Human Aging is Associated with Various Point Mutations in tRNA Genes of Mitochondrial DNA

Münscher, C.; Müller‐Höcker, Josef; Kadenbach, Bernhard

doi:10.1515/bchm3.1993.374.7-12.1099

Cited by 87 publications

(34 citation statements)

References 15 publications

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“…23,24 They may also become fixed in the population as a low-frequency variant and can predispose carriers to late-onset diseases, such as dilated cardiomyopathy. 25 The reactive oxygen species-induced DNA adducts may be the initial mechanism of those mutations.…”

Section: Discussionmentioning

confidence: 99%

Mitochondrial Abnormalities in Tumor Necrosis Factor-α–Induced Heart Failure Are Associated With Impaired DNA Repair Activity

Chen

Watkins

et al. 2001

Circulation

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Background-Recent studies suggest that mutations in cardiac mitochondrial DNA (mtDNA) may contribute to the development of dilated cardiomyopathy. The mechanisms that regulate those mutations, however, remain undefined. Thus, we studied cardiac mtDNA repair mechanisms, mtDNA damage, and mitochondrial structure and function in mice with heart failure secondary to overexpression of TNF-␣ (TNF1.6 mice). Methods and Results-We studied mtDNA repair by measuring the uracil DNA glycosylase (mtUDG) and base excision repair activities. mtDNA damage was assessed by Southern blot of Fpg protein-digested mtDNA. Mitochondrial ultrastructural changes were examined by electron microscopy, and function by cytochrome c oxidase and succinate dehydrogenase activity assays. The results showed that both mtUDG and base excision repair activities were significantly reduced in TNF1.6 mouse heart. Fpg-sensitive sites were markedly increased in TNF1.6 mouse cardiac mtDNA, suggesting increased mtDNA damage. Mitochondrial function as demonstrated by cardiac cytochrome c oxidase activity was also markedly reduced. Cardiac ATP content was not changed, however, suggesting a shift from oxidative phosphorylation to glycolysis, as shown by increased LDH and ALT activities and lactate/pyruvate ratio. Ultrastructurally, the TNF1.6 mouse cardiac mitochondria became irregular in shape and smaller, and the cristae were decreased and appeared disorganized, with breaks. Conclusions-These results suggest that mtDNA mutations and mitochondrial structural and functional alterations in TNF-␣-induced heart failure may be associated with reduced mtDNA repair activity, and the pathophysiological effects of TNF-␣ on the heart may be mediated, at least in part, through these changes in mitochondria.

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Section: Discussionmentioning

confidence: 99%

Mitochondrial Abnormalities in Tumor Necrosis Factor-α–Induced Heart Failure Are Associated With Impaired DNA Repair Activity

Chen

Watkins

et al. 2001

Circulation

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“…It is not clear if this level of defective mitochondrial genomes is sufficient for pathology. But many other mutations, deletions and point mutations (Munscher et al, 1993;Reynier et al, 1995;Melov et al, 1994), accumulate simultaneously in aging humans in parallel with the 4977 mutation, and the total mitochondrial mutational burden is yet to be determined. The 4977 deletion has been likened to the "tip of the mutational iceberg," a frequent mutation that indicates tissues of high mitochondrial damage of many types .…”

Section: +mentioning

confidence: 99%

Mitochondria-Mediated Cell Injury

et al. 1997

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“…96 While the A10006G mutation was found in most elderly CIPO patients, the C12246A mutation was found only in two of the 15 tissue samples examined. 246 In conclusion, the pathogenesis of gastrointestinal involvement was directly related to mitochondrial alterations in digestive smooth muscle cells.…”

Section: The Clinical Phenotypes Of Mitochondrial Trna Mutationsmentioning

confidence: 92%