Mitochondrial DNA Mutations May Contribute to Aging Via Cell Death Caused by Peptides that Induce Cytochrome c Release

摘要

Mice wherein the wild-type mitochondrial DNA polymerase (pol u0002) is replaced by a proofreading-deficient versionnare born with mutation frequencies in mitochondrial DNA (mtDNA) much higher than are ever normallynseen in old rodents or humans. These mice, however, are phenotypically normal at birth, raising the questionnregarding how the much lower frequencies observed in normal aging could possibly contribute to the agingnprocess. In contrast, transgenic mice with cardiac-specific expression of a proofreading-deficient poly u0002 fromnbirth onwards accumulate mtDNA mutations to levels normally seen in aging. But these mice develop dilatedncardiomyopathy suggesting that age-related mtDNA mutations are pathogenic. Using computer simulation,nwe show that both findings are predicted based on the hypotheses that (1) rare lethal mutations that causenapoptosis underlie the pathogenesis of mutagenesis in mtDNA and (2) most sporadic mtDNA mutations arenphenotypically recessive and therefore nonpathogenic. Biochemical evidence is presented that mitochondrianwith mtDNA mutations generate a peptide that causes the release of cytochrome c, providing a mechanism fornthe increased apoptosis observed in aging. Simulation also predicts that normal, age-related accumulation ofnmtDNA mutations causes significant levels of cell death. These findings suggest that mtDNA mutations playnan important role in the aging process and that their pathogenic mechanism is linked to apoptosis.