Mitochondrial mutational spectrum in mammals is sensitive to cellular and organismal longevity by means of A>G transitions

Mutational spectrum of the mitochondrial genome (mtDNA) does not resemble any of the known mutational signatures of the nuclear genome and variation in mtDNA mutational spectra between different tissues and organisms is still incomprehensible. Since mitochondria is tightly involved in energy production, we expect that mtDNA mutational spectra can reflect the level of cellular aerobic metabolism, which varies in different tissues. Analyzing a collection of somatic mtDNA mutations from human cancers, de novo mtDNA germline mutations from the human mother-offspring pairs, as well as mtDNA substitutions in hundreds of mammalian species, we observed that the frequency of AH>GH (heavy strand notation) substitutions is positively correlated with cellular and organismal longevity. For example, epithelium, oocytes of young mothers and mice have decreased AH>GH frequencies. We propose that AH>GH is a marker of cellular and organismal age, which is driven by oxidative damage of the single-stranded mtDNA during replication.