Mitochondrial DNA mutations may contribute to aging via cell death caused by peptides that induce cytochrome c release.

Abstract Mice wherein the wild-type mitochondrial DNA polymerase (pol γ) is replaced by a proofreading-deficient version are born with mutation frequencies in mitochondrial DNA (mtDNA) much higher than are ever normally seen in old rodents or humans. These mice, however, are phenotypically normal at birth, raising the question regarding how the much lower frequencies observed in normal aging could possibly contribute to the aging process. In contrast, transgenic mice with cardiac-specific expression of a proofreading-deficient poly γ from birth onwards accumulate mtDNA mutations to levels normally seen in aging. But these mice develop dilated cardiomyopathy suggesting that age-related mtDNA mutations are pathogenic. Using computer simulation, we show that both findings are predicted based on the hypotheses that (1) rare lethal mutations that cause apoptosis underlie the pathogenesis of mutagenesis in mtDNA and (2) most sporadic mtDNA mutations are phenotypically recessive and therefore nonpathogenic. Bioc...