Mitochondrial DNA Mutations May Contribute to Aging Via Cell Death Caused by Peptides that Induce CytochromecRelease

Abstract

Mice wherein the wild-type mitochondrial DNA polymerase (pol ␥) 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 ␥ 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. 611

The Role of DNA Methylation in Aging, Rejuvenation, and Age-Related Disease

“…Such targets include telomeres, 131 free radicals, 132 DNA repair machinery, 133 mitochondrial enzymes, 134 and many others. This review, drawing upon all of the data mentioned in the previous discussion, asserts that DNA methylation is also a promising target for age-related ailments and rejuvenation.…”

The Aging Heart and Post-Infarction Left Ventricular Remodeling

“…At the cellular level, the footprint of oxidative damaging in aging leaves cardiomyocytes with a high level of disrupted mitochondria, lipofuscin, and other damaged organelles (32). In addition to the accumulation of somatic wear-and-tear waste, aging cells and long-lived cells such as cardiomyocytes are associated with increased nuclear and mitochondrial DNA damage (33). Together, these molecular characteristics can lead to an increase in pro-apoptotic gene expression profile across the heart.…”

Mitochondrial DNA replication and disease: insights from DNA polymerase γ mutations

“…Interestingly, these mutant mice showed no substantial increase of oxidative stress or ROS-induced damage [104, 107], arguing against the model that mtDNA mutations disrupts respiratory chain function and increases ROS production [108]. Evidence from all the exonuclease-deficient mouse models supports the model that increased mutagenesis by a error-prone pol γ causes rare critical mutations that causes mitochondrial dysfunction in a cell, targeting it for apoptosis [109]. The increased frequency of apoptosis leads to the loss of important and irreplaceable cells, tissue damage, and eventually organ failure [105].…”