Mitochondrial DNA Mutagenesis: Feature of and Biomarker for Environmental Exposures and Aging

Mitochondrial dysfunction is a hallmark of aging. Mitochondrial genome (mtDNA) instability contributes to mitochondrial dysfunction, and mtDNA mutagenesis may contribute to aging. However, the origin of mtDNA mutations remains somewhat controversial. The goals of this review are to introduce and review recent literature on mtDNA mutagenesis and aging, address recent animal and epidemiological evidence for the effects of chemicals on mtDNA damage and mutagenesis, propose hypotheses regarding the contribution of environmental toxicant exposure to mtDNA mutagenesis in the context of aging, and suggest future directions and approaches for environmental health researchers. Stressors such as pollutants, pharmaceuticals, and ultraviolet radiation can damage the mitochondrial genome or disrupt mtDNA replication, repair, and organelle homeostatic processes, potentially influencing the rate of accumulation of mtDNA mutations. Accelerated mtDNA mutagenesis could contribute to aging, diseases of aging, and sensitize individuals with pathogenic mtDNA variants to stressors. We propose three potential mechanisms of toxicant-induced effects on mtDNA mutagenesis over lifespan: (1) increased de novo mtDNA mutations, (2) altered frequencies of mtDNA mutations, or (3) both. There are remarkably few studies that have investigated the impact of environmental chemical exposures on mtDNA instability and mutagenesis, and even fewer in the context of aging. More studies are warranted because people are exposed to tens of thousands of chemicals, and are living longer. Finally, we suggest that toxicant-induced mtDNA damage and mutational signatures may be a sensitive biomarker for some exposures.