existence of a depletion layer is evidence that the location of merging must be remote relative to the observation.

  13. Stimulated human mast cells secrete mitochondrial components that have autocrine and paracrine inflammatory actions.

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    Bodi Zhang

    Full Text Available Mast cells are hematopoietically-derived tissue immune cells that participate in acquired and innate immunity, as well as in inflammation through release of many chemokines and cytokines, especially in response to the pro-inflammatory peptide substance P (SP. Inflammation is critical in the pathogenesis of many diseases, but the trigger(s is often unknown. We investigated if mast cell stimulation leads to secretion of mitochondrial components and whether these could elicit autocrine and/or paracrine inflammatory effects. Here we show that human LAD2 mast cells stimulated by IgE/anti-IgE or by the SP led to secretion of mitochondrial particles, mitochondrial (mt mtDNA and ATP without cell death. Mitochondria purified from LAD2 cells and, when mitochondria added to mast cells trigger degranulation and release of histamine, PGD(2, IL-8, TNF, and IL-1β. This stimulatory effect is partially inhibited by an ATP receptor antagonist and by DNAse. These results suggest that the mitochondrial protein fraction may also contribute. Purified mitochondria also stimulate IL-8 and vascular endothelial growth factor (VEGF release from cultured human keratinocytes, and VEGF release from primary human microvascular endothelial cells. In order to investigate if mitochondrial components could be secreted in vivo, we injected rats intraperiotoneally (ip with compound 48/80, which mimicks the action of SP. Peritoneal mast cells degranulated and mitochondrial particles were documented by transimission electron microscopy outside the cells. We also wished to investigate if mitochondrial components secreted locally could reach the systemic circulation. Administration ip of mtDNA isolated from LAD2 cells in rats was detected in their serum within 4 hr, indicating that extravascular mtDNA could enter the systemic circulation. Secretion of mitochondrial components from stimulated live mast cells may act as "autopathogens" contributing to the pathogenesis of inflammatory

  14. The Drosophila effector caspase Dcp-1 regulates mitochondrial dynamics and autophagic flux via SesB.

    Science.gov (United States)

    DeVorkin, Lindsay; Go, Nancy Erro; Hou, Ying-Chen Claire; Moradian, Annie; Morin, Gregg B; Gorski, Sharon M

    2014-05-26

    Increasing evidence reveals that a subset of proteins participates in both the autophagy and apoptosis pathways, and this intersection is important in normal physiological contexts and in pathological settings. In this paper, we show that the Drosophila effector caspase, Drosophila caspase 1 (Dcp-1), localizes within mitochondria and regulates mitochondrial morphology and autophagic flux. Loss of Dcp-1 led to mitochondrial elongation, increased levels of the mitochondrial adenine nucleotide translocase stress-sensitive B (SesB), increased adenosine triphosphate (ATP), and a reduction in autophagic flux. Moreover, we find that SesB suppresses autophagic flux during midoogenesis, identifying a novel negative regulator of autophagy. Reduced SesB activity or depletion of ATP by oligomycin A could rescue the autophagic defect in Dcp-1 loss-of-function flies, demonstrating that Dcp-1 promotes autophagy by negatively regulating SesB and ATP levels. Furthermore, we find that pro-Dcp-1 interacts with SesB in a nonproteolytic manner to regulate its stability. These data reveal a new mitochondrial-associated molecular link between nonapoptotic caspase function and autophagy regulation in vivo. PMID:24862573

  15. Mitochondrial DNA Replication Defects Disturb Cellular dNTP Pools and Remodel One-Carbon Metabolism.

    Science.gov (United States)

    Nikkanen, Joni; Forsström, Saara; Euro, Liliya; Paetau, Ilse; Kohnz, Rebecca A; Wang, Liya; Chilov, Dmitri; Viinamäki, Jenni; Roivainen, Anne; Marjamäki, Päivi; Liljenbäck, Heidi; Ahola, Sofia; Buzkova, Jana; Terzioglu, Mügen; Khan, Nahid A; Pirnes-Karhu, Sini; Paetau, Anders; Lönnqvist, Tuula; Sajantila, Antti; Isohanni, Pirjo; Tyynismaa, Henna; Nomura, Daniel K; Battersby, Brendan J; Velagapudi, Vidya; Carroll, Christopher J; Suomalainen, Anu

    2016-04-12

    Mitochondrial dysfunction affects cellular energy metabolism, but less is known about the consequences for cytoplasmic biosynthetic reactions. We report that mtDNA replication disorders caused by TWINKLE mutations-mitochondrial myopathy (MM) and infantile onset spinocerebellar ataxia (IOSCA)-remodel cellular dNTP pools in mice. MM muscle shows tissue-specific induction of the mitochondrial folate cycle, purine metabolism, and imbalanced and increased dNTP pools, consistent with progressive mtDNA mutagenesis. IOSCA-TWINKLE is predicted to hydrolyze dNTPs, consistent with low dNTP pools and mtDNA depletion in the disease. MM muscle also modifies the cytoplasmic one-carbon cycle, transsulfuration, and methylation, as well as increases glucose uptake and its utilization for de novo serine and glutathione biosynthesis. Our evidence indicates that the mitochondrial replication machinery communicates with cytoplasmic dNTP pools and that upregulation of glutathione synthesis through glucose-driven de novo serine biosynthesis contributes to the metabolic stress response. These results are important for disorders with primary or secondary mtDNA instability and offer targets for metabolic therapy. PMID:26924217

  16. DNA precursor compartmentation in mammalian cells: metabolic and antimetabolic studies of nuclear and mitochondrial DNA synthesis

    International Nuclear Information System (INIS)

    HeLa cells were used for the quantitation of cellular and mitochondrial deoxyribonucleoside triphosphate (dNTP) and ribonucleoside triphosphate (rNTP) pools and of changes in pools in response to treatment with the antimetabolites methotrexate (mtx) and 5-fluorodeoxyuridine (FUdR). Use of an enzymatic assay of dNTPs and of improved nucleotide extraction methods allowed quantitation of mitochondrial dNTP pools. All four mitochondrial dNTP pools expand following treatment with mtx or FUdR whereas cellular dTTP and dGTP pools are depleted. Mitochrondrial rNTP pools were also found to expand in response to these antimetabolites. Mouse L-cells were used to determine the relative contributions of an exogenously supplied precursor to nuclear and mitochrondrial DNA replication. Cells were labeled to near steady state specific activities with 32P-orthophosphate and subsequently labeled with [3H]uridine, a general pyrimidine precursor, in the continuing presence of 32P. Deoxyribonucleoside monophosphates derived from these DNAs were separated by HPLC and the 3H/32P ratio in each pyrimidine determined. The dCMP residues in mitochondrial DNA (mtDNA) were found to be derived exclusively from the exogenous supplied uridine. The dTMP residues from nuclear and mtDNA and the dCMP residues from nuclear DNA were seen to be synthesized partly from exogenous sources and partly from other sources, presumably de novo pyrimidine synthesis

  17. Characteristics of intermittent mitochondrial transport in guinea pig enteric nerve fibers.

    Science.gov (United States)

    Vanden Berghe, Pieter; Hennig, Grant W; Smith, Terence K

    2004-04-01

    Enteric neurons controlling various gut functions are prone to oxidative insults that might damage mitochondria (e.g., intestinal inflammation). To resume local energy supply, mitochondria need to be transported. We used MitoTracker dyes and confocal microscopy to investigate basic characteristics of mitochondrial transport in guinea pig myenteric neurites. During a 10-s observation of 1 mm nerve fiber, on average, three mitochondria were transported at an average speed of 0.41 +/- 0.02 microm/s. Movement patterns were clearly erratic, and velocities were independent of mitochondrial size. The velocity oscillated periodically ( approximately 6 s) but was not consistently affected by structures such as en route boutons, bifurcations, or stationary mitochondria. Also, mitochondria transported in opposite directions did not necessarily affect each others' mobility. Transport was blocked by microtubule disruption (100 microM colchicine), and destabilization (1 microM cytochalasin-D) or stabilization (10 microM phalloidin) of actin filaments, respectively, decreased (0.22 +/- 0.02 microm/s, P plus 2 mM EGTA) had no effect. However, depletion of intracellular stores (thapsigargin) reduced (to 33%) and slowed the transport significantly (0.18 +/- 0.02 microm/s, P fashion and slowed by oligomycin (10 microM). We conclude that mitochondrial transport is remarkably independent of structural nerve fiber properties. We also show that mitochondrial transport is TTX sensitive and speeds up by stabilizing actin and that functional Ca(2+) stores are required for efficient transport. PMID:14592946

  18. Superresolution Imaging of Human Cytomegalovirus vMIA Localization in Sub-Mitochondrial Compartments

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    Shivaprasad Bhuvanendran

    2014-04-01

    Full Text Available The human cytomegalovirus (HCMV viral mitochondria-localized inhibitor of apoptosis (vMIA protein, traffics to mitochondria-associated membranes (MAM, where the endoplasmic reticulum (ER contacts the outer mitochondrial membrane (OMM. vMIA association with the MAM has not been visualized by imaging. Here, we have visualized this by using a combination of confocal and superresolution imaging. Deconvolution of confocal microscopy images shows vMIA localizes away from mitochondrial matrix at the Mitochondria-ER interface. By gated stimulated emission depletion (GSTED imaging, we show that along this interface vMIA is distributed in clusters. Through multicolor, multifocal structured illumination microscopy (MSIM, we find vMIA clusters localize away from MitoTracker Red, indicating its OMM localization. GSTED and MSIM imaging show vMIA exists in clusters of ~100–150 nm, which is consistent with the cluster size determined by Photoactivated Localization Microscopy (PALM. With these diverse superresolution approaches, we have imaged the clustered distribution of vMIA at the OMM adjacent to the ER. Our findings directly compare the relative advantages of each of these superresolution imaging modalities for imaging components of the MAM and sub-mitochondrial compartments. These studies establish the ability of superresolution imaging to provide valuable insight into viral protein location, particularly in the sub-mitochondrial compartments, and into their clustered organization.

  19. Chlorogenic acid ameliorates endotoxin-induced liver injury by promoting mitochondrial oxidative phosphorylation.

    Science.gov (United States)

    Zhou, Yan; Ruan, Zheng; Zhou, Lili; Shu, Xugang; Sun, Xiaohong; Mi, Shumei; Yang, Yuhui; Yin, Yulong

    2016-01-22

    Acute or chronic hepatic injury is a common pathology worldwide. Mitochondrial dysfunction and the depletion of adenosine triphosphate (ATP) play important roles in liver injury. Chlorogenic acids (CGA) are some of the most abundant phenolic acids in human diet. This study was designed to test the hypothesis that CGA may protect against chronic lipopolysaccharide (LPS)-induced liver injury by modulating mitochondrial energy generation. CGA decreased the activities of serum alanine aminotransferase, aspartate aminotransferase and alkaline phosphatase. The contents of ATP and adenosine monophosphate (AMP), as well as the ratio of AMP/ATP, were increased after CGA supplementation. The activities of enzymes that are involved in glycolysis were reduced, while those of enzymes involved in oxidative phosphorylation were increased. Moreover, phosphorylated AMP-activated protein kinase (AMPK), and mRNA levels of AMPK-α, peroxisome proliferator-activated receptor-gamma coactivator 1α (PGC-1α), nuclear respiratory factor 1, and mitochondrial DNA transcription factor A were increased after CGA supplementation. Collectively, these findings suggest that the hepatoprotective effect of CGA might be associated with enhanced ATP production, the stimulation of mitochondrial oxidative phosphorylation and the inhibition of glycolysis. PMID:26740181

  20. Muscle mitochondrial uncoupling dismantles neuromuscular junction and triggers distal degeneration of motor neurons.

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    Luc Dupuis

    Full Text Available BACKGROUND: Amyotrophic lateral sclerosis (ALS, the most frequent adult onset motor neuron disease, is associated with hypermetabolism linked to defects in muscle mitochondrial energy metabolism such as ATP depletion and increased oxygen consumption. It remains unknown whether muscle abnormalities in energy metabolism are causally involved in the destruction of neuromuscular junction (NMJ and subsequent motor neuron degeneration during ALS. METHODOLOGY/PRINCIPAL FINDINGS: We studied transgenic mice with muscular overexpression of uncoupling protein 1 (UCP1, a potent mitochondrial uncoupler, as a model of muscle restricted hypermetabolism. These animals displayed age-dependent deterioration of the NMJ that correlated with progressive signs of denervation and a mild late-onset motor neuron pathology. NMJ regeneration and functional recovery were profoundly delayed following injury of the sciatic nerve and muscle mitochondrial uncoupling exacerbated the pathology of an ALS animal model. CONCLUSIONS/SIGNIFICANCE: These findings provide the proof of principle that a muscle restricted mitochondrial defect is sufficient to generate motor neuron degeneration and suggest that therapeutic strategies targeted at muscle metabolism might prove useful for motor neuron diseases.

  1. The Drosophila effector caspase Dcp-1 regulates mitochondrial dynamics and autophagic flux via SesB.

    Science.gov (United States)

    DeVorkin, Lindsay; Go, Nancy Erro; Hou, Ying-Chen Claire; Moradian, Annie; Morin, Gregg B; Gorski, Sharon M

    2014-05-26

    Increasing evidence reveals that a subset of proteins participates in both the autophagy and apoptosis pathways, and this intersection is important in normal physiological contexts and in pathological settings. In this paper, we show that the Drosophila effector caspase, Drosophila caspase 1 (Dcp-1), localizes within mitochondria and regulates mitochondrial morphology and autophagic flux. Loss of Dcp-1 led to mitochondrial elongation, increased levels of the mitochondrial adenine nucleotide translocase stress-sensitive B (SesB), increased adenosine triphosphate (ATP), and a reduction in autophagic flux. Moreover, we find that SesB suppresses autophagic flux during midoogenesis, identifying a novel negative regulator of autophagy. Reduced SesB activity or depletion of ATP by oligomycin A could rescue the autophagic defect in Dcp-1 loss-of-function flies, demonstrating that Dcp-1 promotes autophagy by negatively regulating SesB and ATP levels. Furthermore, we find that pro-Dcp-1 interacts with SesB in a nonproteolytic manner to regulate its stability. These data reveal a new mitochondrial-associated molecular link between nonapoptotic caspase function and autophagy regulation in vivo.

  2. Detailed analysis of the human mitochondrial contact site complex indicate a hierarchy of subunits.

    Directory of Open Access Journals (Sweden)

    Christine Ott

    Full Text Available Mitochondrial inner membrane folds into cristae, which significantly increase its surface and are important for mitochondrial function. The stability of cristae depends on the mitochondrial contact site (MICOS complex. In human mitochondria, the inner membrane MICOS complex interacts with the outer membrane sorting and assembly machinery (SAM complex, to form the mitochondrial intermembrane space bridging complex (MIB. We have created knockdown cell lines of most of the MICOS and MIB components and have used them to study the importance of the individual subunits for the cristae formation and complex stability. We show that the most important subunits of the MIB complex in human mitochondria are Mic60/Mitofilin, Mic19/CHCHD3 and an outer membrane component Sam50. We provide additional proof that ApoO indeed is a subunit of the MICOS and MIB complexes and propose the name Mic23 for this protein. According to our results, Mic25/CHCHD6, Mic27/ApoOL and Mic23/ApoO appear to be periphery subunits of the MICOS complex, because their depletion does not affect cristae morphology or stability of other components.

  3. EMRE Is a Matrix Ca2+ Sensor that Governs Gatekeeping of the Mitochondrial Ca2+ Uniporter

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    Horia Vais

    2016-01-01

    Full Text Available The mitochondrial uniporter (MCU is an ion channel that mediates Ca2+ uptake into the matrix to regulate metabolism, cell death, and cytoplasmic Ca2+ signaling. Matrix Ca2+ concentration is similar to that in cytoplasm, despite an enormous driving force for entry, but the mechanisms that prevent mitochondrial Ca2+ overload are unclear. Here, we show that MCU channel activity is governed by matrix Ca2+ concentration through EMRE. Deletion or charge neutralization of its matrix-localized acidic C terminus abolishes matrix Ca2+ inhibition of MCU Ca2+ currents, resulting in MCU channel activation, enhanced mitochondrial Ca2+ uptake, and constitutively elevated matrix Ca2+ concentration. EMRE-dependent regulation of MCU channel activity requires intermembrane space-localized MICU1, MICU2, and cytoplasmic Ca2+. Thus, mitochondria are protected from Ca2+ depletion and Ca2+ overload by a unique molecular complex that involves Ca2+ sensors on both sides of the inner mitochondrial membrane, coupled through EMRE.

  4. Important role of energy-dependent mitochondrial pathways in cultured rat cardiac myocyte apoptosis.

    Science.gov (United States)

    Shiraishi, J; Tatsumi, T; Keira, N; Akashi, K; Mano, A; Yamanaka, S; Matoba, S; Asayama, J; Yaoi, T; Fushiki, S; Fliss, H; Nakagawa, M

    2001-10-01

    Recent studies have suggested that apoptosis and necrosis share common features in their signaling pathway and that apoptosis requires intracellular ATP for its mitochondrial/apoptotic protease-activating factor-1 suicide cascade. The present study was, therefore, designed to examine the role of intracellular energy levels in determining the form of cell death in cardiac myocytes. Neonatal rat cardiac myocytes were first incubated for 1 h in glucose-free medium containing oligomycin to achieve metabolic inhibition. The cells were then incubated for another 4 h in similar medium containing staurosporine and graded concentrations of glucose to manipulate intracellular ATP levels. Under ATP-depleting conditions, the cell death caused by staurosporine was primarily necrotic, as determined by creatine kinase release and nuclear staining with ethidium homodimer-1. However, under ATP-replenishing conditions, staurosporine increased the percentage of apoptotic cells, as determined by nuclear morphology and DNA fragmentation. Caspase-3 activation by staurosporine was also ATP dependent. However, loss of mitochondrial transmembrane potential (DeltaPsi(m)), Bax translocation, and cytochrome c release were observed in both apoptotic and necrotic cells. Moreover, cyclosporin A, an inhibitor of mitochondrial permeability transition, attenuated staurosporine-induced apoptosis and necrosis through the inhibition of DeltaPsi(m) reduction, cytochrome c release, and caspase-3 activation. Our data therefore suggest that staurosporine induces cell demise through a mitochondrial death signaling pathway and that the presence of intracellular ATP favors a shift from necrosis to apoptosis through caspase activation. PMID:11557554

  5. Induction of Mitochondrial Dysfunction and Oxidative Stress in Leishmania donovani by Orally Active Clerodane Diterpene

    Science.gov (United States)

    Kathuria, Manoj; Bhattacharjee, Arindam; Sashidhara, Koneni V.; Singh, Suriya Pratap

    2014-01-01

    This study was performed to investigate the mechanistic aspects of cell death induced by a clerodane diterpene (K-09) in Leishmania donovani promastigotes that was previously demonstrated to be safe and orally active against visceral leishmaniasis (VL). K-09 caused depolarization of the mitochondrion and the generation of reactive oxygen species, triggering an apoptotic response in L. donovani promastigotes. Mitochondrial dysfunction subsequently resulted in the release of cytochrome c into the cytosol, impairing ATP production. Oxidative stress caused the depletion of reduced glutathione, while pretreatment with antioxidant N-acetyl cysteine (NAC) was able to abrogate oxidative stress. However, NAC failed to restore the mitochondrial membrane potential or intracellular calcium homeostasis after K-09 treatment, suggesting that the generation of oxidative stress is a downstream event relative to the other events. Caspase-3/-7-like protease activity and genomic DNA fragmentation were observed. Electron microscopy studies revealed gross morphological alterations typical of apoptosis, including severe mitochondrial damage, pyknosis of the nucleus, structural disruption of the mitochondrion-kinetoplast complex, flagellar pocket alterations, and the displacement of organelles. Moreover, an increased number of lipid droplets was detected after K-09 treatment, which is suggestive of altered lipid metabolism. Our results indicate that K-09 induces mitochondrial dysfunction and oxidative stress-mediated apoptotic cell death in L. donovani promastigotes, sharing many features with metazoan apoptosis. These mechanistic insights provide a basis for further investigation toward the development of K-09 as a potential drug candidate for VL. PMID:25070112

  6. A Clinical, Neuropathological and Genetic Study of Homozygous A467T POLG-Related Mitochondrial Disease

    Science.gov (United States)

    Rajakulendran, Sanjeev; Pitceathly, Robert D. S.; Taanman, Jan-Willem; Costello, Harry; Sweeney, Mary G.; Woodward, Cathy E.; Jaunmuktane, Zane; Holton, Janice L.; Jacques, Thomas S.; Harding, Brian N.; Fratter, Carl; Hanna, Michael G.; Rahman, Shamima

    2016-01-01

    Mutations in the nuclear gene POLG (encoding the catalytic subunit of DNA polymerase gamma) are an important cause of mitochondrial disease. The most common POLG mutation, A467T, appears to exhibit considerable phenotypic heterogeneity. The mechanism by which this single genetic defect results in such clinical diversity remains unclear. In this study we evaluate the clinical, neuropathological and mitochondrial genetic features of four unrelated patients with homozygous A467T mutations. One patient presented with the severe and lethal Alpers-Huttenlocher syndrome, which was confirmed on neuropathology, and was found to have a depletion of mitochondrial DNA (mtDNA). Of the remaining three patients, one presented with mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes (MELAS), one with a phenotype in the Myoclonic Epilepsy, Myopathy and Sensory Ataxia (MEMSA) spectrum and one with Sensory Ataxic Neuropathy, Dysarthria and Ophthalmoplegia (SANDO). All three had secondary accumulation of multiple mtDNA deletions. Complete sequence analysis of muscle mtDNA using the MitoChip resequencing chip in all four cases demonstrated significant variation in mtDNA, including a pathogenic MT-ND5 mutation in one patient. These data highlight the variable and overlapping clinical and neuropathological phenotypes and downstream molecular defects caused by the A467T mutation, which may result from factors such as the mtDNA genetic background, nuclear genetic modifiers and environmental stressors. PMID:26735972

  7. A Clinical, Neuropathological and Genetic Study of Homozygous A467T POLG-Related Mitochondrial Disease.

    Directory of Open Access Journals (Sweden)

    Sanjeev Rajakulendran

    Full Text Available Mutations in the nuclear gene POLG (encoding the catalytic subunit of DNA polymerase gamma are an important cause of mitochondrial disease. The most common POLG mutation, A467T, appears to exhibit considerable phenotypic heterogeneity. The mechanism by which this single genetic defect results in such clinical diversity remains unclear. In this study we evaluate the clinical, neuropathological and mitochondrial genetic features of four unrelated patients with homozygous A467T mutations. One patient presented with the severe and lethal Alpers-Huttenlocher syndrome, which was confirmed on neuropathology, and was found to have a depletion of mitochondrial DNA (mtDNA. Of the remaining three patients, one presented with mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes (MELAS, one with a phenotype in the Myoclonic Epilepsy, Myopathy and Sensory Ataxia (MEMSA spectrum and one with Sensory Ataxic Neuropathy, Dysarthria and Ophthalmoplegia (SANDO. All three had secondary accumulation of multiple mtDNA deletions. Complete sequence analysis of muscle mtDNA using the MitoChip resequencing chip in all four cases demonstrated significant variation in mtDNA, including a pathogenic MT-ND5 mutation in one patient. These data highlight the variable and overlapping clinical and neuropathological phenotypes and downstream molecular defects caused by the A467T mutation, which may result from factors such as the mtDNA genetic background, nuclear genetic modifiers and environmental stressors.

  8. Mitochondrial disease heterogeneity: a prognostic challenge.

    Science.gov (United States)

    Moggio, Maurizio; Colombo, Irene; Peverelli, Lorenzo; Villa, Luisa; Xhani, Rubjona; Testolin, Silvia; Di Mauro, Salvatore; Sciacco, Monica

    2014-10-01

    Mitochondrial diseases are a heterogeneous group of progressive, genetically transmitted, multisystem disorders caused by impaired mitochondrial function. The disease course for individuals with mitochondrial myopathies varies greatly from patient to patient because disease progression largely depends on the type of disease and on the degree of involvement of various organs which makes the prognosis unpredictable both within the same family and among families with the same mutation. This is particularly, but not exclusively, true for mitochondrial disorders caused by mtDNA point mutations, which are maternally inherited and subject to the randomness of the heteroplasmy. For this reason, the prognosis cannot be given by single mitochondrial disease, but should be formulated by any single mitochondrial disease-related event or complication keeping in mind that early recognition and treatment of symptoms are crucial for the prognosis. The following approach can help prevent severe organ dysfunctions or at least allow early diagnosis and treatment of disease-related complications. PMID:25709378

  9. Mitochondrial dysfunction and risk of cancer

    DEFF Research Database (Denmark)

    Lund, M; Melbye, M; Diaz, L J;

    2015-01-01

    BACKGROUND: Mitochondrial mutations are commonly reported in tumours, but it is unclear whether impaired mitochondrial function per se is a cause or consequence of cancer. To elucidate this, we examined the risk of cancer in a nationwide cohort of patients with mitochondrial dysfunction. METHODS......: We used nationwide results on genetic testing for mitochondrial disease and the Danish Civil Registration System, to construct a cohort of 311 patients with mitochondrial dysfunction. A total of 177 cohort members were identified from genetic testing and 134 genetically untested cohort members were...... mDNA mutation, cases=13. CONCLUSIONS: Patients with mitochondrial dysfunction do not appear to be at increased risk of cancer compared with the general population....

  10. Oxidative stress, mitochondrial damage and neurodegenerative diseases****

    Institute of Scientific and Technical Information of China (English)

    Chunyan Guo; Li Sun; Xueping Chen; Danshen Zhang

    2013-01-01

    Oxidative stress and mitochondrial damage have been implicated in the pathogenesis of several neurodegenerative diseases, including Alzheimer’s disease, Parkinson’s disease and amyotrophic lateral sclerosis. Oxidative stress is characterized by the overproduction of reactive oxygen species, which can induce mitochondrial DNA mutations, damage the mitochondrial respiratory chain, alter membrane permeability, and influence Ca2+ homeostasis and mitochondrial defense systems. Al these changes are implicated in the development of these neurodegenerative diseases, mediating or amplifying neuronal dysfunction and triggering neurodegeneration. This paper summarizes the contribution of oxidative stress and mitochondrial damage to the onset of neurodegenerative eases and discusses strategies to modify mitochondrial dysfunction that may be attractive thera-peutic interventions for the treatment of various neurodegenerative diseases.

  11. Keshan disease and mitochondrial cardiomyopathy

    Institute of Scientific and Technical Information of China (English)

    YANG; Fuyu

    2006-01-01

    Keshan disease (KD) is a potentially fatal form of cardiomyopathy (disease of the heart muscle) endemic in certain areas of China. From 1984 to 1986, a national comprehensive scientific investigation on KD in Chuxiong region of Yunnan Province in the southwest China was conducted. The investigation team was composed of epidemiologists, clinic doctors, pathologists, biochemists, biophysicists and specialists in ecological environment. Results of pathological, biochemical and biophysical as well as clinical studies showed: an obvious increase of enlarged and swollen mitochondria with distended crista membranes in myocardium from patients with KD; significant reductions in the activity of oxidative phosphorylation (succinate dehydrogenase, cytochrome oxidase, succinate oxidase, H+-ATPase) of affected mitochondria; decrease in CoQ, cardiolipin, Se and GSHPx activity, while obvious increase in the Ca2+ content. So, it was suggested that mitochondria are the predominant target of the pathogenic factors of KD. Before Chuxiong KD survey only a few cases of mitochondrial cardiomyopathy were studied. During the multidisciplinary scientific investigation on KD in Chuxiong a large amount of samples from KD cases and the positive controls were examined. On the basis of the results obtained it was suggested that KD might be classified as a "Mitochondrial Cardiomyopathy" endemic in China. This is one of the achievements in the three years' survey in Chuxiong and is valuable not only to the deeper understanding of pathogenic mechanism of KD but also to the study of mitochondrial cardiomyopathy in general.Keshan disease is not a genetic disease, but is closely related to the malnutrition (especially microelement Se deficiency). KD occurs along a low Se belt, and Se supplementation has been effective in prevention of such disease. The incidence of KD has sharply decreased along with the steady raise of living standard and realization of preventive measures. At present, patients of

  12. Pharmacological effect of carvacrol on D: -galactosamine-induced mitochondrial enzymes and DNA damage by single-cell gel electrophoresis.

    Science.gov (United States)

    Aristatile, Balakrishnan; Al-Numair, Khalid S; Al-Assaf, Abdullah H; Pugalendi, Kodukkur Viswanathan

    2011-07-01

    The present study aimed at investigating the effect of carvacrol on hepatic mitochondrial enzyme activities and DNA damage in D: -galactosamine (D: -GalN)-induced hepatotoxicity in male albino Wistar rats. The activities of hepatic mitochondrial enzymes such as isocitrate dehydrogenase, α-ketoglutarate dehydrogenase, succinate dehydrogenase, malate dehydrogenase, NADPH dehydrogenase and cytochrome c oxidase significantly decreased in D: -GalN-hepatotoxic rats, and administration of carvacrol brought these parameters towards normality. In D: -GalN-hepatotoxic rats, the hepatic mitochondrial concentration of thiobarbituric acid reactive substances significantly increased, and administration of carvacrol significantly reduced them towards normality. Furthermore, the activities of enzymatic antioxidants such as superoxide dismutase and glutathione peroxidase and the levels of non-enzymatic antioxidants such as vitamin C, vitamin E and reduced glutathione decreased significantly in the liver mitochondria. Administration of carvacrol returned the enzymatic and non-enzymatic antioxidants towards normality. D: -GalN-hepatotoxic rats had increased DNA damage, which administration of carvacrol significantly decreased. These results suggest that carvacrol has liver mitochondrial antioxidant properties and possesses a defensive effect against mitochondrial enzymes and DNA damage in D: -GalN-induced rats.

  13. Influence of Roller Burnishing Parameters on Depletion of Plasticity Reserve

    Science.gov (United States)

    Blumenstein, V. Yu; Petrenko, K. P.

    2016-04-01

    Roller burnishing process considerably increases surface quality and service life of machine parts. Efficiency of roller burnishing rises greatly when technological inheritance (TI) is taken into account. Research results of degree of plasticity reserve depletion (DPRD) while roller burnishing are presented. Results obtained made it possible to establish mechanisms of strain accumulation and plasticity reserve depletion according to roller burnishing parameters.

  14. Use, effects and legal standing of depleted uranium munitions

    International Nuclear Information System (INIS)

    The paper provides a brief description of depleted uranium and its use in weapons. Several exposure scenarios are described, and examples of the use of DU ammunition in training, testing, and combat are provided. A summary of depleted uranium's health and environmental effects follows, and the paper concludes with a brief analysis of the legal standing of DU munitions under international humanitarian law

  15. Effect of greenhouse gas emissions on stratospheric ozone depletion

    NARCIS (Netherlands)

    Velders GJM; LLO

    1997-01-01

    The depletion of the ozone layer is caused mainly by the increase in emissions of chlorine- and bromine-containing compounds like CFCs, halons, carbon tetrachloride, methyl chloroform and methyl bromide. Emissions of greenhouse gases can affect the depletion of the ozone layer through atmospheric i

  16. Renal manifestations of genetic mitochondrial disease

    OpenAIRE

    O’Toole JF

    2014-01-01

    John F O'Toole Department of Internal Medicine, Division of Nephrology, MetroHealth Medical System, Case Western Reserve University School of Medicine, Cleveland, OH, USA Abstract: Mitochondrial diseases can be related to mutations in either the nuclear or mitochondrial genome. Childhood presentations are commonly associated with renal tubular dysfunction, but renal involvement is less commonly reported outside of this age-group. Mitochondrial diseases are notable for the significant...

  17. Mitochondrial Dynamics in Cardiovascular Health and Disease

    OpenAIRE

    Ong, Sang-Bing; Andrew R. Hall; Hausenloy, Derek J

    2013-01-01

    Significance: Mitochondria are dynamic organelles capable of changing their shape and distribution by undergoing either fission or fusion. Changes in mitochondrial dynamics, which is under the control of specific mitochondrial fission and fusion proteins, have been implicated in cell division, embryonic development, apoptosis, autophagy, and metabolism. Although the machinery for modulating mitochondrial dynamics is present in the cardiovascular system, its function there has only recently be...

  18. Mitochondrial Diseases: Clinical Features- Management of Patients

    Directory of Open Access Journals (Sweden)

    Filiz Koc

    2003-02-01

    Full Text Available Mitochondria are unique organells which their own DNA in cells. Human mitochondrial DNA is circular, double-stranded molecule and small. Because all mitochondria are contributed by the ovum during the formation of the zygote, the mitochondrial genom is transmitted by maternal inheritance. Multisystem disorders such as deafness, cardiomyopathy, miyopathy can be seen in mitochondrial diseases. [Archives Medical Review Journal 2003; 12(0.100: 14-31

  19. The mixture of "ecstasy" and its metabolites impairs mitochondrial fusion/fission equilibrium and trafficking in hippocampal neurons, at in vivo relevant concentrations.

    Science.gov (United States)

    Barbosa, Daniel José; Serrat, Romàn; Mirra, Serena; Quevedo, Martí; de Barreda, Elena Goméz; Àvila, Jesús; Ferreira, Luísa Maria; Branco, Paula Sério; Fernandes, Eduarda; Lourdes Bastos, Maria de; Capela, João Paulo; Soriano, Eduardo; Carvalho, Félix

    2014-06-01

    3,4-Methylenedioxymethamphetamine (MDMA; "ecstasy") is a potentially neurotoxic recreational drug of abuse. Though the mechanisms involved are still not completely understood, formation of reactive metabolites and mitochondrial dysfunction contribute to MDMA-related neurotoxicity. Neuronal mitochondrial trafficking, and their targeting to synapses, is essential for proper neuronal function and survival, rendering neurons particularly vulnerable to mitochondrial dysfunction. Indeed, MDMA-associated disruption of Ca(2+) homeostasis and ATP depletion have been described in neurons, thus suggesting possible MDMA interference on mitochondrial dynamics. In this study, we performed real-time functional experiments of mitochondrial trafficking to explore the role of in situ mitochondrial dysfunction in MDMA's neurotoxic actions. We show that the mixture of MDMA and six of its major in vivo metabolites, each compound at 10μM, impaired mitochondrial trafficking and increased the fragmentation of axonal mitochondria in cultured hippocampal neurons. Furthermore, the overexpression of mitofusin 2 (Mfn2) or dynamin-related protein 1 (Drp1) K38A constructs almost completely rescued the trafficking deficits caused by this mixture. Finally, in hippocampal neurons overexpressing a Mfn2 mutant, Mfn2 R94Q, with impaired fusion and transport properties, it was confirmed that a dysregulation of mitochondrial fission/fusion events greatly contributed to the reported trafficking phenotype. In conclusion, our study demonstrated, for the first time, that the mixture of MDMA and its metabolites, at concentrations relevant to the in vivo scenario, impaired mitochondrial trafficking and increased mitochondrial fragmentation in hippocampal neurons, thus providing a new insight in the context of "ecstasy"-induced neuronal injury.

  20. CGP37157, an inhibitor of the mitochondrial Na+/Ca2+ exchanger, protects neurons from excitotoxicity by blocking voltage-gated Ca2+ channels.

    Science.gov (United States)

    Ruiz, A; Alberdi, E; Matute, C

    2014-04-10

    Inhibition of the mitochondrial Na(+)/Ca(2+) exchanger (NCLX) by CGP37157 is protective in models of neuronal injury that involve disruption of intracellular Ca(2+) homeostasis. However, the Ca(2+) signaling pathways and stores underlying neuroprotection by that inhibitor are not well defined. In the present study, we analyzed how intracellular Ca(2+) levels are modulated by CGP37157 (10 μM) during NMDA insults in primary cultures of rat cortical neurons. We initially assessed the presence of NCLX in mitochondria of cultured neurons by immunolabeling, and subsequently, we analyzed the effects of CGP37157 on neuronal Ca(2+) homeostasis using cameleon-based mitochondrial Ca(2+) and cytosolic Ca(2+) ([Ca(2+)]i) live imaging. We observed that NCLX-driven mitochondrial Ca(2+) exchange occurs in cortical neurons under basal conditions as CGP37157 induced a decrease in [Ca(2)]i concomitant with a Ca(2+) accumulation inside the mitochondria. In turn, CGP37157 also inhibited mitochondrial Ca(2+) efflux after the stimulation of acetylcholine receptors. In contrast, CGP37157 strongly prevented depolarization-induced [Ca(2+)]i increase by blocking voltage-gated Ca(2+) channels (VGCCs), whereas it did not induce depletion of ER Ca(2+) stores. Moreover, mitochondrial Ca(2+) overload was reduced as a consequence of diminished Ca(2+) entry through VGCCs. The decrease in cytosolic and mitochondrial Ca(2+) overload by CGP37157 resulted in a reduction of excitotoxic mitochondrial damage, characterized here by a reduction in mitochondrial membrane depolarization, oxidative stress and calpain activation. In summary, our results provide evidence that during excitotoxicity CGP37157 modulates cytosolic and mitochondrial Ca(2+) dynamics that leads to attenuation of NMDA-induced mitochondrial dysfunction and neuronal cell death by blocking VGCCs.

  1. Mitochondrial transcription termination factor 2 binds to entire mitochondrial DNA and negatively regulates mitochondrial gene expression

    Institute of Scientific and Technical Information of China (English)

    Weiwei Huang; Min Yu; Yang Jiao; Jie Ma; Mingxing Ma; Zehua Wang; Hong Wu; Deyong Tan

    2011-01-01

    Mitochondrial transcription termination factor 2 (mTERF2) is a mitochondriai matrix protein that binds to the mitochondriai DNA.Previous studies have shown that overexpression of mTERF2 can inhibit cell proliferation, but the mechanism has not been well defined so far.This study aimed to present the binding pattern of mTERF2 to the mitochondrial DNA (mtDNA) in vivo, and investigated the biological function of mTERF2 on the replication of mtDNA, mRNA transcription, and protein translation.The mTERF2 binding to entire mtDNA was identified via the chromatin immunoprecipitation analysis.The mtDNA replication efficiency and expression levels of mitochondria genes were significantly inhibited when the mTERF2 was overexpressed in HeLa cells.The inhibition level of mtDNA content was the same with the decreased levels of mRNA and mitochondrial protein expression.Overall, the mTERF2 might be a cell growth inhibitor based on its negative effect on mtDNA replication, which eventually own-regulated all of the oxidative phosphorylation components in the mitochondria that were essential for the cell's energy metabolism.

  2. The Abiotic Depletion Potential: Background, Updates, and Future

    Directory of Open Access Journals (Sweden)

    Lauran van Oers

    2016-03-01

    Full Text Available Depletion of abiotic resources is a much disputed impact category in life cycle assessment (LCA. The reason is that the problem can be defined in different ways. Furthermore, within a specified problem definition, many choices can still be made regarding which parameters to include in the characterization model and which data to use. This article gives an overview of the problem definition and the choices that have been made when defining the abiotic depletion potentials (ADPs for a characterization model for abiotic resource depletion in LCA. Updates of the ADPs since 2002 are also briefly discussed. Finally, some possible new developments of the impact category of abiotic resource depletion are suggested, such as redefining the depletion problem as a dilution problem. This means taking the reserves in the environment and the economy into account in the reserve parameter and using leakage from the economy, instead of extraction rate, as a dilution parameter.

  3. Ozone depletion during solar proton events in solar cycle 21

    Science.gov (United States)

    Mcpeters, R. D.; Jackman, C. H.

    1985-01-01

    Ozone profile data from the Solar Backscattered Ultraviolet Instrument on Nimbus 7 from 1979 to the present and clear cases of ozone destruction associated with five sudden proton events (SPEs) on June 7, 1979, August 21, 1979, October 13-14, 1981, July 13, 1982, and December 8, 1982 are found. During the SPE on July 13, 1982, the largest of this solar cycle, no depletion at all at 45 km is observed, but there is a 15 percent ozone depletion at 50 km increasing to 27 percent at 55 km, all at a solar zenith angle of 85 deg. A strong variation of the observed depletion with solar zenith angle is found, with maximum depletion occurring at the largest zenith angles (near 85 deg) decreasing to near zero for angles below about 70 deg. The observed depletion is short lived, disappearing within hours of the end of the SPE.

  4. Regulation of new depleted uranium uses

    International Nuclear Information System (INIS)

    This report evaluates how the existing U.S. Nuclear Regulatory Commission (NRC) regulatory structure and pending modifications would affect full deployment into radiologically uncontrolled areas of certain new depleted uranium (DU) uses being studied as part of the U.S. Department of Energy's DU uses research and development program. Such new DU uses include as catalysts (for destroying volatile organic compounds in off-gases from industrial processes and for hydrodesulfurization [HDS] of petroleum fuels), semiconductors (for fabricating integrated circuits, solar cells, or thermoelectric devices, especially if such articles are expected to have service in hostile environments), and electrodes (for service in solid oxide fuel cells, in photoelectrochemical cells used to produce hydrogen, and in batteries). The report describes each new DU use and provides a detailed analysis of whether any existing NRC licensing exemption or general license would be available to users of products and devices manufactured to deploy the new use. Although one existing licensing exemption was found to be possibly available for catalysts used for HDS of petroleum fuels and one general license was found to be possibly available for catalysts, semiconductors, and electrodes used in hydrogen production or batteries, existing regulations would require most users of products and devices deploying new DU uses to obtain specific source material licenses from the NRC or an Agreement State. This situation would not be improved by pending regulatory modifications. Thus, deployment of new DU uses may be limited because persons having no previous experience with NRC or Agreement State regulations may be hesitant to incur the costs and inconvenience of regulatory compliance, unless using a DU-containing product or device offers a substantial economic benefit over nonradioactive alternatives. Accordingly, estimating the risk of deploying new DU-containing products and devices in certain

  5. Deuterium depleted water. Present applications and prospects

    International Nuclear Information System (INIS)

    The deuterium depleted water, DDW, is distilled, microbiologically pure water with an isotopic concentration D/(D+H) under 145 ppm, the natural water value. At ICSI Rm Valcea a procedure was developed and a patent was recorded for the method and installation for obtaining DDW. The procedure consists in vacuum distillation of natural water on columns equipped with highly performing ordered packing. The system allows obtaining DDW at isotopic concentration within the range 20-120 ppm. Biological studies showed that treatment with this DDW reduced significantly the high rate in L929 linear fibroblast cells and annihilated the tumoral growth in xenotransplant. It was suggested that the deuterium occurring naturally has an essential in converting the signals regulating the cellular cycling. A vast program based on collaborations of ICSI with different specialized research institutes in Romania was initiated and important results already obtained among which one can mention: - DDW determines an increase of vascular reactivity seemingly endotelio-dependent and implying radical species (superoxides, nitric oxides); - immunity defense reaction represented by the opsonic, bactericide and phagocytic capacity are stimulated; - animals pre-treated with DDW present an increased resistance to both sub-lethal and lethal doses of gamma radiations, suggesting a radioprotective property; - study of artificial fecundation in fishes with fecundating solution containing an 1:1 mixture of DDW and distilled water showed the beneficent effects both in embryonal development and growth in alevins; - an increase of metabolism rate in aquatic macrophytes following the dilution of spectral energy of sea water mixed with DDW was observed; - studies on three genotypes of Zea mays showed significant effects on coleoptile growth. At present programs for studying prevention and treatment of tumors and various cancer forms are underway

  6. Ozone Depletion Potential of CH3Br

    Science.gov (United States)

    Sander, Stanley P.; Ko, Malcolm K. W.; Sze, Nien Dak; Scott, Courtney; Rodriquez, Jose M.; Weisenstein, Debra K.

    1998-01-01

    The ozone depletion potential (ODP) of methyl bromide (CH3Br) can be determined by combining the model-calculated bromine efficiency factor (BEF) for CH3Br and its atmospheric lifetime. This paper examines how changes in several key kinetic data affect BEF. The key reactions highlighted in this study include the reaction of BrO + H02, the absorption cross section of HOBr, the absorption cross section and the photolysis products of BrON02, and the heterogeneous conversion of BrON02 to HOBR and HN03 on aerosol particles. By combining the calculated BEF with the latest estimate of 0.7 year for the atmospheric lifetime of CH3Br, the likely value of ODP for CH3Br is 0.39. The model-calculated concentration of HBr (approximately 0.3 pptv) in the lower stratosphere is substantially smaller than the reported measured value of about I pptv. Recent publications suggested models can reproduce the measured value if one assumes a yield for HBr from the reaction of BrO + OH or from the reaction of BrO + H02. Although the DeAlore et al. evaluation concluded any substantial yield of HBr from BrO + HO2 is unlikely, for completeness, we calculate the effects of these assumed yields on BEF for CH3Br. Our calculations show that the effects are minimal: practically no impact for an assumed 1.3% yield of HBr from BrO + OH and 10% smaller for an assumed 0.6% yield from BrO + H02.

  7. Impact of ozone depletion on immune function

    Energy Technology Data Exchange (ETDEWEB)

    Jeevan, A.; Kripke, M.L. (Univ. of Texas, Houston, TX (United States). Dept. of Immunology)

    1993-06-01

    Depletion of stratospheric ozone is expected to lead to an increase in the amount of UV-B radiation present in sunlight. In addition to its well known ability to cause skin cancer, UV-B radiation has been shown to alter the immune system. The immune system is the body's primary defense mechanism against infectious diseases and protects against the development of certain types of cancer. Any impairment of immune function may jeopardize health by increasing susceptibility to infectious diseases, increasing the severity of infections, or delaying recovery for infections. In addition, impaired immune function can increase the incidence of certain cancers, particularly cancers of the skin. Research carried out with laboratory animals over the past 15 years has demonstrated that exposure of the skin to UV-B radiation can suppress certain types of immune responses. These include rejection of UV-induced skin cancers and melanomas, contact allergy reactions to chemicals, delayed-type hypersensitivity responses to microbial and other antigens, and phagocytosis and elimination of certain bacteria from lymphoid tissues. Recent studies with mycobacterial infection of mice demonstrated that exposure to UV-B radiation decreased the delayed hypersensitivity response to mycobacterial antigens and increased the severity of infection. In humans, UV-B radiation has also been shown to impair the contact allergy response. These studies demonstrate that UV radiation can decrease immune responses in humans and laboratory and raise the possibility that increased exposure to UV-B radiation could adversely affect human health by increasing the incidence or severity of certain infectious diseases.

  8. Deuterium depleted water. Romanian achievements and prospects

    International Nuclear Information System (INIS)

    The deuterium depleted water (DDW) is microbiologically pure distilled water with a deuterium content lower than that of natural waters which amounts to 140 - 150 ppm D/(D+H); variations depend on geographical zone and altitude. The procedure of obtaining DDW is based on isotopic separation of natural water by vacuum distillation. Isotope concentration can be chosen within 20 to 120 ppm D/(D+H). The ICSI at Rm. Valcea has patented the procedure and equipment for the production of DDW. According to the document SF-01-2002/INC-DTCI - ICSI Rm. Valcea, the product has a D/(D+H) isotope concentration of 25 ± 5. Studies and research for finding the effects and methods of application in different fields were initiated and developed in collaboration with different institutes in Romania. The following important results obtained so far could be mentioned: - absence of toxicity upon organisms; - activation of vascular reactivity; - enhancement of defence capacity of the organism through non-specific immunity activation; - increase of salmonid reproduction capacity and enhancement of the adaptability of alevins to the environmental conditions; - radioprotective effect to ionizing radiation; - maintaining meat freshness through osmotic shock; - stimulation of growth of aquatic macrophytes; - enhancement of culture plant development in certain ontogenetic stages. Mostly, the results and practical applications of the research were patented and awarded with gold medals at international invention fairs. At present, research-development programmes are undergoing to find active biological features of DDW in fighting cancer, on one hand, and its applicability as food additive of pets or performing animals, on the other hand

  9. Mitochondrial Cristae: Where Beauty Meets Functionality.

    Science.gov (United States)

    Cogliati, Sara; Enriquez, Jose A; Scorrano, Luca

    2016-03-01

    Mitochondrial cristae are dynamic bioenergetic compartments whose shape changes under different physiological conditions. Recent discoveries have unveiled the relation between cristae shape and oxidative phosphorylation (OXPHOS) function, suggesting that membrane morphology modulates the organization and function of the OXPHOS system, with a direct impact on cellular metabolism. As a corollary, cristae-shaping proteins have emerged as potential modulators of mitochondrial bioenergetics, a concept confirmed by genetic experiments in mouse models of respiratory chain deficiency. Here, we review our knowledge of mitochondrial ultrastructural organization and how it impacts mitochondrial metabolism.

  10. Mitochondrial Cristae: Where Beauty Meets Functionality.

    Science.gov (United States)

    Cogliati, Sara; Enriquez, Jose A; Scorrano, Luca

    2016-03-01

    Mitochondrial cristae are dynamic bioenergetic compartments whose shape changes under different physiological conditions. Recent discoveries have unveiled the relation between cristae shape and oxidative phosphorylation (OXPHOS) function, suggesting that membrane morphology modulates the organization and function of the OXPHOS system, with a direct impact on cellular metabolism. As a corollary, cristae-shaping proteins have emerged as potential modulators of mitochondrial bioenergetics, a concept confirmed by genetic experiments in mouse models of respiratory chain deficiency. Here, we review our knowledge of mitochondrial ultrastructural organization and how it impacts mitochondrial metabolism. PMID:26857402

  11. Drosophila Porin/VDAC affects mitochondrial morphology.

    Directory of Open Access Journals (Sweden)

    Jeehye Park

    Full Text Available Voltage-dependent anion channel (VDAC has been suggested to be a mediator of mitochondrial-dependent cell death induced by Ca(2+ overload, oxidative stress and Bax-Bid activation. To confirm this hypothesis in vivo, we generated and characterized Drosophila VDAC (porin mutants and found that Porin is not required for mitochondrial apoptosis, which is consistent with the previous mouse studies. We also reported a novel physiological role of Porin. Loss of porin resulted in locomotive defects and male sterility. Intriguingly, porin mutants exhibited elongated mitochondria in indirect flight muscle, whereas Porin overexpression produced fragmented mitochondria. Through genetic analysis with the components of mitochondrial fission and fusion, we found that the elongated mitochondria phenotype in porin mutants were suppressed by increased mitochondrial fission, but enhanced by increased mitochondrial fusion. Furthermore, increased mitochondrial fission by Drp1 expression suppressed the flight defects in the porin mutants. Collectively, our study showed that loss of Drosophila Porin results in mitochondrial morphological defects and suggested that the defective mitochondrial function by Porin deficiency affects the mitochondrial remodeling process.

  12. Complete mitochondrial genome of Drosophila albomicans.

    Science.gov (United States)

    Kang, Xiongbin; Luo, Xiao; Zhang, Zhi; Zhang, Zhen; Yang, Junqing; Bi, Guiqi

    2016-09-01

    Drosophila albomicans has been widely used as an important animal model for chromosome evolution. In this study, the mitochondrial genome sequence of this species is determined and described for the first time. The mitochondrial genome (15 849 bp) encompasses two rRNA, 22 tRNA, and 13 protein-coding genes. Genome content and structure are similar to those reported from other Drosophila mitochondrial genomes. Phylogeny analysis indicates that D. albomicans have a closer genetic relationship with Drosophil aincompta and Drosophil alittoralis. This mitochondrial genome is potentially important for studying molecular evolution and conservation genetics in Drosophila genus. PMID:26358579

  13. Senior Administrators Should Have Administrative Contracts.

    Science.gov (United States)

    Posner, Gary J.

    1987-01-01

    Recognizing that termination is viewed by the employee as the equivalent to capital punishment of a career, an administrative contract can reduce the emotional and financial entanglements that often result. Administrative contracts are described. (MLW)

  14. Loss of mitochondrial exo/endonuclease EXOG affects mitochondrial respiration and induces ROS mediated cardiomyocyte hypertrophy

    NARCIS (Netherlands)

    Tigchelaar, Wardit; Yu, Hongjuan; De Jong, Anne Margreet; van Gilst, Wiek H; van der Harst, Pim; Westenbrink, B Daan; de Boer, Rudolf A; Sillje, Herman H W

    2015-01-01

    Recently, a genetic variant in the mitochondrial exo/endo nuclease EXOG, which has been implicated in mitochondrial DNA repair, was associated with cardiac function. The function of EXOG in cardiomyocytes is still elusive. Here we investigated the role of EXOG in mitochondrial function and hypertrop

  15. The mitochondrial transcription factor A functions in mitochondrial base excision repair

    DEFF Research Database (Denmark)

    Canugovi, Chandrika; Maynard, Scott; Bayne, Anne-Cécile V;

    2010-01-01

    Mitochondrial transcription factor A (TFAM) is an essential component of mitochondrial nucleoids. TFAM plays an important role in mitochondrial transcription and replication. TFAM has been previously reported to inhibit nucleotide excision repair (NER) in vitro but NER has not yet been detected i...

  16. Restoration of normal embryogenesis by mitochondrial supplementation in pig oocytes exhibiting mitochondrial DNA deficiency.

    Science.gov (United States)

    Cagnone, Gael L M; Tsai, Te-Sha; Makanji, Yogeshwar; Matthews, Pamela; Gould, Jodee; Bonkowski, Michael S; Elgass, Kirstin D; Wong, Ashley S A; Wu, Lindsay E; McKenzie, Matthew; Sinclair, David A; St John, Justin C

    2016-03-18

    An increasing number of women fail to achieve pregnancy due to either failed fertilization or embryo arrest during preimplantation development. This often results from decreased oocyte quality. Indeed, reduced mitochondrial DNA copy number (mitochondrial DNA deficiency) may disrupt oocyte quality in some women. To overcome mitochondrial DNA deficiency, whilst maintaining genetic identity, we supplemented pig oocytes selected for mitochondrial DNA deficiency, reduced cytoplasmic maturation and lower developmental competence, with autologous populations of mitochondrial isolate at fertilization. Supplementation increased development to blastocyst, the final stage of preimplantation development, and promoted mitochondrial DNA replication prior to embryonic genome activation in mitochondrial DNA deficient oocytes but not in oocytes with normal levels of mitochondrial DNA. Blastocysts exhibited transcriptome profiles more closely resembling those of blastocysts from developmentally competent oocytes. Furthermore, mitochondrial supplementation reduced gene expression patterns associated with metabolic disorders that were identified in blastocysts from mitochondrial DNA deficient oocytes. These results demonstrate the importance of the oocyte's mitochondrial DNA investment in fertilization outcome and subsequent embryo development to mitochondrial DNA deficient oocytes.

  17. The effect of mitochondrial calcium uniporter on mitochondrial fission in hippocampus cells ischemia/reperfusion injury

    Energy Technology Data Exchange (ETDEWEB)

    Zhao, Lantao; Li, Shuhong; Wang, Shilei, E-mail: wshlei@aliyun.com; Yu, Ning; Liu, Jia

    2015-06-05

    The mitochondrial calcium uniporter (MCU) transports free Ca{sup 2+} into the mitochondrial matrix, maintaining Ca{sup 2+} homeostasis, thus regulates the mitochondrial morphology. Previous studies have indicated that there was closely crosstalk between MCU and mitochondrial fission during the process of ischemia/reperfusion injury. This study constructed a hypoxia reoxygenation model using primary hippocampus neurons to mimic the cerebral ischemia/reperfusion injury and aims to explore the exactly effect of MCU on the mitochondrial fission during the process of ischemia/reperfusion injury and so as the mechanisms. Our results found that the inhibitor of the MCU, Ru360, decreased mitochondrial Ca{sup 2+} concentration, suppressed the expression of mitochondrial fission protein Drp1, MIEF1 and Fis1, and thus improved mitochondrial morphology significantly. Whereas spermine, the agonist of the MCU, had no significant impact compared to the I/R group. This study demonstrated that the MCU regulates the process of mitochondrial fission by controlling the Ca{sup 2+} transport, directly upregulating mitochondrial fission proteins Drp1, Fis1 and indirectly reversing the MIEF1-induced mitochondrial fusion. It also provides new targets for brain protection during ischemia/reperfusion injury. - Highlights: • We study MCU with primary neuron culture. • MCU induces mitochondrial fission. • MCU reverses MIEF1 effect.

  18. Protective effect of Phyllanthus fraternus against bromobenzene-induced mitochondrial dysfunction in rat kidney

    Institute of Scientific and Technical Information of China (English)

    Vadde Ramakrishna; Sriram Gopi; Oruganti H.Setty

    2012-01-01

    Phyllanthus fraternus (PF) (Euphorbiaceae) is used in ancient Indian traditional phytomedicine to treat various human diseases including hepatic and renal disorders.The present study was designed to investigate the protective effect of PF aqueous extract against bromobenzene-induced mitochondrial dysfunction in rat kidney,compared with vitamin E used as positive control.Male Wistar rats divided into six (A-F) groups and the experimental animals were administered bromobenzene with or without prior administration of PF extract or vitamin E.Animals were sacrificed and the kidneys obtained for studying mitochondrial function and histopathology.Administration of bromobenzene caused significant changes,including decrease in the mitochondrial respiration and P/O ratios,an increase in lipid peroxidation and protein oxidation,and a decrease in the activities of antioxidant enzymes (catalase,superoxide dismutase,glutathione reductase,and glutathione peroxidase) in mitochondria with significant histopathological changes in the kidney.However,prior administration of the PF extract showed significant protection against bromobenzene induced renal damage by reversing all above parameters.Mitochondrial dysfunction induced by bromobenzene was protected much better with the PF extract than with vitamin E.These results suggested that the Phyllanthus fraternus extract is an efficient armament against nephrotoxicity induced by bromobenzene.

  19. Tempol, a superoxide dismutase mimetic agent, ameliorates cisplatin-induced nephrotoxicity through alleviation of mitochondrial dysfunction in mice.

    Directory of Open Access Journals (Sweden)

    Lamiaa A Ahmed

    Full Text Available Mitochondrial dysfunction is a crucial mechanism by which cisplatin, a potent chemotherapeutic agent, causes nephrotoxicity where mitochondrial electron transport complexes are shifted mostly toward imbalanced reactive oxygen species versus energy production. In the present study, the protective role of tempol, a membrane-permeable superoxide dismutase mimetic agent, was evaluated on mitochondrial dysfunction and the subsequent damage induced by cisplatin nephrotoxicity in mice.Nephrotoxicity was assessed 72 h after a single i.p. injection of cisplatin (25 mg/kg with or without oral administration of tempol (100 mg/kg/day. Serum creatinine and urea as well as glucosuria and proteinuria were evaluated. Both kidneys were isolated for estimation of oxidative stress markers, adenosine triphosphate (ATP content and caspase-3 activity. Moreover, mitochondrial oxidative phosphorylation capacity, complexes I-IV activities and mitochondrial nitric oxide synthase (mNOS protein expression were measured along with histological examinations of renal tubular damage and mitochondrial ultrastructural changes. Tempol was effective against cisplatin-induced elevation of serum creatinine and urea as well as glucosuria and proteinuria. Moreover, pretreatment with tempol notably inhibited cisplatin-induced oxidative stress and disruption of mitochondrial function by restoring mitochondrial oxidative phosphorylation, complexes I and III activities, mNOS protein expression and ATP content. Tempol also provided significant protection against apoptosis, tubular damage and mitochondrial ultrastructural changes. Interestingly, tempol did not interfere with the cytotoxic effect of cisplatin against the growth of solid Ehrlich carcinoma.This study highlights the potential role of tempol in inhibiting cisplatin-induced nephrotoxicity without affecting its antitumor activity via amelioration of oxidative stress and mitochondrial dysfunction.

  20. Possible role of mtDNA depletion and respiratory chain defects in aristolochic acid I-induced acute nephrotoxicity

    Energy Technology Data Exchange (ETDEWEB)

    Jiang, Zhenzhou, E-mail: jiangcpu@yahoo.com.cn; Bao, Qingli, E-mail: bao_ql@126.com; Sun, Lixin, E-mail: slxcpu@126.com; Huang, Xin, E-mail: huangxinhx66@sohu.com; Wang, Tao, E-mail: wangtao1331@126.com; Zhang, Shuang, E-mail: cat921@sina.com; Li, Han, E-mail: hapo1101@163.com; Zhang, Luyong, E-mail: lyzhang@cpu.edu.cn

    2013-01-15

    This report describes an investigation of the pathological mechanism of acute renal failure caused by toxic tubular necrosis after treatment with aristolochic acid I (AAI) in Sprague–Dawley (SD) rats. The rats were gavaged with AAI at 0, 5, 20, or 80 mg/kg/day for 7 days. The pathologic examination of the kidneys showed severe acute tubular degenerative changes primarily affecting the proximal tubules. Supporting these results, we detected significantly increased concentrations of blood urea nitrogen (BUN) and creatinine (Cr) in the rats treated with AAI, indicating damage to the kidneys. Ultrastructural examination showed that proximal tubular mitochondria were extremely enlarged and dysmorphic with loss and disorientation of their cristae. Mitochondrial function analysis revealed that the two indicators for mitochondrial energy metabolism, the respiratory control ratio (RCR) and ATP content, were reduced in a dose-dependent manner after AAI treatment. The RCR in the presence of substrates for complex I was reduced more significantly than in the presence of substrates for complex II. In additional experiments, the activity of respiratory complex I, which is partly encoded by mitochondrial DNA (mtDNA), was more significantly impaired than that of respiratory complex II, which is completely encoded by nuclear DNA (nDNA). A real-time PCR assay revealed a marked reduction of mtDNA in the kidneys treated with AAI. Taken together, these results suggested that mtDNA depletion and respiratory chain defects play critical roles in the pathogenesis of kidney injury induced by AAI, and that the same processes might contribute to aristolochic acid-induced nephrotoxicity in humans. -- Highlights: ► AAI-induced acute renal failure in rats and the proximal tubule was the target. ► Tubular mitochondria were morphologically aberrant in ultrastructural examination. ► AAI impair mitochondrial bioenergetic function and mtDNA replication.

  1. Possible role of mtDNA depletion and respiratory chain defects in aristolochic acid I-induced acute nephrotoxicity

    International Nuclear Information System (INIS)

    This report describes an investigation of the pathological mechanism of acute renal failure caused by toxic tubular necrosis after treatment with aristolochic acid I (AAI) in Sprague–Dawley (SD) rats. The rats were gavaged with AAI at 0, 5, 20, or 80 mg/kg/day for 7 days. The pathologic examination of the kidneys showed severe acute tubular degenerative changes primarily affecting the proximal tubules. Supporting these results, we detected significantly increased concentrations of blood urea nitrogen (BUN) and creatinine (Cr) in the rats treated with AAI, indicating damage to the kidneys. Ultrastructural examination showed that proximal tubular mitochondria were extremely enlarged and dysmorphic with loss and disorientation of their cristae. Mitochondrial function analysis revealed that the two indicators for mitochondrial energy metabolism, the respiratory control ratio (RCR) and ATP content, were reduced in a dose-dependent manner after AAI treatment. The RCR in the presence of substrates for complex I was reduced more significantly than in the presence of substrates for complex II. In additional experiments, the activity of respiratory complex I, which is partly encoded by mitochondrial DNA (mtDNA), was more significantly impaired than that of respiratory complex II, which is completely encoded by nuclear DNA (nDNA). A real-time PCR assay revealed a marked reduction of mtDNA in the kidneys treated with AAI. Taken together, these results suggested that mtDNA depletion and respiratory chain defects play critical roles in the pathogenesis of kidney injury induced by AAI, and that the same processes might contribute to aristolochic acid-induced nephrotoxicity in humans. -- Highlights: ► AAI-induced acute renal failure in rats and the proximal tubule was the target. ► Tubular mitochondria were morphologically aberrant in ultrastructural examination. ► AAI impair mitochondrial bioenergetic function and mtDNA replication.

  2. Cost estimate report for the long-term management of depleted uranium hexafluoride : storage of depleted uranium metal

    International Nuclear Information System (INIS)

    This report contains a cost analysis of the long-term storage of depleted uranium in the form of uranium metal. Three options are considered for storage of the depleted uranium. These options are aboveground buildings, partly underground vaults, and mined cavities. Three cases are presented. In the first case, all the depleted uranium metal that would be produced from the conversion of depleted uranium hexafluoride (UF6) generated by the US Department of Energy (DOE) prior to July 1993 would be stored at the storage facility (100% Case). In the second case, half the depleted uranium metal would be stored at this storage facility (50% Case). In the third case, one-quarter of the depleted uranium metal would be stored at the storage facility (25% Case). The technical basis for the cost analysis presented in this report is principally found in the companion report, ANL/EAD/TM-100, ''Engineering Analysis Report for the Long-Term Management of Depleted Uranium Hexafluoride: Storage of Depleted Uranium Metal'', prepared by Argonne National Laboratory

  3. Differential effects of chronic monocyte depletion on macrophage populations

    Energy Technology Data Exchange (ETDEWEB)

    Volkman, A.; Chang, N.C.; Strausbauch, P.H.; Morahan, P.S.

    1983-09-01

    The administration of the bone-seeking isotope, /sup 89/Sr, to mice results in severe monocytopenia without any apparent effect on the numbers of resident peritoneal macrophages (M luminal diameter). An explanation for this dichotomy was sought by determining whether the residual blood monocytes were still an effective source of M luminal diameter after /sup 89/Sr treatment. Stem cell enumeration showed that a 90% fall in bone marrow macrophage colony-forming cells after /sup 89/Sr was accompanied by a 10-fold rise in splenic M-CFC. Splenectomy performed before /sup 89/Sr treatment, however, resulted in little additional monocytopenia and had no affect on the numbers of resident peritoneal M luminal diameter even when sampling was extended to 31 days, an interval beyond the accepted half-time for peritoneal M luminal diameter. Intraperitoneal injections of thioglycollate or Corynebacterium parvum elicited few or no monocyte-M luminal diameter during respective intervals of 4 and 7 days. Elicitation with thioglycollate was attempted in tritiated thymidine-labeled mice 26 days after /sup 89/Sr. Four days later only a 2-fold increase in labeled peritoneal M luminal diameter was found in the /sup 89/Sr-treated mice compared with a 150-fold increase in the controls. Studies of the ectoenzymes 5'-nucleotidase, alkaline phosphodiesterase I, and leucine aminopeptidase in such elicitation experiments suggested that the observed changes in activities reflected the direct stimulation of resident M luminal diameter rather than monocyte immigration. Overall, the results indicate that treatment with /sup 89/Sr distinguishes two large populations of M luminal diameter on the basis of their dependence on bone marrow. M luminal diameter of inflammation reflect the monocytopenia and are severely and rapidly depleted by such treatment.

  4. Metallothionein deficiency aggravates depleted uranium-induced nephrotoxicity.

    Science.gov (United States)

    Hao, Yuhui; Huang, Jiawei; Gu, Ying; Liu, Cong; Li, Hong; Liu, Jing; Ren, Jiong; Yang, Zhangyou; Peng, Shuangqing; Wang, Weidong; Li, Rong

    2015-09-15

    Depleted uranium (DU) has been widely used in both civilian and military activities, and the kidney is the main target organ of DU during acute high-dose exposures. In this study, the nephrotoxicity caused by DU in metallothionein-1/2-null mice (MT-/-) and corresponding wild-type (MT+/+) mice was investigated to determine any associations with MT. Each MT-/- or MT+/+ mouse was pretreated with a single dose of DU (10mg/kg, intraperitoneal injection) or an equivalent volume of saline. After 4days of DU administration, kidney changes were assessed. After DU exposure, serum creatinine and serum urea nitrogen in MT-/- mice significantly increased than in MT+/+ mice, with more severe kidney pathological damage. Moreover, catalase and superoxide dismutase (SOD) decreased, and generation of reactive oxygen species and malondialdehyde increased in MT-/- mice. The apoptosis rate in MT-/- mice significantly increased, with a significant increase in both Bax and caspase 3 and a decrease in Bcl-2. Furthermore, sodium-glucose cotransporter (SGLT) and sodium-phosphate cotransporter (NaPi-II) were significantly reduced after DU exposure, and the change of SGLT was more evident in MT-/- mice. Finally, exogenous MT was used to evaluate the correlation between kidney changes induced by DU and MT doses in MT-/- mice. The results showed that, the pathological damage and cell apoptosis decreased, and SOD and SGLT levels increased with increasing dose of MT. In conclusion, MT deficiency aggravated DU-induced nephrotoxicity, and the molecular mechanisms appeared to be related to the increased oxidative stress and apoptosis, and decreased SGLT expression. PMID:26148447

  5. Mitochondrial tRNA cleavage by tRNA-targeting ribonuclease causes mitochondrial dysfunction observed in mitochondrial disease

    Energy Technology Data Exchange (ETDEWEB)

    Ogawa, Tetsuhiro, E-mail: atetsu@mail.ecc.u-tokyo.ac.jp; Shimizu, Ayano; Takahashi, Kazutoshi; Hidaka, Makoto; Masaki, Haruhiko, E-mail: amasaki@mail.ecc.u-tokyo.ac.jp

    2014-08-15

    Highlights: • MTS-tagged ribonuclease was translocated successfully to the mitochondrial matrix. • MTS-tagged ribonuclease cleaved mt tRNA and reduced COX activity. • Easy and reproducible method of inducing mt tRNA dysfunction. - Abstract: Mitochondrial DNA (mtDNA) is a genome possessed by mitochondria. Since reactive oxygen species (ROS) are generated during aerobic respiration in mitochondria, mtDNA is commonly exposed to the risk of DNA damage. Mitochondrial disease is caused by mitochondrial dysfunction, and mutations or deletions on mitochondrial tRNA (mt tRNA) genes are often observed in mtDNA of patients with the disease. Hence, the correlation between mt tRNA activity and mitochondrial dysfunction has been assessed. Then, cybrid cells, which are constructed by the fusion of an enucleated cell harboring altered mtDNA with a ρ{sup 0} cell, have long been used for the analysis due to difficulty in mtDNA manipulation. Here, we propose a new method that involves mt tRNA cleavage by a bacterial tRNA-specific ribonuclease. The ribonuclease tagged with a mitochondrial-targeting sequence (MTS) was successfully translocated to the mitochondrial matrix. Additionally, mt tRNA cleavage, which resulted in the decrease of cytochrome c oxidase (COX) activity, was observed.

  6. Mitochondrial tRNA cleavage by tRNA-targeting ribonuclease causes mitochondrial dysfunction observed in mitochondrial disease

    International Nuclear Information System (INIS)

    Highlights: • MTS-tagged ribonuclease was translocated successfully to the mitochondrial matrix. • MTS-tagged ribonuclease cleaved mt tRNA and reduced COX activity. • Easy and reproducible method of inducing mt tRNA dysfunction. - Abstract: Mitochondrial DNA (mtDNA) is a genome possessed by mitochondria. Since reactive oxygen species (ROS) are generated during aerobic respiration in mitochondria, mtDNA is commonly exposed to the risk of DNA damage. Mitochondrial disease is caused by mitochondrial dysfunction, and mutations or deletions on mitochondrial tRNA (mt tRNA) genes are often observed in mtDNA of patients with the disease. Hence, the correlation between mt tRNA activity and mitochondrial dysfunction has been assessed. Then, cybrid cells, which are constructed by the fusion of an enucleated cell harboring altered mtDNA with a ρ0 cell, have long been used for the analysis due to difficulty in mtDNA manipulation. Here, we propose a new method that involves mt tRNA cleavage by a bacterial tRNA-specific ribonuclease. The ribonuclease tagged with a mitochondrial-targeting sequence (MTS) was successfully translocated to the mitochondrial matrix. Additionally, mt tRNA cleavage, which resulted in the decrease of cytochrome c oxidase (COX) activity, was observed

  7. Deuterium depleted water. Current and potential applications

    International Nuclear Information System (INIS)

    Deuterium depleted water (DDW) is distilled, microbiologically pure water with a D/(D+H) isotopic content lower than the value 145 ppm of natural water. It is practically unnoxious, with a toxic potential pT 50 > 0.01 mol/kg c.m. At ICSI a procedure was worked out and patented and a facility was achieved for obtaining DDW. The procedure consists in continuous vacuum distillation of natural water on columns with highly performing ordered packings. DDW of controlled isotopic concentration D/(D+H) within the range 20-120 ppm, of quality similar to distilled water can be currently produced. Many studies were reported in literature evidencing the active biological properties of DDW. DDW lowered significantly the high division rate of the L929 linear fibroblast cell and blocked the tumoral growth in xenotransplants. It was suggested that the naturally occurring deuterium plays a prominent role in converting the signal implied in cellular cycle mechanism. Having in view the high significance of the experiments in this field, ICSI has promoted a programme of collaborations with Romanian institutes of various specialties to evaluate the biological effects of DDW with a D/(D+H) concentration of about 30 ppm. The following results obtained so far obtained should be highlighted: - DDW causes an increase of vascular reactivity both in rings isolated from thorax aorta and in vivo upon arterial pressure. The reactivity increase seems to be endothelium-depended and is achieved with participation of the radical species (superoxides, nitric oxide); - DDW stimulates the immunodefence reaction, as represented by the opsonic, bactericide and phagocytic capacity of the immunity system as well as by the increase of the number of polymorphonucleates; - animals pre-treated with DDW exhibit an increased resistance both to sublethal and lethal γ radiation doses, what suggests a radioprotective effect; - studies on artificial fecundation in fishes with fecundant solutions containing a 1

  8. Transcription-independent role for human mitochondrial RNA polymerase in mitochondrial ribosome biogenesis

    OpenAIRE

    Surovtseva, Yulia V; Shadel, Gerald S.

    2013-01-01

    Human mitochondrial RNA polymerase, POLRMT, is required for mitochondrial DNA (mtDNA) transcription and forms initiation complexes with human mitochondrial transcription factor B2 (h-mtTFB2). However, POLRMT also interacts with the paralogue of h-mtTFB2, h-mtTFB1, which is a 12S ribosomal RNA methyltransferase required for small (28S) mitochondrial ribosome subunit assembly. Herein, we show that POLRMT associates with h-mtTFB1 in 28S mitochondrial ribosome complexes that are stable in the abs...

  9. Ghrelin reduces hepatic mitochondrial fatty acid beta oxidation.

    Science.gov (United States)

    Rigault, C; Le Borgne, F; Georges, B; Demarquoy, J

    2007-04-01

    Ghrelin is a 28-amino-acid peptide secreted during starvation by gastric cells. Ghrelin physiologically induces food intake and seems to alter lipid and glucid metabolism in several tissues such as adipose tissue and liver. Liver has a key position in lipid metabolism as it allows the metabolic orientation of fatty acids between oxidation and esterification. We investigated the effects of peripheral ghrelin administration on 2 crucial parameters of fatty acid oxidation: the levocarnitine (L-carnitine)-dependent entry of the fatty acids in the mitochondria and the mitochondrial fatty acid oxidation. Ghrelin was either given to rats prior to the hepatocyte preparation and culture or used to treat hepatocytes prepared from control animals. Direct incubation of ghrelin to raw hepatocytes did not induce any change in the studied parameters. In hepatocytes prepared from 3 nmol ghrelin-treated rats, a 44% reduction of the mitochondrial fatty acid oxidation while no alteration of the L-carnitine-related parameters were observed. These results suggested (a) that ghrelin has no direct effect on liver, and (b) that when administrated to a whole organism, ghrelin may alter the lipid metabolism and the energy balance through a marked decrease in liver fatty acid oxidation. PMID:17556859

  10. Associative Interactions in Crowded Solutions of Biopolymers Counteract Depletion Effects.

    Science.gov (United States)

    Groen, Joost; Foschepoth, David; te Brinke, Esra; Boersma, Arnold J; Imamura, Hiromi; Rivas, Germán; Heus, Hans A; Huck, Wilhelm T S

    2015-10-14

    The cytosol of Escherichia coli is an extremely crowded environment, containing high concentrations of biopolymers which occupy 20-30% of the available volume. Such conditions are expected to yield depletion forces, which strongly promote macromolecular complexation. However, crowded macromolecule solutions, like the cytosol, are very prone to nonspecific associative interactions that can potentially counteract depletion. It remains unclear how the cytosol balances these opposing interactions. We used a FRET-based probe to systematically study depletion in vitro in different crowded environments, including a cytosolic mimic, E. coli lysate. We also studied bundle formation of FtsZ protofilaments under identical crowded conditions as a probe for depletion interactions at much larger overlap volumes of the probe molecule. The FRET probe showed a more compact conformation in synthetic crowding agents, suggesting strong depletion interactions. However, depletion was completely negated in cell lysate and other protein crowding agents, where the FRET probe even occupied slightly more volume. In contrast, bundle formation of FtsZ protofilaments proceeded as readily in E. coli lysate and other protein solutions as in synthetic crowding agents. Our experimental results and model suggest that, in crowded biopolymer solutions, associative interactions counterbalance depletion forces for small macromolecules. Furthermore, the net effects of macromolecular crowding will be dependent on both the size of the macromolecule and its associative interactions with the crowded background.

  11. CO depletion in ATLASGAL-selected high-mass clumps

    Science.gov (United States)

    Giannetti, A.; Wyrowski, F.; Brand, J.; Csengeri, T.; Fontani, F.; Walmsley, C. M.; Nguyen Luong, Q.; Beuther, H.; Schuller, F.; Güsten, R.; Menten, K. M.

    2016-05-01

    In the low-mass regime, it is found that the gas-phase abundances of C-bearing molecules in cold starless cores rapidly decrease with increasing density. Here the molecules tend to stick to the grains, forming ice mantles. We study CO depletion in the TOP100 sample of the ATLASGAL survey, and investigate its correlation with evolutionary stage and with the physical parameters of the sources. We use low-J emission lines of CO isotopologues and the dust continuum emission to infer the depletion factor fD. RATRAN one-dimensional models were also used to determine fD and to investigate the presence of depletion above a density threshold. The isotopic ratios and optical depth were derived with a Bayesian approach. We find a significant number of clumps with a large CO depletion, up to ˜20. Larger values are found for colder clumps, thus for earlier evolutionary phases. For massive clumps in the earliest stages of evolution we estimate the radius of the region where CO depletion is important to be a few tenths of a pc. CO depletion in high-mass clumps seems to behave as in the low-mass regime, with less evolved clumps showing larger values for the depletion than their more evolved counterparts, and increasing for denser sources.

  12. Development of the point-depletion code DEPTH

    International Nuclear Information System (INIS)

    Highlights: ► The DEPTH code has been developed for the large-scale depletion system. ► DEPTH uses the data library which is convenient to couple with MC codes. ► TTA and matrix exponential methods are implemented and compared. ► DEPTH is able to calculate integral quantities based on the matrix inverse. ► Code-to-code comparisons prove the accuracy and efficiency of DEPTH. -- Abstract: The burnup analysis is an important aspect in reactor physics, which is generally done by coupling of transport calculations and point-depletion calculations. DEPTH is a newly-developed point-depletion code of handling large burnup depletion systems and detailed depletion chains. For better coupling with Monte Carlo transport codes, DEPTH uses data libraries based on the combination of ORIGEN-2 and ORIGEN-S and allows users to assign problem-dependent libraries for each depletion step. DEPTH implements various algorithms of treating the stiff depletion systems, including the Transmutation trajectory analysis (TTA), the Chebyshev Rational Approximation Method (CRAM), the Quadrature-based Rational Approximation Method (QRAM) and the Laguerre Polynomial Approximation Method (LPAM). Three different modes are supported by DEPTH to execute the decay, constant flux and constant power calculations. In addition to obtaining the instantaneous quantities of the radioactivity, decay heats and reaction rates, DEPTH is able to calculate the integral quantities by a time-integrated solver. Through calculations compared with ORIGEN-2, the validity of DEPTH in point-depletion calculations is proved. The accuracy and efficiency of depletion algorithms are also discussed. In addition, an actual pin-cell burnup case is calculated to illustrate the DEPTH code performance in coupling with the RMC Monte Carlo code

  13. Overexpression of mitochondrial sirtuins alters glycolysis and mitochondrial function in HEK293 cells.

    Directory of Open Access Journals (Sweden)

    Michelle Barbi de Moura

    Full Text Available SIRT3, SIRT4, and SIRT5 are mitochondrial deacylases that impact multiple facets of energy metabolism and mitochondrial function. SIRT3 activates several mitochondrial enzymes, SIRT4 represses its targets, and SIRT5 has been shown to both activate and repress mitochondrial enzymes. To gain insight into the relative effects of the mitochondrial sirtuins in governing mitochondrial energy metabolism, SIRT3, SIRT4, and SIRT5 overexpressing HEK293 cells were directly compared. When grown under standard cell culture conditions (25 mM glucose all three sirtuins induced increases in mitochondrial respiration, glycolysis, and glucose oxidation, but with no change in growth rate or in steady-state ATP concentration. Increased proton leak, as evidenced by oxygen consumption in the presence of oligomycin, appeared to explain much of the increase in basal oxygen utilization. Growth in 5 mM glucose normalized the elevations in basal oxygen consumption, proton leak, and glycolysis in all sirtuin over-expressing cells. While the above effects were common to all three mitochondrial sirtuins, some differences between the SIRT3, SIRT4, and SIRT5 expressing cells were noted. Only SIRT3 overexpression affected fatty acid metabolism, and only SIRT4 overexpression altered superoxide levels and mitochondrial membrane potential. We conclude that all three mitochondrial sirtuins can promote increased mitochondrial respiration and cellular metabolism. SIRT3, SIRT4, and SIRT5 appear to respond to excess glucose by inducing a coordinated increase of glycolysis and respiration, with the excess energy dissipated via proton leak.

  14. The effect of mitochondrial calcium uniporter on mitochondrial fission in hippocampus cells ischemia/reperfusion injury.

    Science.gov (United States)

    Zhao, Lantao; Li, Shuhong; Wang, Shilei; Yu, Ning; Liu, Jia

    2015-06-01

    The mitochondrial calcium uniporter (MCU) transports free Ca(2+) into the mitochondrial matrix, maintaining Ca(2+) homeostasis, thus regulates the mitochondrial morphology. Previous studies have indicated that there was closely crosstalk between MCU and mitochondrial fission during the process of ischemia/reperfusion injury. This study constructed a hypoxia reoxygenation model using primary hippocampus neurons to mimic the cerebral ischemia/reperfusion injury and aims to explore the exactly effect of MCU on the mitochondrial fission during the process of ischemia/reperfusion injury and so as the mechanisms. Our results found that the inhibitor of the MCU, Ru360, decreased mitochondrial Ca(2+) concentration, suppressed the expression of mitochondrial fission protein Drp1, MIEF1 and Fis1, and thus improved mitochondrial morphology significantly. Whereas spermine, the agonist of the MCU, had no significant impact compared to the I/R group. This study demonstrated that the MCU regulates the process of mitochondrial fission by controlling the Ca(2+) transport, directly upregulating mitochondrial fission proteins Drp1, Fis1 and indirectly reversing the MIEF1-induced mitochondrial fusion. It also provides new targets for brain protection during ischemia/reperfusion injury.

  15. Progress in drug development for Alzheimer's disease: An overview in relation to mitochondrial energy metabolism.

    Science.gov (United States)

    Hroudová, Jana; Singh, Namrata; Fišar, Zdeněk; Ghosh, Kallol K

    2016-10-01

    Current possibilities of Alzheimer's disease (AD) treatment are very limited and are based on administration of cholinesterase inhibitors (donepezil, rivastigmine, galantamine) and/or N-methyl-d-aspartate receptor antagonist, memantine. Newly synthesized drugs affect multiple AD pathophysiological pathways and can act as inhibitors of cholinesterases (AChE, BuChE), inhibitors of monoamine oxidases (MAO-A, MAO-B), modulators of mitochondrial permeability transition pores, modulators of amyloid-beta binding alcohol dehydrogenase and antioxidants. Effects of clinically used as well as newly developed AD drugs were studied in relation to energy metabolism and mitochondrial functions, including oxidative phosphorylation, activities of enzymes of citric acid cycle or electron transfer system, mitochondrial membrane potential, calcium homeostasis, production of reactive oxygen species and MAO activity. PMID:27094132

  16. Role of mitochondrial calcium uniporter in regulating mitochondrial fission in the cerebral cortexes of living rats.

    Science.gov (United States)

    Liang, Nan; Wang, Peng; Wang, Shilei; Li, Shuhong; Li, Yu; Wang, Jinying; Wang, Min

    2014-06-01

    The mitochondrial calcium uniporter (MCU) transports Ca2+ from the cytoplasm to the mitochondrial matrix and thus maintains Ca2+ homeostasis. Previous studies have reported that inhibition of MCU by ruthenium red (RR) protects the brain from ischemia/reperfusion (I/R) injury and that mitochondrial fission plays an important role in I/R injury. However, it is still not known whether MCU affects mitochondrial fission. In the present study, treatment with RR was found to decrease the concentration of free calcium in the mitochondria, calcineurin enzyme activity and dynamin-related protein 1 expression, and treatment with spermine was found to have the opposite effect in organisms subjected to occlusion of the middle cerebral artery lasting 2 h followed by 24 h reperfusion. These results indicate that MCU may be related to mitochondrial fission via modulating mitochondrial Ca2+ uptake and this relationship between MCU and mitochondrial fission may protect the brain from I/R injury.

  17. Platelet mitochondrial membrane potential in Parkinson's disease

    NARCIS (Netherlands)

    Antony, P.M.; Boyd, O.; Trefois, C.; Ammerlaan, W.; Ostaszewski, M.; Baumuratov, A.S.; Longhino, L.; Antunes, L.; Koopman, W.J.H.; Balling, R.; Diederich, N.J.

    2015-01-01

    OBJECTIVE: Mitochondrial dysfunction is a hallmark of idiopathic Parkinson's disease (IPD), which has been reported not to be restricted to striatal neurons. However, studies that analyzed mitochondrial function at the level of selected enzymatic activities in peripheral tissues have produced confli

  18. Mitochondrial transcription: How does it end

    Energy Technology Data Exchange (ETDEWEB)

    J Byrnes; M Garcia-Diaz

    2011-12-31

    The structure of the mitochondrial transcription termination factor (MTERF1) provides novel insight into the mechanism of binding, recognition of the termination sequence and the conformational changes involved in mediating termination. Besides its functional implications, this structure provides a framework to understand the consequences of numerous diseases associated with mitochondrial DNA mutations.

  19. Mitochondrial dynamics in mammalian health and disease.

    Science.gov (United States)

    Liesa, Marc; Palacín, Manuel; Zorzano, Antonio

    2009-07-01

    The meaning of the word mitochondrion (from the Greek mitos, meaning thread, and chondros, grain) illustrates that the heterogeneity of mitochondrial morphology has been known since the first descriptions of this organelle. Such a heterogeneous morphology is explained by the dynamic nature of mitochondria. Mitochondrial dynamics is a concept that includes the movement of mitochondria along the cytoskeleton, the regulation of mitochondrial architecture (morphology and distribution), and connectivity mediated by tethering and fusion/fission events. The relevance of these events in mitochondrial and cell physiology has been partially unraveled after the identification of the genes responsible for mitochondrial fusion and fission. Furthermore, during the last decade, it has been identified that mutations in two mitochondrial fusion genes (MFN2 and OPA1) cause prevalent neurodegenerative diseases (Charcot-Marie Tooth type 2A and Kjer disease/autosomal dominant optic atrophy). In addition, other diseases such as type 2 diabetes or vascular proliferative disorders show impaired MFN2 expression. Altogether, these findings have established mitochondrial dynamics as a consolidated area in cellular physiology. Here we review the most significant findings in the field of mitochondrial dynamics in mammalian cells and their implication in human pathologies.

  20. Mitochondrial Fusion Proteins and Human Diseases

    Directory of Open Access Journals (Sweden)

    Michela Ranieri

    2013-01-01

    Full Text Available Mitochondria are highly dynamic, complex organelles that continuously alter their shape, ranging between two opposite processes, fission and fusion, in response to several stimuli and the metabolic demands of the cell. Alterations in mitochondrial dynamics due to mutations in proteins involved in the fusion-fission machinery represent an important pathogenic mechanism of human diseases. The most relevant proteins involved in the mitochondrial fusion process are three GTPase dynamin-like proteins: mitofusin 1 (MFN1 and 2 (MFN2, located in the outer mitochondrial membrane, and optic atrophy protein 1 (OPA1, in the inner membrane. An expanding number of degenerative disorders are associated with mutations in the genes encoding MFN2 and OPA1, including Charcot-Marie-Tooth disease type 2A and autosomal dominant optic atrophy. While these disorders can still be considered rare, defective mitochondrial dynamics seem to play a significant role in the molecular and cellular pathogenesis of more common neurodegenerative diseases, for example, Alzheimer’s and Parkinson’s diseases. This review provides an overview of the basic molecular mechanisms involved in mitochondrial fusion and focuses on the alteration in mitochondrial DNA amount resulting from impairment of mitochondrial dynamics. We also review the literature describing the main disorders associated with the disruption of mitochondrial fusion.

  1. Exercise training improves vascular mitochondrial function.

    Science.gov (United States)

    Park, Song-Young; Rossman, Matthew J; Gifford, Jayson R; Bharath, Leena P; Bauersachs, Johann; Richardson, Russell S; Abel, E Dale; Symons, J David; Riehle, Christian

    2016-04-01

    Exercise training is recognized to improve cardiac and skeletal muscle mitochondrial respiratory capacity; however, the impact of chronic exercise on vascular mitochondrial respiratory function is unknown. We hypothesized that exercise training concomitantly increases both vascular mitochondrial respiratory capacity and vascular function. Arteries from both sedentary (SED) and swim-trained (EX, 5 wk) mice were compared in terms of mitochondrial respiratory function, mitochondrial content, markers of mitochondrial biogenesis, redox balance, nitric oxide (NO) signaling, and vessel function. Mitochondrial complex I and complex I + II state 3 respiration and the respiratory control ratio (complex I + II state 3 respiration/complex I state 2 respiration) were greater in vessels from EX relative to SED mice, despite similar levels of arterial citrate synthase activity and mitochondrial DNA content. Furthermore, compared with the SED mice, arteries from EX mice displayed elevated transcript levels ofperoxisome proliferative activated receptor-γ coactivator-1αand the downstream targetscytochrome c oxidase subunit IV isoform 1,isocitrate dehydrogenase(Idh)2, andIdh3a, increased manganese superoxide dismutase protein expression, increased endothelial NO synthase phosphorylation (Ser(1177)), and suppressed reactive oxygen species generation (allPrespiratory capacity and evidence of improved redox balance, which may, at least in part, be attributable to elevated NO bioavailability, have the potential to protect against age- and disease-related challenges to arterial function. PMID:26825520

  2. Parkin suppresses Drp1-independent mitochondrial division.

    Science.gov (United States)

    Roy, Madhuparna; Itoh, Kie; Iijima, Miho; Sesaki, Hiromi

    2016-07-01

    The cycle of mitochondrial division and fusion disconnect and reconnect individual mitochondria in cells to remodel this energy-producing organelle. Although dynamin-related protein 1 (Drp1) plays a major role in mitochondrial division in cells, a reduced level of mitochondrial division still persists even in the absence of Drp1. It is unknown how much Drp1-mediated mitochondrial division accounts for the connectivity of mitochondria. The role of a Parkinson's disease-associated protein-parkin, which biochemically and genetically interacts with Drp1-in mitochondrial connectivity also remains poorly understood. Here, we quantified the number and connectivity of mitochondria using mitochondria-targeted photoactivatable GFP in cells. We show that the loss of Drp1 increases the connectivity of mitochondria by 15-fold in mouse embryonic fibroblasts (MEFs). While a single loss of parkin does not affect the connectivity of mitochondria, the connectivity of mitochondria significantly decreased compared with a single loss of Drp1 when parkin was lost in the absence of Drp1. Furthermore, the loss of parkin decreased the frequency of depolarization of the mitochondrial inner membrane that is caused by increased mitochondrial connectivity in Drp1-knockout MEFs. Therefore, our data suggest that parkin negatively regulates Drp1-indendent mitochondrial division.

  3. Autism Spectrum Disorder and Mitochondrial Disease

    Science.gov (United States)

    ... that the cells need to work. In mitochondrial diseases, the mitochondria cannot efficiently turn sugar and oxygen into energy, so the cells do not work correctly. There are many types of mitochondrial disease, and they can affect different parts of the ...

  4. The Neurologic Manifestations of Mitochondrial Disease

    Science.gov (United States)

    Parikh, Sumit

    2010-01-01

    The nervous system contains some of the body's most metabolically demanding cells that are highly dependent on ATP produced via mitochondrial oxidative phosphorylation. Thus, the neurological system is consistently involved in patients with mitochondrial disease. Symptoms differ depending on the part of the nervous system affected. Although almost…

  5. Mitochondrial accumulation of APP and Abeta

    DEFF Research Database (Denmark)

    Pavlov, Pavel F; Petersen, Anna Camilla Hansson; Glaser, Elzbieta;

    2009-01-01

    mitochondrial function of neurons within specific brain regions. This is accompanied by an elevated production of reactive oxygen species contributing to increased rates of neuronal loss in the AD-affected brain regions. In this review, we will discuss the role of mitochondrial function and dysfunction in AD...

  6. [Mitochondrial diseases; thinking beyond organ specialism necessary

    NARCIS (Netherlands)

    Smits, B.W.; Smeitink, J.A.M.; Engelen, B.G.M. van

    2008-01-01

    Mitochondrial disorders are caused by a defect in intracellular energy production. In general, these are multi-system disorders, predominantly affecting organs with high energy requirements. Due to the fact that mitochondrial disorders are not as rare as is generally assumed, and due to the diversit

  7. Parkin suppresses Drp1-independent mitochondrial division.

    Science.gov (United States)

    Roy, Madhuparna; Itoh, Kie; Iijima, Miho; Sesaki, Hiromi

    2016-07-01

    The cycle of mitochondrial division and fusion disconnect and reconnect individual mitochondria in cells to remodel this energy-producing organelle. Although dynamin-related protein 1 (Drp1) plays a major role in mitochondrial division in cells, a reduced level of mitochondrial division still persists even in the absence of Drp1. It is unknown how much Drp1-mediated mitochondrial division accounts for the connectivity of mitochondria. The role of a Parkinson's disease-associated protein-parkin, which biochemically and genetically interacts with Drp1-in mitochondrial connectivity also remains poorly understood. Here, we quantified the number and connectivity of mitochondria using mitochondria-targeted photoactivatable GFP in cells. We show that the loss of Drp1 increases the connectivity of mitochondria by 15-fold in mouse embryonic fibroblasts (MEFs). While a single loss of parkin does not affect the connectivity of mitochondria, the connectivity of mitochondria significantly decreased compared with a single loss of Drp1 when parkin was lost in the absence of Drp1. Furthermore, the loss of parkin decreased the frequency of depolarization of the mitochondrial inner membrane that is caused by increased mitochondrial connectivity in Drp1-knockout MEFs. Therefore, our data suggest that parkin negatively regulates Drp1-indendent mitochondrial division. PMID:27181353

  8. Mitochondrial mutations and polymorphisms in psychiatric disorders

    NARCIS (Netherlands)

    V. Sequeira (Vasco); M.V. Martin (Maureen); S.M. Rollins; E.A. Moon (Emily); W.E. Bunney (William E); F. MacCiardi (Fabio); S. Lupoli (Sara); G.D. Smith; J. Kelsoe (John); C.N. Magnan (Christophe); M. van Oven (Mannis); P. Baldi (Pierre); D.C. Wallace; M.P. Vawter (Marquis)

    2012-01-01

    textabstractMitochondrial deficiencies with unknown causes have been observed in schizophrenia (SZ) and bipolar disorder (BD) in imaging and postmortem studies. Polymorphisms and somatic mutations in mitochondrial DNA (mtDNA) were investigated as potential causes with next generation sequencing of m

  9. Mitochondrial transcription: how does it end?

    Science.gov (United States)

    Byrnes, James; Garcia-Diaz, Miguel

    2011-01-01

    The structure of the mitochondrial transcription termination factor (MTERF1) provides novel insight into the mechanism of binding, recognition of the termination sequence and the conformational changes involved in mediating termination. Besides its functional implications, this structure provides a framework to understand the consequences of numerous diseases associated with mitochondrial DNA mutations.

  10. Solution of depletion chain equations using nonsingular Bateman coefficients

    International Nuclear Information System (INIS)

    The exact solution of the depletion chain equations for arbitrary values of depletion constants is obtained. New nonsingular coefficients are introduced, and recurrence formulas that provide an efficient and accurate method of calculation are derived. Generality and simplicity of the method are found to be useful in evaluating depletion chains with one hundred or more nuclides in the chain, such as the s-process chain in studies of nucleosynthesis by neutron capture. The method can also be used to check the validity of approximate solutions

  11. Iron Depletion into Dust Grains in Galactic Planetary Nebulae

    CERN Document Server

    Delgado-Inglada, G

    2010-01-01

    We present preliminary results of an analysis of the iron depletion factor into dust grains for a sample of 20 planetary nebulae (PNe) from the Galactic bulge. We compare these results with the ones we obtained in a prior analysis of 28 Galactic disk PNe and 8 Galactic H II regions. We derive high depletion factors in all the objects, suggesting that more than 80% of their iron atoms are condensed into dust grains. The range of iron depletions in the sample PNe covers about two orders of magnitude, and we explore here if the differences are related to the PN morphology. However, we do not find any significant correlation.

  12. Next generation sequencing analysis of human platelet PolyA+ mRNAs and rRNA-depleted total RNA.

    Directory of Open Access Journals (Sweden)

    Antheia Kissopoulou

    Full Text Available BACKGROUND: Platelets are small anucleate cells circulating in the blood vessels where they play a key role in hemostasis and thrombosis. Here, we compared platelet RNA-Seq results obtained from polyA+ mRNA and rRNA-depleted total RNA. MATERIALS AND METHODS: We used purified, CD45 depleted, human blood platelets collected by apheresis from three male and one female healthy blood donors. The Illumina HiSeq 2000 platform was employed to sequence cDNA converted either from oligo(dT isolated polyA+ RNA or from rRNA-depleted total RNA. The reads were aligned to the GRCh37 reference assembly with the TopHat/Cufflinks alignment package using Ensembl annotations. A de novo assembly of the platelet transcriptome using the Trinity software package and RSEM was also performed. The bioinformatic tools HTSeq and DESeq from Bioconductor were employed for further statistical analyses of read counts. RESULTS: Consistent with previous findings our data suggests that mitochondrially expressed genes comprise a substantial fraction of the platelet transcriptome. We also identified high transcript levels for protein coding genes related to the cytoskeleton function, chemokine signaling, cell adhesion, aggregation, as well as receptor interaction between cells. Certain transcripts were particularly abundant in platelets compared with other cell and tissue types represented by RNA-Seq data from the Illumina Human Body Map 2.0 project. Irrespective of the different library preparation and sequencing protocols, there was good agreement between samples from the 4 individuals. Eighteen differentially expressed genes were identified in the two sexes at 10% false discovery rate using DESeq. CONCLUSION: The present data suggests that platelets may have a unique transcriptome profile characterized by a relative over-expression of mitochondrially encoded genes and also of genomic transcripts related to the cytoskeleton function, chemokine signaling and surface components

  13. Administrative Data Repository (ADR)

    Data.gov (United States)

    Department of Veterans Affairs — The Administrative Data Repository (ADR) was established to provide support for the administrative data elements relative to multiple categories of a person entity...

  14. EPA Administrative Enforcement Dockets

    Data.gov (United States)

    U.S. Environmental Protection Agency — The EPA Administrative Enforcement Dockets database contains the electronic dockets for administrative penalty cases filed by EPA Regions and Headquarters. Visitors...

  15. The defective expression of gtpbp3 related to tRNA modification alters the mitochondrial function and development of zebrafish.

    Science.gov (United States)

    Chen, Danni; Li, Feng; Yang, Qingxian; Tian, Miao; Zhang, Zengming; Zhang, Qinghai; Chen, Ye; Guan, Min-Xin

    2016-08-01

    Human mitochondrial DNA (mtDNA) mutations have been associated with a wide spectrum of clinical abnormalities. However, nuclear modifier gene(s) modulate the phenotypic expression of pathogenic mtDNA mutations. In our previous investigation, we identified the human GTPBP3 related to mitochondrial tRNA modification, acting as a modifier to influence of deafness-associated mtDNA mutation. Mutations in GTPBP3 have been found to be associated with other human diseases. However, the pathophysiology of GTPBP3-associated disorders is still not fully understood. Here, we reported the generation and characterization of Gtpbp3 depletion zebrafish model using antisense morpholinos. Zebrafish gtpbp3 has three isoforms localized at mitochondria. Zebrafish gtpbp3 is expressed at various embryonic stages and in multiple tissues. In particular, the gtpbp3 was expressed more abundantly in adult zebrafish ovary and testis. The expression of zebrafish gtpbp3 can functionally restore the growth defects caused by the mss1/gtpbp3 mutation in yeast. A marked decrease of mitochondrial ATP generation accompanied by increased levels of apoptosis and reactive oxygen species were observed in gtpbp3 knockdown zebrafish embryos. The Gtpbp3 morphants exhibited defective in embryonic development including bleeding, melenin, oedema and curved tails within 5days post fertilization, as compared with uninjected controls. The co-injection of wild type gtpbp3 mRNA partially rescued these defects in Gtpbp3 morphants. These data suggest that zebrafish Gtpbp3 is a structural and functional homolog of human and yeast GTPBP3. The mitochondrial dysfunction caused by defective Gtpbp3 may alter the embryonic development in the zebrafish. In addition, this zebrafish model of mitochondrial disease may provide unique opportunities for studying defective tRNA modification, mitochondrial biogenesis, and pathophysiology of mitochondrial disorders. PMID:27184967

  16. Ginsenoside Rg3 improves cardiac mitochondrial population quality: Mimetic exercise training

    International Nuclear Information System (INIS)

    Highlights: •Rg3 is an ergogenic aid. •Rg3 improves mitochondrial antioxidant capacity. •Rg3 regulates mitochondria dynamic remodeling. •Rg3 alone matches some the benefits of aerobic exercise. -- Abstract: Emerging evidence indicates exercise training could mediate mitochondrial quality control through the improvement of mitochondrial dynamics. Ginsenoside Rg3 (Rg3), one of the active ingredients in Panax ginseng, is well known in herbal medicine as a tonic and restorative agent. However, the molecular mechanism underlying the beneficial effects of Rg3 has been elusive. In the present study, we compared the effects of Rg3 administration with aerobic exercise on mitochondrial adaptation in cardiac muscle tissue of Sprague–Dawley (SD) rats. Three groups of SD rats were studied: (1) sedentary control, (2) Rg3-treated and (3) aerobic exercise trained. Both aerobic exercise training and Rg3 supplementation enhanced peroxisome proliferator-activated receptor coactivator 1 alpha (PGC-1α) and nuclear factor-E2-related factor 2 (Nrf2) protein levels in cardiac muscle. The activation of PGC-1α led to increased mRNA levels of mitochondrial transcription factor A (Tfam) and nuclear related factor 1(Nrf1), these changes were accompanied by increases in mitochondrial DNA copy number and complex protein levels, while activation of Nrf2 increased levels of phase II detoxifying enzymes, including nicotinamide adenine dinucleotide phosphate:quinone oxidoreductase 1(NQO1), superoxide dismutase (MnSOD) and catalase. Aerobic exercise also enhanced mitochondrial autophagy pathway activity, including increased conversion of LC3-I to LC3-II and greater expression of beclin1 and autophagy-related protein 7 (ATG7), these effects of aerobic exercise are comparable to that of Rg3. These results demonstrate that Rg3 mimics improved cardiac adaptations to exercise by regulating mitochondria dynamic remodeling and enhancing the quantity and quality of mitochondria

  17. Ginsenoside Rg3 improves cardiac mitochondrial population quality: Mimetic exercise training

    Energy Technology Data Exchange (ETDEWEB)

    Sun, Mengwei [Key Laboratory of State General Administration of Sport, Shanghai Research Institute of Sports Science, Shanghai 200031 (China); Huang, Chenglin [Shanghai Key Laboratory of Vascular Biology, Department of Hypertension and Pharmacology, Ruijin Hospital, Shanghai Jiaotong University, School of Medicine, Shanghai 200025 (China); Wang, Cheng; Zheng, Jianheng; Zhang, Peng; Xu, Yangshu [Key Laboratory of State General Administration of Sport, Shanghai Research Institute of Sports Science, Shanghai 200031 (China); Chen, Hong, E-mail: hchen100@hotmail.com [Shanghai Key Laboratory of Vascular Biology, Department of Hypertension and Pharmacology, Ruijin Hospital, Shanghai Jiaotong University, School of Medicine, Shanghai 200025 (China); Shen, Weili, E-mail: weili_shen@hotmail.com [Shanghai Key Laboratory of Vascular Biology, Department of Hypertension and Pharmacology, Ruijin Hospital, Shanghai Jiaotong University, School of Medicine, Shanghai 200025 (China)

    2013-11-08

    Highlights: •Rg3 is an ergogenic aid. •Rg3 improves mitochondrial antioxidant capacity. •Rg3 regulates mitochondria dynamic remodeling. •Rg3 alone matches some the benefits of aerobic exercise. -- Abstract: Emerging evidence indicates exercise training could mediate mitochondrial quality control through the improvement of mitochondrial dynamics. Ginsenoside Rg3 (Rg3), one of the active ingredients in Panax ginseng, is well known in herbal medicine as a tonic and restorative agent. However, the molecular mechanism underlying the beneficial effects of Rg3 has been elusive. In the present study, we compared the effects of Rg3 administration with aerobic exercise on mitochondrial adaptation in cardiac muscle tissue of Sprague–Dawley (SD) rats. Three groups of SD rats were studied: (1) sedentary control, (2) Rg3-treated and (3) aerobic exercise trained. Both aerobic exercise training and Rg3 supplementation enhanced peroxisome proliferator-activated receptor coactivator 1 alpha (PGC-1α) and nuclear factor-E2-related factor 2 (Nrf2) protein levels in cardiac muscle. The activation of PGC-1α led to increased mRNA levels of mitochondrial transcription factor A (Tfam) and nuclear related factor 1(Nrf1), these changes were accompanied by increases in mitochondrial DNA copy number and complex protein levels, while activation of Nrf2 increased levels of phase II detoxifying enzymes, including nicotinamide adenine dinucleotide phosphate:quinone oxidoreductase 1(NQO1), superoxide dismutase (MnSOD) and catalase. Aerobic exercise also enhanced mitochondrial autophagy pathway activity, including increased conversion of LC3-I to LC3-II and greater expression of beclin1 and autophagy-related protein 7 (ATG7), these effects of aerobic exercise are comparable to that of Rg3. These results demonstrate that Rg3 mimics improved cardiac adaptations to exercise by regulating mitochondria dynamic remodeling and enhancing the quantity and quality of mitochondria.

  18. Mitochondrial involvement in propofol-induced cardioprotection: An in vitro study in human myocardium

    Science.gov (United States)

    Zhu, Lan; Gress, Steeve; Gérard, Jean-Louis; Allouche, Stéphane; Hanouz, Jean-Luc

    2016-01-01

    Propofol has been shown to exert cardioprotection, but the underlying mechanisms remain incompletely understood. We examined: (1) whether propofol-induced cardioprotection depended on the time and the dose of administration; (2) the role of mitochondrial adenosine triphosphate-sensitive potassium channels, nitric oxide synthase, and mitochondrial respiratory chain activity in propofol-induced cardioprotection. Human right atrial trabeculae were obtained during cardiopulmonary bypass for coronary artery bypass and aortic valve replacement. Isometric force of contraction of human right atrial trabeculae hanged in an oxygenated Tyrode’s solution was recorded during 30-min hypoxia and 60-min reoxygenation (Control). Propofol 0.1, 1, and 10 µM was administered: (1) 5 min before hypoxia until the end of the experiment; (2) 5 min followed by 5-min washout before hypoxia; (3) during the reoxygenation period, propofol 10 µM was administered in presence of 5-hydroxydecanoate (antagonist of mitochondrial adenosine triphosphate-sensitive potassium channels), and NG-nitro-L-arginine methyl ester (inhibitor of nitric oxide synthase). In addition, mitochondria were isolated from human right atrial at 15 min of reoxygenation. The effect of propofol on activity of the mitochondrial respiratory chain complexes was evaluated by spectrophotometry. The force of contraction (% of baseline) and the complex activity between the different groups were compared with an analysis of variance and post hoc test. Propofol 10 µM administered during the reoxygenation period significantly improved the recovery of force of contraction at the end of reoxygenation (82 ± 6% of baseline value vs. 49 ± 6% in Control; P mitochondrial respiratory chain complexes, in reoxygenation period, compared to their respective untreated controls. In conclusion, in human myocardium, propofol-induced cardioprotection was mediated by mitochondrial adenosine triphosphate-sensitive potassium

  19. Glucocorticoids Suppress Mitochondrial Oxidant Production via Upregulation of Uncoupling Protein 2 in Hyperglycemic Endothelial Cells.

    Directory of Open Access Journals (Sweden)

    Domokos Gerö

    Full Text Available Diabetic complications are the leading cause of morbidity and mortality in diabetic patients. Elevated blood glucose contributes to the development of endothelial and vascular dysfunction, and, consequently, to diabetic micro- and macrovascular complications, because it increases the mitochondrial proton gradient and mitochondrial oxidant production. Therapeutic approaches designed to counteract glucose-induced mitochondrial reactive oxygen species (ROS production in the vasculature are expected to show efficacy against all diabetic complications, but direct pharmacological targeting (scavenging of mitochondrial oxidants remains challenging due to the high reactivity of some of these oxidant species. In a recent study, we have conducted a medium-throughput cell-based screening of a focused library of well-annotated pharmacologically active compounds and identified glucocorticoids as inhibitors of mitochondrial superoxide production in microvascular endothelial cells exposed to elevated extracellular glucose. The goal of the current study was to investigate the mechanism of glucocorticoids' action. Our findings show that glucocorticoids induce the expression of the mitochondrial UCP2 protein and decrease the mitochondrial potential. UCP2 silencing prevents the protective effect of the glucocorticoids on ROS production. UCP2 induction also increases the oxygen consumption and the "proton leak" in microvascular endothelial cells. Furthermore, glutamine supplementation augments the effect of glucocorticoids via further enhancing the expression of UCP2 at the translational level. We conclude that UCP2 induction represents a novel experimental therapeutic intervention in diabetic vascular complications. While direct repurposing of glucocorticoids may not be possible for the therapy of diabetic complications due to their significant side effects that develop during chronic administration, the UCP2 pathway may be therapeutically targetable by other

  20. Glucocorticoids Suppress Mitochondrial Oxidant Production via Upregulation of Uncoupling Protein 2 in Hyperglycemic Endothelial Cells

    Science.gov (United States)

    Szabo, Csaba

    2016-01-01

    Diabetic complications are the leading cause of morbidity and mortality in diabetic patients. Elevated blood glucose contributes to the development of endothelial and vascular dysfunction, and, consequently, to diabetic micro- and macrovascular complications, because it increases the mitochondrial proton gradient and mitochondrial oxidant production. Therapeutic approaches designed to counteract glucose-induced mitochondrial reactive oxygen species (ROS) production in the vasculature are expected to show efficacy against all diabetic complications, but direct pharmacological targeting (scavenging) of mitochondrial oxidants remains challenging due to the high reactivity of some of these oxidant species. In a recent study, we have conducted a medium-throughput cell-based screening of a focused library of well-annotated pharmacologically active compounds and identified glucocorticoids as inhibitors of mitochondrial superoxide production in microvascular endothelial cells exposed to elevated extracellular glucose. The goal of the current study was to investigate the mechanism of glucocorticoids' action. Our findings show that glucocorticoids induce the expression of the mitochondrial UCP2 protein and decrease the mitochondrial potential. UCP2 silencing prevents the protective effect of the glucocorticoids on ROS production. UCP2 induction also increases the oxygen consumption and the “proton leak” in microvascular endothelial cells. Furthermore, glutamine supplementation augments the effect of glucocorticoids via further enhancing the expression of UCP2 at the translational level. We conclude that UCP2 induction represents a novel experimental therapeutic intervention in diabetic vascular complications. While direct repurposing of glucocorticoids may not be possible for the therapy of diabetic complications due to their significant side effects that develop during chronic administration, the UCP2 pathway may be therapeutically targetable by other, glucocorticoid

  1. Mitochondrial H2O2 generated from electron transport chain complex 1 stimulates muscle differentiation

    Institute of Scientific and Technical Information of China (English)

    Seonmin Lee; Eunyoung Tak; Jisun Lee; MA Rashid; Michael P Murphy; Joohun Ha; Sung Soo Kim

    2011-01-01

    Mitochondrial reactive oxygen species(mROS)have been considered detrimental to cells. However, their physiological roles as signaling mediators have not been thoroughly explored. Here, we investigated whether mROS generated from mitochondrial electron transport chain(mETC)complex I stimulated muscle differentiation. Our results showed that the quantity of mROS was increased and that manganese superoxide dismutase(MnSOD)was induced via NF-KB activation during muscle differentiation. Mitochondria-targeted antioxidants(MitoQ and MitoTEMPOL)and mitochondria-targeted catalase decreased mROS quantity and suppressed muscle differentiation without affecting the amount of ATP Mitochondrial alterations, including the induction of mitochondrial transcription factor A and an increase in the number and size of mitochondria, and functional activations were observed during muscle differentiation. In particular, increased expression levels of mETC complex I subunits and a higher activity of complex I than other complexes were observed. Rotenone, an inhibitor of mETC complex I, decreased the mitochondrial NADH/NAD+ ratio and mROS levels during muscle differentiation. The inhibition of complex I using small interfering RNAs and rotenone reduced mROS levels, suppressed muscle differentiation, and depleted ATP levels with a concomitant increase in glycolysis. From these results, we conclude that complex I-derived O2, produced through reverse electron transport due to enhanced metabolism and a high activity of complex I, was dismutated into H2O2 by MnSOD induced via NF-KB activation and that the dismutated mH202 stimulated muscle differentiation as a signaling messenger.

  2. Groundwater depletion in the United States (1900-2008)

    Data.gov (United States)

    U.S. Geological Survey, Department of the Interior — A natural consequence of groundwater withdrawals is the removal of water from subsurface storage, but the overall rates and magnitude of groundwater depletion in...

  3. Prediction Method of Safety Mud Density in Depleted Oilfields

    Directory of Open Access Journals (Sweden)

    Yuan Jun-Liang

    2013-04-01

    Full Text Available At present, many oilfields were placed in the middle and late development period and the reservoir pressure depleted usually, resulting in more serious differential pressure sticking and drilling mud leakage both in the reservoir and cap rock. In view of this situation, a systematic prediction method of safety mud density in depleted oilfields was established. The influence of reservoir depletion on stress and strength in reservoir and cap formation were both studied and taken into the prediction of safety mud density. The research showed that the risk of differential pressure sticking and drilling mud leakage in reservoir and cap formation were both increased and they were the main prevention object in depleted oilfields drilling. The research results were used to guide the practice drilling work, the whole progress gone smoothly.

  4. TISSUE DISTRIBUTION AND RESIDUE DEPLETION OF OXYTETRACYCLINE IN THE RABBIT

    OpenAIRE

    Villa, R.; Cagnardi, P; Bacchetta, P.; Sonzogni, O.; Faustini, M.; Carli, S.

    2001-01-01

    Abstract not available. Villa, R.; Cagnardi, P.; Bacchetta, P.; Sonzogni, O.; Faustini, M.; Carli, S. (2001). TISSUE DISTRIBUTION AND RESIDUE DEPLETION OF OXYTETRACYCLINE IN THE RABBIT. http://hdl.handle.net/10251/10016.

  5. Verification of Depleted Uranium in non-Nuclear use

    International Nuclear Information System (INIS)

    The present work describes a system for the verification of depleted uranium-being recognized by the International Atomic Energy as a Nuclear which should be accounted for and put under Nuclear Safeguards even if it is used for non-nuclear applications such as in shielding against gamma radiation in Radiotherapy facilities, industrial radiography systems or as counterweights in air craft. Measurement of depleted uranium is performed by employing Non-Destructive Assay techniques, which use a gamma-ray spectrometer system and/or a neutron coincidence counter system. Results show that the used techniques can detect the presence of depleted uranium in the investigated materials. Also, quantitative values of U-235 enrichment and mass content of the assayed material could be obtained with a precision of better than 7%. This work would find important applications for the verification and control of depleted uranium for the purposes of Nuclear Safeguards

  6. Mass measurement of depleted uranium components with coincidence neutron count

    International Nuclear Information System (INIS)

    The technique of the mass measurement of depleted uranium components was studied with active and passive coincidence neutron count. A well neutron coincidence counter was used to measure the coincidence neutron counts of the depleted uranium components with various mass. Am-Be source was selected as the external neutron source for induced fission in the active measurement, and a shield was optimized to reduce the accidental coincidence counts. In the active measurement, the maximum relative deviation of the linear fit mass from the nominal mass of the depleted uranium components is 11.71%, compared to 4.05% in the passive measurement. It is proved that because of the weakening of the shape influence, the passive method is more accurate and reliable to measure the mass of depleted uranium components than the active method. (authors)

  7. Asymmetric spindle pole formation in CPAP-depleted mitotic cells.

    Science.gov (United States)

    Lee, Miseon; Chang, Jaerak; Chang, Sunghoe; Lee, Kyung S; Rhee, Kunsoo

    2014-02-21

    CPAP is an essential component for centriole formation. Here, we report that CPAP is also critical for symmetric spindle pole formation during mitosis. We observed that pericentriolar material between the mitotic spindle poles were asymmetrically distributed in CPAP-depleted cells even with intact numbers of centrioles. The length of procentrioles was slightly reduced by CPAP depletion, but the length of mother centrioles was not affected. Surprisingly, the young mother centrioles of the CPAP-depleted cells are not fully matured, as evidenced by the absence of distal and subdistal appendage proteins. We propose that the selective absence of centriolar appendages at the young mother centrioles may be responsible for asymmetric spindle pole formation in CPAP-depleted cells. Our results suggest that the neural stem cells with CPAP mutations might form asymmetric spindle poles, which results in premature initiation of differentiation.

  8. The Role of Gluon Depletion in J/$\\psi$ Suppression

    CERN Document Server

    Hwa, R C; Pisútová, N

    1997-01-01

    The depletion of gluons as the parton flux traverses a nucleus in a heavy-ion collision can influence the production rate of heavy-quark states. Thus the suppression of $J/\\psi$ can be due to gluon depletion in the initial state in addition to nuclear and hadronic absorption in the final state. A formalism is developed to describe the depletion effect. It is shown that, without constraints from other experimental facts beside the $J/\\psi$ suppression data in $pA$ and $AB$ collisions, it is not possible to determine the relative importance of depletion vs absorption. Possible relevance to the enhanced suppression seen in the $Pb - Pb$ data is mentioned but not studied.

  9. IL-6 regulation on skeletal muscle mitochondrial remodeling during cancer cachexia in the ApcMin/+ mouse

    Directory of Open Access Journals (Sweden)

    White James P

    2012-07-01

    Full Text Available Abstract Background Muscle protein turnover regulation during cancer cachexia is being rapidly defined, and skeletal muscle mitochondria function appears coupled to processes regulating muscle wasting. Skeletal muscle oxidative capacity and the expression of proteins regulating mitochondrial biogenesis and dynamics are disrupted in severely cachectic ApcMin/+ mice. It has not been determined if these changes occur at the onset of cachexia and are necessary for the progression of muscle wasting. Exercise and anti-cytokine therapies have proven effective in preventing cachexia development in tumor bearing mice, while their effect on mitochondrial content, biogenesis and dynamics is not well understood. The purposes of this study were to 1 determine IL-6 regulation on mitochondrial remodeling/dysfunction during the progression of cancer cachexia and 2 to determine if exercise training can attenuate mitochondrial dysfunction and the induction of proteolytic pathways during IL-6 induced cancer cachexia. Methods ApcMin/+ mice were examined during the progression of cachexia, after systemic interleukin (IL-6r antibody treatment, or after IL-6 over-expression with or without exercise. Direct effects of IL-6 on mitochondrial remodeling were examined in cultured C2C12 myoblasts. Results Mitochondrial content was not reduced during the initial development of cachexia, while muscle PGC-1α and fusion (Mfn1, Mfn2 protein expression was repressed. With progressive weight loss mitochondrial content decreased, PGC-1α and fusion proteins were further suppressed, and fission protein (FIS1 was induced. IL-6 receptor antibody administration after the onset of cachexia improved mitochondrial content, PGC-1α, Mfn1/Mfn2 and FIS1 protein expression. IL-6 over-expression in pre-cachectic mice accelerated body weight loss and muscle wasting, without reducing mitochondrial content, while PGC-1α and Mfn1/Mfn2 protein expression was suppressed and FIS1 protein expression

  10. PRKAA1/AMPKα1 is required for autophagy-dependent mitochondrial clearance during erythrocyte maturation.

    Science.gov (United States)

    Zhu, Huaiping; Foretz, Marc; Xie, Zhonglin; Zhang, Miao; Zhu, Zhiren; Xing, Junjie; Leclerc, Jocelyne; Gaudry, Murielle; Viollet, Benoit; Zou, Ming-Hui

    2014-09-01

    AMP-activated protein kinase α1 knockout (prkaa1(-/-)) mice manifest splenomegaly and anemia. The underlying molecular mechanisms, however, remain to be established. In this study, we tested the hypothesis that defective autophagy-dependent mitochondrial clearance in prkaa1(-/-) mice exacerbates oxidative stress, thereby enhancing erythrocyte destruction. The levels of ULK1 phosphorylation, autophagical flux, mitochondrial contents, and reactive oxygen species (ROS) were examined in human erythroleukemia cell line, K562 cells, as well as prkaa1(-/-) mouse embryonic fibroblasts and erythrocytes. Deletion of Prkaa1 resulted in the inhibition of ULK1 phosphorylation at Ser555, prevented the formation of ULK1 and BECN1- PtdIns3K complexes, and reduced autophagy capacity. The suppression of autophagy was associated with enhanced damaged mitochondrial accumulation and ROS production. Compared with wild-type (WT) mice, prkaa1(-/-) mice exhibited a shortened erythrocyte life span, hemolytic destruction of erythrocytes, splenomegaly, and anemia, all of which were alleviated by the administration of either rapamycin to activate autophagy or Mito-tempol, a mitochondria-targeted antioxidant, to scavenge mitochondrial ROS. Furthermore, transplantation of WT bone marrow into prkaa1(-/-) mice restored mitochondrial removal, reduced intracellular ROS levels, and normalized hematologic parameters and spleen size. Conversely, transplantation of prkaa1 (-/-) bone marrow into WT mice recapitulated the prkaa1(-/-) mouse phenotypes. We conclude that PRKAA1-dependent autophagy-mediated clearance of damaged mitochondria is required for erythrocyte maturation and homeostasis.

  11. Mitochondrial Pyruvate Carrier 2 Hypomorphism in Mice Leads to Defects in Glucose-Stimulated Insulin Secretion

    Directory of Open Access Journals (Sweden)

    Patrick A. Vigueira

    2014-06-01

    Full Text Available Carrier-facilitated pyruvate transport across the inner mitochondrial membrane plays an essential role in anabolic and catabolic intermediary metabolism. Mitochondrial pyruvate carrier 2 (Mpc2 is believed to be a component of the complex that facilitates mitochondrial pyruvate import. Complete MPC2 deficiency resulted in embryonic lethality in mice. However, a second mouse line expressing an N-terminal truncated MPC2 protein (Mpc2Δ16 was viable but exhibited a reduced capacity for mitochondrial pyruvate oxidation. Metabolic studies demonstrated exaggerated blood lactate concentrations after pyruvate, glucose, or insulin challenge in Mpc2Δ16 mice. Additionally, compared with wild-type controls, Mpc2Δ16 mice exhibited normal insulin sensitivity but elevated blood glucose after bolus pyruvate or glucose injection. This was attributable to reduced glucose-stimulated insulin secretion and was corrected by sulfonylurea KATP channel inhibitor administration. Collectively, these data are consistent with a role for MPC2 in mitochondrial pyruvate import and suggest that Mpc2 deficiency results in defective pancreatic β cell glucose sensing.

  12. Relationship between coumarin-induced hepatocellular toxicity and mitochondrial function in rats.

    Science.gov (United States)

    Tanaka, Yasuhiro; Fujii, Wataru; Hori, Hisako; Kitagawa, Yoshinori; Ozaki, Kiyokazu

    2016-04-01

    The manifestation of coumarin-induced hepatocellular toxicity may differ and depends on the frequency of administration to rats. A single coumarin dose induces hepatocellular necrosis while repeated doses induce only hepatocyte degeneration. However, the mechanism underlying these effects remains unclear. Therefore, we investigated the mechanism of coumarin-induced hepatotoxicity in rats. Coumarin was administered to male rats as a single dose or for 4 consecutive days, and samples were obtained 4 or 24 h after a single dose or 24 h after the repeated doses. A single coumarin dose significantly induced hepatocellular necrosis in rats; however, toxicity was attenuated after repeated dosing. With a single dose, hepatocellular necrosis was preceded by increased mitochondrial number and size and decreased mitochondrial function. An increased expression of granular cytochrome P450 (CYP) 2E1 protein was observed in the cytoplasm and mitochondria of coumarin-treated rats compared to the expression in the untreated controls. Nevertheless, repeated dosing showed mitochondrial function that was equivalent to that of the control while enlarged CYP2E1 protein droplets were distributed outside the mitochondria. These results suggest that mitochondrial function and CYP2E1 expression might be involved in coumarin-induced hepatocellular toxicity in rats. A reduction in mitochondrial CYP2E1 might be implicated in the acquisition of coumarin resistance after repeated doses.

  13. Depletion of Abundant Sequences by Hybridization (DASH): using Cas9 to remove unwanted high-abundance species in sequencing libraries and molecular counting applications.

    Science.gov (United States)

    Gu, W; Crawford, E D; O'Donovan, B D; Wilson, M R; Chow, E D; Retallack, H; DeRisi, J L

    2016-01-01

    Next-generation sequencing has generated a need for a broadly applicable method to remove unwanted high-abundance species prior to sequencing. We introduce DASH (Depletion of Abundant Sequences by Hybridization). Sequencing libraries are 'DASHed' with recombinant Cas9 protein complexed with a library of guide RNAs targeting unwanted species for cleavage, thus preventing them from consuming sequencing space. We demonstrate a more than 99 % reduction of mitochondrial rRNA in HeLa cells, and enrichment of pathogen sequences in patient samples. We also demonstrate an application of DASH in cancer. This simple method can be adapted for any sample type and increases sequencing yield without additional cost. PMID:26944702

  14. Use of Depleted Uranium Weapons in Contemporary Military Interventions

    OpenAIRE

    Okafor-Yarwood, Ifesinachi Marybenedette

    2014-01-01

    This research note examines the use of depleted uranium weapons in contemporarymilitary interventions and the hazardous effects of their use. It also demonstratesattempts made by the United States and the United Kingdom to block anyinternational efforts to ban the use of these weapons. Although there is no laboratory evidence, experiential evidence from Iraq indicates that depleted uranium weapons are dangerous to human health and the environment. This research note argues that the United Nat...

  15. Depletion models can predict shorebird distribution at different spatial scales.

    OpenAIRE

    Gill, J. A.; Sutherland, W. J.; Norris, K.

    2001-01-01

    Predicting the impact of habitat change on populations requires an understanding of the number of animals that a given area can support. Depletion models enable predictions of the numbers of individuals an area can support from prey density and predator searching efficiency and handling time. Depletion models have been successfully employed to predict patterns of abundance over small spatial scales, but most environmental change occurs over large spatial scales. We test the ability of depleti...

  16. Assessment Of Depleted Uranium Contamination In Selective IRAQI Soils

    International Nuclear Information System (INIS)

    The aim of this research was to measure the radiation exposure rates in three selected Locations in southren part of Iraq (two in Nassireya, and one in Amara) resulted from the existence of depleted uranium in soil and metal pieces have been taken from destroyed tank and study mathmatically the concentration of Depleted Uranium by its dispersion from soil surface by winds and rains from 2003 to 2007. The exposure rates were measured using inspector device, while depleted uranium concentration in soil samples and tank's matal pieces were detected with Solid State Nuclear Track Detectors(SSNTDs). The wind and rain effects were considered in the calculation of dispersion effect on depleted uranium concentration in soil, where the wind effect were calculated with respect to the sites nature and soil conditions, and rain effect with respect to dispersive-convective equation for radionuclide in soil. The results obtained for the exposure rates were high near the penetrated surfac, moderate and low in soil and metal pices. The Depleted Uranium concentration in soil and metal pieces have the highest value in Nassireya. The results from dispersion calculation (wind & rain) showed that the depleted uranium concentration in 2008 will be less than the danger level and in allowable contamination range

  17. The Optimal Depletion of Exhaustible Resource under Different Commitment

    Institute of Scientific and Technical Information of China (English)

    Zhou Wei; Wu Kangping

    2012-01-01

    There are few papers in the literature focusing on the issue of the optimal depletion of exhaustible resources in the framework of variable time preference. This paper attempts to analyze the pure consumption of exhaustible resource under hy- perbolic time preference, and to discuss the optimal depletion rate and the effect of the protection of the exhaustible resource under different commitment abilities. The results of model show that the case of the hyperbolic discount with the full commitment of the govemment is equivalent to the case of constant discount of the social planner problem. In that case, the optimal depletion rate and the initial consumption of exhaustible resource are the slowest. On the contrary, they are the highest and the myopic behaviors lead to excessive consumption of exhaustible resources inevitably without commitment. Otherwise, in the case of partial commit- ment, the results are between the cases of full commitment and of no commitment. Therefore, with the hyperbolic time preference, the optimal depletion rate of resource depends on the commitment ability. Higher commitment ability leads to lower effective rate of time preference, and consequently, lower depletion rate and lower initial depletion value. The improvement of commitment ability can decrease the impatience and myopia behaviors, and contribute to the protection of the exhaustible resources.

  18. Organization/Administration.

    Science.gov (United States)

    Chaffee, Ellen Earle

    Patterns that emerged from reviewing 26 syllabi for courses on organization and administration in higher education are discussed, and six sample syllabi are presented. The syllabi focused more on organization than administration. Of the 26 syllabi, 19 dealt with organization and administration generally; 5 with administration in a specific…

  19. Mitochondrial dysfunction and respiratory chain defects in a rodent model of methotrexate-induced enteritis.

    Science.gov (United States)

    Kolli, V K; Natarajan, K; Isaac, B; Selvakumar, D; Abraham, P

    2014-10-01

    The efficacy of methotrexate (MTX), a widely used chemotherapeutic drug, is limited by its gastrointestinal toxicity and the mechanism of which is not clear. The present study investigates the possible role of mitochondrial damage in MTX-induced enteritis. Small intestinal injury was induced in Wistar rats by the administration of 7 mg kg(-1) body wt. MTX intraperitoneally for 3 consecutive days. MTX administration resulted in severe small intestinal injury and extensive damage to enterocyte mitochondria. Respiratory control ratio, the single most useful and reliable test of mitochondrial function, and 3-(4,5-dimethylthiazol-2-yll)-2,5-diphenyltetrazolium bromide reduction, a measure of cell viability were significantly reduced in all the fractions of MTX-treated rat enterocytes. A massive decrease (nearly 70%) in the activities of complexes II and IV was also observed. The results of the present study suggest that MTX-induced damage to enterocyte mitochondria may play a critical role in enteritis. MTX-induced alteration in mitochondrial structure may cause its dysfunction and decreases the activities of the electron chain complexes. MTX-induced mitochondrial damage can result in reduced adenosine triphosphate synthesis, thereby interfering with nutrient absorption and enterocyte renewal. This derangement may contribute to malabsorption of nutrients, diarrhea, and weight loss seen in patients on MTX chemotherapy.

  20. Mitochondrial dysfunction induced by frataxin deficiency is associated with cellular senescence and abnormal calcium metabolism

    Directory of Open Access Journals (Sweden)

    Arantxa eBolinches-Amorós

    2014-05-01

    Full Text Available Friedreich ataxia is considered a neurodegenerative disorder involving both the peripheral and central nervous systems. Dorsal root ganglia (DRG are the major target tissue structures. This neuropathy is caused by mutations in the FXN gene that encodes frataxin. Here, we investigated the mitochondrial and cell consequences of frataxin depletion in a cellular model based on frataxin silencing in SH-SY5Y human neuroblastoma cells, a cell line that has been used widely as in vitro models for studies on neurological diseases. We showed that the reduction of frataxin induced mitochondrial dysfunction due to a bioenergetic deficit and abnormal Ca2+ homeostasis in the mitochondria that were associated with oxidative and endoplasmic reticulum stresses. The depletion of frataxin did not cause cell death but increased autophagy, which may have a cytoprotective effect against cellular insults such as oxidative stress. Frataxin silencing provoked slow cell growth associated with cellular senescence, as demonstrated by increased SA-βgal activity and cell cycle arrest at the G1 phase. We postulate that cellular senescence might be related to a hypoplastic defect in the DRG during neurodevelopment, as suggested by necropsy studies.

  1. Zidovudine-induced mitochondrial myopathy is associated with muscle carnitine deficiency and lipid storage.

    Science.gov (United States)

    Dalakas, M C; Leon-Monzon, M E; Bernardini, I; Gahl, W A; Jay, C A

    1994-04-01

    The use of zidovudine (AZT) for the treatment of acquired immunodeficiency syndrome (AIDS) induces a DNA-depleting mitochondrial myopathy, which is histologically characterized by the presence of muscle fibers with "ragged-red"-like features, red-rimmed or empty cracks, granular degeneration, and rods (AZT fibers). Because dysfunctioning muscle mitochondria may lead to defects of beta-oxidation of fatty acids, we examined the degree of neutral fat accumulation and muscle carnitine levels in the muscle biopsy specimens from 21 patients with AZT-induced myopathic symptoms of varying severity. Six patients with no AZT fibers had normal endomyofibrillar lipid deposits and muscle carnitine levels; 7 patients with fewer than 5 AZT fibers per field had a mild (+) to moderate (++) increase in lipid droplets, and reduced muscle carnitine levels (3 patients); and 8 patients with more than 5 AZT fibers had severe muscle changes, a ++ to marked ( ) increase in lipid droplets, and reduced muscle carnitine levels (6 patients). Serial sections showed lipid globules often within "cracks" or vacuoles of the abnormal muscle fibers. We conclude that the muscle mitochondrial impairment caused by AZT results in (1) accumulation of lipid within the muscle fibers owing to poor utilization of long-chain fatty acids, (2) reduction of muscle carnitine levels probably due to decreased carnitine uptake by the muscle, and (3) depletion of energy stores within the muscle fibers. The findings may have potential therapeutic implications in the treatment of AZT-induced myopathic symptoms using oral carnitine supplementation.

  2. Engineering analysis report for the long-term management of depleted uranium hexafluoride : storage of depleted uranium metal

    International Nuclear Information System (INIS)

    This report contains an engineering analysis of long-term storage of uranium metal in boxes as an option for long-term management of depleted uranium hexafluoride (UF6). Three storage facilities are considered: buildings, vaults, and mined cavities. Three cases are considered: either all, half, or a quarter of the depleted uranium metal that would be produced from the conversion of depleted UF6 is stored at the facility. The analysis of these alternatives is based on a box design used in the Final Programmatic Environmental Impact Statement for Alternative Strategies for the Long-Term Management and Use of Depleted Uranium Hexafluoride, report DOE/EIS-0269, published in 1999 by the US Department of Energy. This box design does not appear to effectively use space within the box. Hence, an alternative box design that allows for a reduced storage area is addressed in the appendices for long-term storage in buildings

  3. Unravelling the mechanisms regulating muscle mitochondrial biogenesis.

    Science.gov (United States)

    Hood, David A; Tryon, Liam D; Carter, Heather N; Kim, Yuho; Chen, Chris C W

    2016-08-01

    Skeletal muscle is a tissue with a low mitochondrial content under basal conditions, but it is responsive to acute increases in contractile activity patterns (i.e. exercise) which initiate the signalling of a compensatory response, leading to the biogenesis of mitochondria and improved organelle function. Exercise also promotes the degradation of poorly functioning mitochondria (i.e. mitophagy), thereby accelerating mitochondrial turnover, and preserving a pool of healthy organelles. In contrast, muscle disuse, as well as the aging process, are associated with reduced mitochondrial quality and quantity in muscle. This has strong negative implications for whole-body metabolic health and the preservation of muscle mass. A number of traditional, as well as novel regulatory pathways exist in muscle that control both biogenesis and mitophagy. Interestingly, although the ablation of single regulatory transcription factors within these pathways often leads to a reduction in the basal mitochondrial content of muscle, this can invariably be overcome with exercise, signifying that exercise activates a multitude of pathways which can respond to restore mitochondrial health. This knowledge, along with growing realization that pharmacological agents can also promote mitochondrial health independently of exercise, leads to an optimistic outlook in which the maintenance of mitochondrial and whole-body metabolic health can be achieved by taking advantage of the broad benefits of exercise, along with the potential specificity of drug action. PMID:27470593

  4. Melatonin in Mitochondrial Dysfunction and Related Disorders

    Directory of Open Access Journals (Sweden)

    Venkatramanujam Srinivasan

    2011-01-01

    Full Text Available Mitochondrial dysfunction is considered one of the major causative factors in the aging process, ischemia/reperfusion (I/R, septic shock, and neurodegenerative disorders like Parkinson's disease (PD, Alzheimer's disease (AD, and Huntington's disease (HD. Increased free radical generation, enhanced mitochondrial inducible nitric oxide (NO synthase activity, enhanced NO production, decreased respiratory complex activity, impaired electron transport system, and opening of mitochondrial permeability transition pore all have been suggested as factors responsible for impaired mitochondrial function. Melatonin, the major hormone of the pineal gland, also acts as an antioxidant and as a regulator of mitochondrial bioenergetic function. Both in vitro and in vivo, melatonin was effective for preventing oxidative stress/nitrosative stress-induced mitochondrial dysfunction seen in experimental models of PD, AD, and HD. In addition, melatonin is known to retard aging and to inhibit the lethal effects of septic shock or I/R lesions by maintaining respiratory complex activities, electron transport chain, and ATP production in mitochondria. Melatonin is selectively taken up by mitochondrial membranes, a function not shared by other antioxidants. Melatonin has thus emerged as a major potential therapeutic tool for treating neurodegenerative disorders such as PD or AD, and for preventing the lethal effects of septic shock or I/R.

  5. ORGANIZATION OF PUBLIC ADMINISTRATION

    OpenAIRE

    Mrkša, Jožica

    2012-01-01

    In the thesis titled Organization of Public Administration I concentrated in the review of national and foreign literature. My decision for this topic is based on the personal interest and relevance of the topic in this particular period of time. The purpose of my work was to present the public administration in general, with focus in public administration of Slovenia. At first, the theoretical background of public administration is presented, with following topics addressed: public administr...

  6. Legionella pneumophila Secretes a Mitochondrial Carrier Protein during Infection

    OpenAIRE

    Pavel Dolezal; Margareta Aili; Janette Tong; Jhih-Hang Jiang; Marobbio, Carlo M.T.; Sau Fung Lee; Ralf Schuelein; Simon Belluzzo; Eva Binova; Aurelie Mousnier; Gad Frankel; Giulia Giannuzzi; Ferdinando Palmieri; Kipros Gabriel; Thomas Naderer

    2012-01-01

    Author Summary Mitochondrial carrier proteins evolved during endosymbiosis to transport substrates across the mitochondrial inner membrane. As such the proteins are associated exclusively with eukaryotic organisms. Despite this, we identified putative mitochondrial carrier proteins in the genomes of different intracellular bacterial pathogens, including Legionella pneumophila, the causative agent of Legionnaire's disease. We named the mitochondrial carrier protein from L. pneumophila LncP and...

  7. Olaquindox induces DNA damage via the lysosomal and mitochondrial pathway involving ROS production and p53 activation in HEK293 cells.

    Science.gov (United States)

    Yang, Yang; Jiang, Liping; She, Yan; Chen, Min; Li, Qiujuan; Yang, Guang; Geng, Chengyan; Tang, Liyun; Zhong, Laifu; Jiang, Lijie; Liu, Xiaofang

    2015-11-01

    Olaquindox (OLA) is a potent antibacterial agent used as a feed additive and growth promoter. In this study, the genotoxic potential of OLA was investigated in the human embryonic kidney cell line 293 (HEK293). Results showed that OLA caused significant increases of DNA migration. Lysosomal membrane permeability and mitochondrial membrane potential were reduced after treatment with OLA. OLA was shown to induce ROS production and GSH depletion. The expression of p53 protein is increased in cells incubated with OLA. The activation of p53 and ATM gene was assessed by exposure to OLA. Furthermore, NAC reduced DNA migration, ROS formation, GSH depletion and the expression of the p53 protein and gene. And desipramine significantly decreased AO fluorescence intensity and the expression of the p53 protein and gene. These results support the assumption that OLA exerted genotoxic effects and induced DNA strand breaks in HEK293 cells, possibly through lysosomal-mitochondrial pathway involving ROS production and p53 activation.

  8. The Potato Tuber Mitochondrial Proteome

    DEFF Research Database (Denmark)

    Salvato, Fernanda; Havelund, Jesper F; Chen, Mingjie;

    2014-01-01

    Mitochondria are called the powerhouses of the cell. To better understand the role of mitochondria in maintaining and regulating metabolism in storage tissues, highly purified mitochondria were isolated from dormant potato tubers (Solanum tuberosum ‘Folva’) and their proteome investigated. Proteins....../transporters, a number of new proteins involved in coenzyme biosynthesis and iron metabolism, the pyruvate dehydrogenase kinase, and a type 2C protein phosphatase that may catalyze the dephosphorylation of the pyruvate dehydrogenase complex. Systematic analysis of prominent posttranslational modifications revealed...... that more than 50% of the identified proteins harbor at least one modification. The most prominently observed class of posttranslational modifications was oxidative modifications. This study reveals approximately 500 new or previously unconfirmed plant mitochondrial proteins and outlines a facile strategy...

  9. Mitochondrial base excision repair assays

    DEFF Research Database (Denmark)

    Maynard, Scott; de Souza-Pinto, Nadja C; Scheibye-Knudsen, Morten;

    2010-01-01

    glycosylases, AP endonuclease, DNA polymerase (POLgamma in mitochondria) and DNA ligase. This article outlines procedures for measuring oxidative damage formation and BER in mitochondria, including isolation of mitochondria from tissues and cells, protocols for measuring BER enzyme activities, gene......The main source of mitochondrial DNA (mtDNA) damage is reactive oxygen species (ROS) generated during normal cellular metabolism. The main mtDNA lesions generated by ROS are base modifications, such as the ubiquitous 8-oxoguanine (8-oxoG) lesion; however, base loss and strand breaks may also occur....... Many human diseases are associated with mtDNA mutations and thus maintaining mtDNA integrity is critical. All of these lesions are repaired primarily by the base excision repair (BER) pathway. It is now known that mammalian mitochondria have BER, which, similarly to nuclear BER, is catalyzed by DNA...

  10. Central 5-HT depletion enhances impulsive responding without affecting the accuracy of attentional performance: interactions with dopaminergic mechanisms.

    Science.gov (United States)

    Harrison, A A; Everitt, B J; Robbins, T W

    1997-10-01

    A series of ten experiments examined the effects of profound central 5-HT depletion on attentional performance in the rat in the five-choice serial reaction time task, and also determined the effects of such depletion on responding affected by d-amphetamine and by selective dopamine receptor antagonists. Rats were trained to detect and locate brief visual stimuli randomly presented in one of five spatial locations. When performance had stabilised (> 80% correct, choice serial reaction time task with the same degree of accuracy as the sham-operated controls. However, 5-HT depletion reduced the percentage of omitted trials and increased the number of premature/anticipatory responses. This pattern of behaviour following 5-HT depletion could not be attributed to enhanced primary motivation as demonstrated by measures of food intake and latencies to collect food reinforcement. The lesion attenuated the increase of premature responding induced by high doses of systemically administered d-amphetamine. 5-HT depletion also attenuated the dose-dependent decrease in accuracy induced by (-)-sulpiride, a D2 receptor antagonist, although the effects of this drug on response latencies and premature responding were similar in both groups. However, the systemic administration of the D1 receptor antagonist, SCH 23390, blocked the impulsive responding produced by the lesion as indicated by a lack of lesion effects on the percentage of omitted trials and premature responding. The results suggest that central 5-HT depletion results in impulsive, fast responding, which nevertheless does not impair accuracy of visual discrimination performance. The increased impulsivity may be mediated by altered 5-HT-dopamine interactions, with the lesion removing an inhibitory influence over dopamine neurotransmission. PMID:9372531

  11. The influence of ego depletion on sprint start performance in athletes without track and field experience

    OpenAIRE

    Englert, Chris; Persaud, Brittany N.; Oudejans, Raôul R. D.; Bertrams, Alex

    2015-01-01

    We tested the assumption that ego depletion would affect the sprint start in a sample of N = 38 athletes without track and field experience in an experiment by applying a mixed between- (depletion vs. non-depletion) within- (T1: before manipulation of ego depletion vs. T2: after manipulation of ego depletion) subjects design. We assumed that ego depletion would increase the possibility for a false start, as regulating the impulse to initiate the sprinting movement too soon before the starting...

  12. Activation of Akt is essential for the propagation of mitochondrial respiratory stress signaling and activation of the transcriptional coactivator heterogeneous ribonucleoprotein A2.

    Science.gov (United States)

    Guha, Manti; Fang, Ji-Kang; Monks, Robert; Birnbaum, Morris J; Avadhani, Narayan G

    2010-10-15

    Mitochondrial respiratory stress (also called mitochondrial retrograde signaling) activates a Ca(2+)/calcineurin-mediated signal that culminates in transcription activation/repression of a large number of nuclear genes. This signal is propagated through activation of the regulatory proteins NFκB c-Rel/p50, C/EBPδ, CREB, and NFAT. Additionally, the heterogeneous ribonucleoprotein A2 (hnRNPA2) functions as a coactivator in up-regulating the transcription of Cathepsin L, RyR1, and Glut-4, the target genes of stress signaling. Activation of IGF1R, which causes a metabolic switch to glycolysis, cell invasiveness, and resistance to apoptosis, is a phenotypic hallmark of C2C12 myoblasts subjected to mitochondrial stress. In this study, we report that mitochondrial stress leads to increased expression, activation, and nuclear localization of Akt1. Mitochondrial respiratory stress also activates Akt1-gene expression, which involves hnRNPA2 as a coactivator, indicating a complex interdependency of these two factors. Using Akt1(-/-) mouse embryonic fibroblasts and Akt1 mRNA-silenced C2C12 cells, we show that Akt1-mediated phosphorylation is crucial for the activation and recruitment of hnRNPA2 to the enhanceosome complex. Akt1 mRNA silencing in mtDNA-depleted cells resulted in reversal of the invasive phenotype, accompanied by sensitivity to apoptotic stimuli. These results show that Akt1 is an important regulator of the nuclear transcriptional response to mitochondrial stress.

  13. Amelioration of Mitochondrial Dysfunction-Induced Insulin Resistance in Differentiated 3T3-L1 Adipocytes via Inhibition of NF-κB Pathways

    Directory of Open Access Journals (Sweden)

    Mohamad Hafizi Abu Bakar

    2014-12-01

    Full Text Available A growing body of evidence suggests that activation of nuclear factor kappa B (NF-κB signaling pathways is among the inflammatory mechanism involved in the development of insulin resistance and chronic low-grade inflammation in adipose tissues derived from obese animal and human subjects. Nevertheless, little is known about the roles of NF-κB pathways in regulating mitochondrial function of the adipose tissues. In the present study, we sought to investigate the direct effects of celastrol (potent NF-κB inhibitor upon mitochondrial dysfunction-induced insulin resistance in 3T3-L1 adipocytes. Celastrol ameliorates mitochondrial dysfunction by altering mitochondrial fusion and fission in adipocytes. The levels of oxidative DNA damage, protein carbonylation and lipid peroxidation were down-regulated. Further, the morphology and quantification of intracellular lipid droplets revealed the decrease of intracellular lipid accumulation with reduced lipolysis. Moreover, massive production of the pro-inflammatory mediators tumor necrosis factor-α (TNF-α and interleukin-1β (IL-1β were markedly depleted. Insulin-stimulated glucose uptake activity was restored with the enhancement of insulin signaling pathways. This study signified that the treatments modulated towards knockdown of NF-κB transcription factor may counteract these metabolic insults exacerbated in our model of synergy between mitochondrial dysfunction and inflammation. These results demonstrate for the first time that NF-κB inhibition modulates mitochondrial dysfunction induced insulin resistance in 3T3-L1 adipocytes.

  14. The NFL-TBS.40-63 anti-glioblastoma peptide disrupts microtubule and mitochondrial networks in the T98G glioma cell line.

    Directory of Open Access Journals (Sweden)

    Romain Rivalin

    Full Text Available Despite aggressive therapies, including combinations of surgery, radiotherapy and chemotherapy, glioblastoma remains a highly aggressive brain cancer with the worst prognosis of any central nervous system disease. We have previously identified a neurofilament-derived cell-penetrating peptide, NFL-TBS.40-63, that specifically enters by endocytosis in glioblastoma cells, where it induces microtubule destruction and inhibits cell proliferation. Here, we explore the impact of NFL-TBS.40-63 peptide on the mitochondrial network and its functions by using global cell respiration, quantitative PCR analysis of the main actors directing mitochondrial biogenesis, western blot analysis of the oxidative phosphorylation (OXPHOS subunits and confocal microscopy. We show that the internalized peptide disturbs mitochondrial and microtubule networks, interferes with mitochondrial dynamics and induces a rapid depletion of global cell respiration. This effect may be related to reduced expression of the NRF-1 transcription factor and of specific miRNAs, which may impact mitochondrial biogenesis, in regard to default mitochondrial mobility.

  15. Metallothionein deficiency aggravates depleted uranium-induced nephrotoxicity

    Energy Technology Data Exchange (ETDEWEB)

    Hao, Yuhui; Huang, Jiawei; Gu, Ying; Liu, Cong; Li, Hong; Liu, Jing; Ren, Jiong; Yang, Zhangyou [State Key Laboratory of Trauma, Burns and Combined Injury, Institute of Combined Injury, Chongqing Engineering Research Center for Nanomedicine, College of Preventive Medicine, Third Military Medical University, No. 30 Gaotanyan Street, Shapingba District, Chongqing 400038 (China); Peng, Shuangqing [Evaluation and Research Center for Toxicology, Institute of Disease Control and Prevention, Academy of Military Medical Science, 20 Dongdajie Street, Fengtai District, Beijing 100071 (China); Wang, Weidong, E-mail: wwdwyl@sina.com [Department of Radiation Oncology, Shanghai Jiao Tong University Affiliated Sixth People' s Hospital, Shanghai 200233 (China); Li, Rong, E-mail: yuhui_hao@126.com [State Key Laboratory of Trauma, Burns and Combined Injury, Institute of Combined Injury, Chongqing Engineering Research Center for Nanomedicine, College of Preventive Medicine, Third Military Medical University, No. 30 Gaotanyan Street, Shapingba District, Chongqing 400038 (China)

    2015-09-15

    Depleted uranium (DU) has been widely used in both civilian and military activities, and the kidney is the main target organ of DU during acute high-dose exposures. In this study, the nephrotoxicity caused by DU in metallothionein-1/2-null mice (MT −/−) and corresponding wild-type (MT +/+) mice was investigated to determine any associations with MT. Each MT −/− or MT +/+ mouse was pretreated with a single dose of DU (10 mg/kg, intraperitoneal injection) or an equivalent volume of saline. After 4 days of DU administration, kidney changes were assessed. After DU exposure, serum creatinine and serum urea nitrogen in MT −/− mice significantly increased than in MT +/+ mice, with more severe kidney pathological damage. Moreover, catalase and superoxide dismutase (SOD) decreased, and generation of reactive oxygen species and malondialdehyde increased in MT −/− mice. The apoptosis rate in MT −/− mice significantly increased, with a significant increase in both Bax and caspase 3 and a decrease in Bcl-2. Furthermore, sodium-glucose cotransporter (SGLT) and sodium-phosphate cotransporter (NaPi-II) were significantly reduced after DU exposure, and the change of SGLT was more evident in MT −/− mice. Finally, exogenous MT was used to evaluate the correlation between kidney changes induced by DU and MT doses in MT −/− mice. The results showed that, the pathological damage and cell apoptosis decreased, and SOD and SGLT levels increased with increasing dose of MT. In conclusion, MT deficiency aggravated DU-induced nephrotoxicity, and the molecular mechanisms appeared to be related to the increased oxidative stress and apoptosis, and decreased SGLT expression. - Highlights: • MT −/− and MT +/+ mice were used to evaluate nephrotoxicity of DU. • Renal damage was more evident in the MT −/− mice after exposure to DU. • Exogenous MT also protects against DU-induced nephrotoxicity. • MT deficiency induced more ROS and apoptosis after exposure to

  16. Metallothionein deficiency aggravates depleted uranium-induced nephrotoxicity

    International Nuclear Information System (INIS)

    Depleted uranium (DU) has been widely used in both civilian and military activities, and the kidney is the main target organ of DU during acute high-dose exposures. In this study, the nephrotoxicity caused by DU in metallothionein-1/2-null mice (MT −/−) and corresponding wild-type (MT +/+) mice was investigated to determine any associations with MT. Each MT −/− or MT +/+ mouse was pretreated with a single dose of DU (10 mg/kg, intraperitoneal injection) or an equivalent volume of saline. After 4 days of DU administration, kidney changes were assessed. After DU exposure, serum creatinine and serum urea nitrogen in MT −/− mice significantly increased than in MT +/+ mice, with more severe kidney pathological damage. Moreover, catalase and superoxide dismutase (SOD) decreased, and generation of reactive oxygen species and malondialdehyde increased in MT −/− mice. The apoptosis rate in MT −/− mice significantly increased, with a significant increase in both Bax and caspase 3 and a decrease in Bcl-2. Furthermore, sodium-glucose cotransporter (SGLT) and sodium-phosphate cotransporter (NaPi-II) were significantly reduced after DU exposure, and the change of SGLT was more evident in MT −/− mice. Finally, exogenous MT was used to evaluate the correlation between kidney changes induced by DU and MT doses in MT −/− mice. The results showed that, the pathological damage and cell apoptosis decreased, and SOD and SGLT levels increased with increasing dose of MT. In conclusion, MT deficiency aggravated DU-induced nephrotoxicity, and the molecular mechanisms appeared to be related to the increased oxidative stress and apoptosis, and decreased SGLT expression. - Highlights: • MT −/− and MT +/+ mice were used to evaluate nephrotoxicity of DU. • Renal damage was more evident in the MT −/− mice after exposure to DU. • Exogenous MT also protects against DU-induced nephrotoxicity. • MT deficiency induced more ROS and apoptosis after exposure to

  17. Exercise-induced mitochondrial biogenesis - with special reference to mitochondrial transcription factors and lipin-1

    OpenAIRE

    Wallman Appel, Susanna E

    2012-01-01

    Mitochondrial biogenesis is one prominent adaptation to endurance training in skeletal muscle tissue. An increased mitochondrial density of the muscle fibres contributes to an enhanced aerobic capacity and thereby to improved fatigueresistance. Multiple signalling pathways and transcriptional networks are involved in controlling mitochondrial biogenesis. The transcriptional co-regulator lipin-1 is one factor proposed to contribute, based on its ability to interact with PGC-1α a...

  18. Impaired Mitochondrial Function and Insulin Resistance of Skeletal Muscle in Mitochondrial Diabetes

    OpenAIRE

    Szendroedi, Julia; Schmid, Albrecht Ingo; Meyerspeer, Martin; Cervin, Camilla; Kacerovsky, Michaela; Smekal, Gerhard; Gräser-Lang, Sabine; Groop, Leif; Roden, Michael

    2009-01-01

    OBJECTIVE Impaired muscular mitochondrial function is related to common insulin resistance in type 2 diabetes. Mitochondrial diseases frequently lead to diabetes, which is mostly attributed to defective β-cell mitochondria and secretion. RESEARCH DESIGN AND METHODS We assessed muscular mitochondrial function and lipid deposition in liver (hepatocellular lipids [HCLs]) and muscle (intramyocellular lipids [IMCLs]) using 31P/1H magnetic resonance spectroscopy and insulin sensitivity and endogeno...

  19. Mitochondrial Dysregulation in the Pathogenesis of Diabetes: Potential for Mitochondrial Biogenesis-Mediated Interventions

    OpenAIRE

    Anna-Maria Joseph; Joanisse, Denis R.; Baillot, Richard G.; Hood, David A.

    2012-01-01

    Muscle mitochondrial metabolism is a tightly controlled process that involves the coordination of signaling pathways and factors from both the nuclear and mitochondrial genomes. Perhaps the most important pathway regulating metabolism in muscle is mitochondrial biogenesis. In response to physiological stimuli such as exercise, retrograde signaling pathways are activated that allow crosstalk between the nucleus and mitochondria, upregulating hundreds of genes and leading to higher mitochondria...

  20. Human mitochondrial transcription factor A reduction and mitochondrial dysfunction in Hashimoto's hypothyroid myopathy.

    OpenAIRE

    Siciliano, Gabriele; Monzani, Fabio; Manca, Maria Laura; Tessa, Alessandra; Caraccio, Nadia; Tozzi, Giulia; Piemonte, Fiorella; Mancuso, Michelangelo; Santorelli, Filippo Maria; Ferrannini, Eleuterio; Murri, Luigi

    2002-01-01

    BACKGROUND: Mitochondrial changes have been described in muscle tissue in acquired hypothyroidism. Among the molecular mechanisms by which thyroid hormones regulate expression of nuclear genes encoding for regulatory proteins of mitochondrial respiratory function, the mitochondrial transcription factor A (h-mtTFA) has been proposed to be a target of thyroid hormone action. The aim of this study has been to relate h-mtTFA levels in the skeletal muscle of patients affected by Hashimoto's hypoth...