Mammalian mitochondrial mutational spectrum as a hallmark of cellular and organismal aging

Mutational spectrum of the mitochondrial genome (mtDNA) does not resemble signatures of any known mutagens and variation in mtDNA mutational spectra between different tissues and organisms is still incomprehensible. Since mitochondria is tightly involved in aerobic energy production, it is expected that mtDNA mutational spectra may be affected by the oxidative damage which is increasing with cellular and organismal aging. However, the well-documented mutational signature of the oxidative damage, G>T substitutions, is typical only for the nuclear genome while it is extremely rare and age-independent in mtDNA. Thus it is still unclear if there is a mitochondria - specific mutational signature of the oxidative damage. Here, reconstructing mtDNA mutational spectra for human cancers originated from 21 tissues with various cell turnover rate, human oocytes fertilized at different ages, and 424 mammalian species with variable generation length which is a proxy for oocyte age, we observed that the frequency of A H >G H substitutions ( H - heavy chain notation) is positively correlated with cellular and organismal longevity. Moreover, this mutational bias from A H to G H affects nucleotide content at the fourfold degenerative synonymous positions leading to a deficit of A H and excess of G H , which is especially pronounced in long-lived mammals. Taking into account additionally, that A H >G H is sensitive to time being single stranded during mtDNA asynchronous replication and A>G is associated with oxidative damage of single-stranded DNA in recent bacterial experiments we propose that A H >G H is a mutational signature of oxidative damage in mtDNA.