Mitochondrial DNA mutations may contribute to aging via cell death caused by peptides that induce cytochrome c release.
Mice wherein the wild-type mitochondrial DNA polymerase (pol gamma) 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 gamma 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. Biochemical evidence is presented that mitochondria with mtDNA mutations generate a peptide that causes the release of cytochrome c, providing a mechanism for the increased apoptosis observed in aging. Simulation also predicts that normal, age-related accumulation of mtDNA mutations causes significant levels of cell death. These findings suggest that mtDNA mutations play an important role in the aging process and that their pathogenic mechanism is linked to apoptosis.
Dubec
Steven J
SJ
Department of Molecular Microbiology and Immunology, St Louis University School of Medicine, St Louis, MO 63104, USA.
Aurora
Rajeev
R
Zassenhaus
H Peter
HP
D000818:Animals; D017209:Apoptosis; D003198:Computer Simulation; D045304:Cytochromes c / Q000378:metabolism*; D004272:DNA, Mitochondrial / Q000235:genetics*; D047908:Intracellular Signaling Peptides and Proteins / Q000502:physiology; D051379:Mice; D009154:Mutation; D010455:Peptides / Q000502:physiology*
D004272:DNA, Mitochondrial; D047908:Intracellular Signaling Peptides and Proteins; D010455:Peptides; C427211:humanin; D045304:Cytochromes c