Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.6.3.14 (ATP synthase)
 7,042 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A progressive dysfunction of the mitochondrion probably plays a decisive role in the aging process. In the present hypothesis it is suggested that the functional defect specifically concerns the catalytic subunit of the mitochondrial F1-ATPase. This proposal is based on observations concerning two classical models of the aging process. 1. The Werner syndrome of premature aging is autosomally recessive; meaning that this disorder--in analogy with other recessive inborn errors of metabolism--results from a single specific mutation, typically resulting in an enzyme defect. 2. The strong association between the ATPase activity of the SV40 T-antigen and the process of cellular immortalization in vitro, suggests that the putative enzyme dysfunction could concern an ATPase. The decrease with aging in the activity of the mitochondrial F1-ATPase--the main producer of ATP--could lay behind the progressive lack of homeostasis observed in senescence.
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PMID:The mitochondrial F1-ATPase and the aging process. 793 87

Mitochondrial DNA (mtDNA) is essential for proper mitochondrial function and encodes 22 tRNAs, 2 rRNAs and 13 polypeptides that make up subunits of complex I, III, IV, in the electron transport chain and complex V, the ATP synthase. Although mitochondrial dysfunction has been implicated in processes such as premature aging, neurodegeneration, and cancer, it has not been shown whether persistent mtDNA damage causes a loss of oxidative phosphorylation. We addressed this question by treating mouse embryonic fibroblasts with either hydrogen peroxide (H(2)O(2)) or the alkylating agent methyl methanesulfonate (MMS) and measuring several endpoints, including mtDNA damage and repair rates using QPCR, levels of mitochondrial- and nuclear-encoded proteins using antibody analysis, and a pharmacologic profile of mitochondria using the Seahorse Extracellular Flux Analyzer. We show that a 60min treatment with H(2)O(2) causes persistent mtDNA lesions, mtDNA loss, decreased levels of a nuclear-encoded mitochondrial subunit, a loss of ATP-linked oxidative phosphorylation and a loss of total reserve capacity. Conversely, a 60min treatment with 2mM MMS causes persistent mtDNA lesions but no mtDNA loss, no decrease in levels of a nuclear-encoded mitochondrial subunit, and no mitochondrial dysfunction. These results suggest that persistent mtDNA damage is not sufficient to cause mitochondrial dysfunction.
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PMID:Oxidants and not alkylating agents induce rapid mtDNA loss and mitochondrial dysfunction. 2276 55