Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:2.3.3.1 (citrate synthase)
 4,488 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Numerous studies have reported effects of antiviral nucleoside analogs on mitochondrial function, but they have not correlated well with the observed toxic side effects. By comparing the effects of the five Food and Drug Administration-approved anti-human immunodeficiency virus nucleoside analogs, zidovudine (3'-azido-3'-deoxythymidine) (AZT), 2',3'-dideoxycytidine (ddC), 2', 3'-dideoxyinosine (ddI), 2',3'-didehydro-2',3'-deoxythymidine (d4T), and beta-L-2',3'-dideoxy-3'-thiacytidine (3TC), as well as the metabolite of AZT, 3'-amino-3'-deoxythymidine (AMT), on mitochondrial function in a human hepatoma cell line, this issue has been reexamined. Evidence for a number of mitochondrial defects with AZT, ddC, and ddI was found, but only AZT induced a marked rise in lactic acid levels. Only in mitochondria isolated from AZT (50 microM)-treated cells was significant inhibition of cytochrome c oxidase and citrate synthase found. Our investigations also demonstrated that AZT, d4T, and 3TC did not affect the synthesis of the 11 polypeptides encoded by mitochondrial DNA, while ddC caused 70% reduction of total polypeptide content and ddI reduced by 43% the total content of 8 polypeptides (including NADH dehydrogenase subunits 1, 2, 4, and 5, cytochrome c oxidase subunits I to III, and cytochrome b). We hypothesize that in hepatocytes the reserve capacity for mitochondrial respiration is such that inhibition of respiratory enzymes is unlikely to become critical. In contrast, the combined inhibition of the citric acid cycle and electron transport greatly enhances the dependence of the cell on glycolysis and may explain why apparent mitochondrial dysfunction is more prevalent with AZT treatment.
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PMID:Differential effects of antiretroviral nucleoside analogs on mitochondrial function in HepG2 cells. 1068 9

Nucleoside analogue use is often related to mitochondrial DNA (mtDNA) depletion, but mitochondrial function is preserved in most asymptomatic patients. We determined whether homeostatic mechanisms are able to compensate for this mtDNA depletion in patients receiving stavudine plus didanosine (d4T + ddI), an antiretroviral combination with great in vitro and in vivo capacity to decrease mtDNA. We included 28 asymptomatic HIV-infected individuals: 17 subjects (cases) on a first-line antiretroviral regimen consisting of d4T + ddI as the nucleoside backbone plus nevirapine or nelfinavir for at least 6 months (mean: 16 +/- 8 months) and 11 naive subjects (controls). We assessed the following in peripheral blood mononuclear cells: mitochondrial mass by citrate synthase activity, mtDNA content by real-time polymerase chain reaction, cytochrome c oxidase subunit II (COX-II) expression by Western blot analysis, and COX activity by spectrophotometry. The mitochondrial mass and mtDNA content of cases decreased when compared with controls, whether normalized per cell or per mitochondrion. Conversely, COX-II expression and COX activity were similar in cases and controls. COX-II expression was constant and independent of the mtDNA content, whereas it was closely related to COX activity. We concluded that treatment with dd4T + ddI is associated with decreased mitochondrial mass and mtDNA content but that COX-II expression and COX activity remain unaltered. These data suggest that upregulatory transcriptional or posttranscriptional mechanisms compensate for mtDNA depletion caused by d4T + ddI before profound mtDNA depletion occurs.
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PMID:Upregulatory mechanisms compensate for mitochondrial DNA depletion in asymptomatic individuals receiving stavudine plus didanosine. 1557 6

Mitochondrial dysfunction as a consequence of mitochondrial DNA (mtDNA) depletion due to therapy with nucleoside analogue reverse transcriptase inhibitors (NRTI) has been proposed as a pathogenic mechanism leading to lipoatrophy in HIV-infected patients. The aim of our study was to investigate the impact of NRTI treatment on mtDNA abundance and the activities of respiratory chain complexes in primary human subcutaneous preadipocytes (phsPA). We studied adipocyte phenotypes, viability, and differentiation (CCAAT/enhancer-binding protein alpha [C/EBPalpha] and peroxisome proliferator-activated receptor gamma [PPARgamma] expression) and adiponectin production, mtDNA content, mitochondrial membrane potential, mitochondrial mass, and respiratory chain enzyme and citrate synthase activities in both proliferating and differentiating phsPA. Cells were exposed to zidovudine (6 microM), stavudine (d4T; 3 microM), and zalcitabine (ddC; 0.1 microM) for 8 weeks. NRTI-induced mtDNA depletion occurred in proliferating and differentiating phsPA after exposure to therapeutic drug concentrations of d4T and ddC. At these concentrations, ddC and d4T led to an almost 50% decrease in the number of mtDNA copies per cell without major impact on adipocyte differentiation. Despite mtDNA depletion by NRTI, the activities of the respiratory chain complexes, the mitochondrial membrane potential, and the mitochondrial mass were found to be unaffected. Severe NRTI-mediated mtDNA depletion in phsPA is not inevitably associated with impaired respiratory chain activity or altered mitochondrial membrane potential.
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PMID:Mitochondrial DNA depletion and respiratory chain activity in primary human subcutaneous adipocytes treated with nucleoside analogue reverse transcriptase inhibitors. 1980 55