Mitochondrial DNA Mutations, Oxidative Stress, and Apoptosis in Mammalian Aging

TLDR

Mutations in mitochondrial DNA accumulate in mammalian tissues and are hypothesized to contribute to aging. Mice with a proofreading‑deficient mitochondrial DNA polymerase accumulate mtDNA mutations, exhibit accelerated aging, and show increased apoptotic markers without oxidative stress or proliferation defects, suggesting that mtDNA‑induced apoptosis is a key driver of mammalian aging.

Abstract

Mutations in mitochondrial DNA (mtDNA) accumulate in tissues of mammalian species and have been hypothesized to contribute to aging. We show that mice expressing a proofreading-deficient version of the mitochondrial DNA polymerase g (POLG) accumulate mtDNA mutations and display features of accelerated aging. Accumulation of mtDNA mutations was not associated with increased markers of oxidative stress or a defect in cellular proliferation, but was correlated with the induction of apoptotic markers, particularly in tissues characterized by rapid cellular turnover. The levels of apoptotic markers were also found to increase during aging in normal mice. Thus, accumulation of mtDNA mutations that promote apoptosis may be a central mechanism driving mammalian aging.