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

Abstract

It has been shown recently that mitochondrial (mtDNA) somatic variants are numerous enough to trace cellular lineages in our body. Here we extend this statement and demonstrate that mtDNA variants can be interpreted not only as neutral markers of cell divisions but the relative frequency of different mtDNA substitutions (i.e. mtDNA mutational spectrum) can inform us about important biological properties such as cell longevity. Analysing 7611 somatic mtDNA mutations from 37 types of human cancers and more than 2000 somatic mtDNA mutations from 25 healthy human tissues we observed that mtDNA mutational spectrum is associated with cell turnover rate: the ratio of T>C to G>A is increasing with cell longevity. To extend this logic we considered that, if universal, the discovered mutation bias may drive the differences in mtDNA mutational spectrum between mammalian species with short-(‘mice’) and long-(‘elephants’) lived oocytes. Based on presumably neutral polymorphisms in MT-CYB we reconstructed mutational spectra for 424 mammalian species and obtained that the fraction of T>C positively correlated with the species-specific generation length, which is a good proxy for oocyte longevity. Next, comparing complete mitochondrial genomes of 650 mammalian species we confirmed that exactly the same process shapes the nucleotide content of the most neutral sites in the whole mitochondrial genomes of short-(high T, low C) versus long-(low T, high C) lived mammals. Altogether analysing mtDNA mutations in time interval from dozens of years (somatic mutations) through the hundreds of thousands of years (within species polymorphisms) to millions of years (between species substitutions) we demonstrated that T>C/G>A positively correlates with cellular and organismal longevity. We hypothesize that the discovered mtDNA signature presents a chemical damage which is associated with the level of oxidative metabolism which, in turn, correlates with cellular and organismal longevity. The described properties of mtDNA mutational spectrum shed light on mtDNA replication, mtDNA evolution of mammals and can be used as a marker of cell longevity in single-cell analyses of heterogeneous samples.

The Role of Mitochondria in Oocyte Maturation

“…The nucleoid seems to be a layered structure in which replication and transcription occur in the central core, whereas translation and complex assembly occur in the peripheral region [ 12 ]. The mtDNA has some unique features in comparison to nuclear DNA: (i) multicopy nature of mtDNA with a broad range from several copies in sperm cells [ 13 ] to several thousand copies in the mature oocytes [ 14 ]; (ii) the mutagenesis rate of the mitochondrial genome is 20 times higher than the mutation rate of the nuclear DNA, with some unique features in its distribution across the genome [ 15 ]; and (iii) the multicopy nature of mtDNA allows the existence of mixed populations of mtDNA molecules—a phenomenon called heteroplasmy, when there is more than one mtDNA variant in a cell or an organism [ 16 ]. The clinical consequences of mutated mtDNA manifest only once a threshold of the mutant load is exceeded and these functional threshold levels vary, depending on the type of mtDNA mutation [ 17 ].…”

A>G substitutions on a heavy chain of mitochondrial genome marks an increased level of aerobic metabolism in warm versus cold vertebrates

“…Here we propose an extension of utility for mtDNA polymorphic data in GenBank by deriving species-specific mutational spectra for many vertebrates. We have shown recently that mammalian mtDNA mutational spectrum, and precisely AH>GH substitution (hereafter index H marks mtDNA heavy chain annotation, Methods), is associated with different aspects of longevity, such as mammalian lifespan, human maternal age and tissue-specific turnover time (Mikhailova et al 2019). Here, we hypothesise that mtDNA mutation spectrum can be sensitive to speciesspecific metabolic rate.…”

“…This trend is robust to phylogenetic inertia and stays qualitatively similar in two subgroups: early-and -late maturing species (Methods, Supplementary Mat. ).In mammalian species AH>GH is shown to positively correlate with generation length (Mikhailova et al 2019). To test this relationship in fishes, we used an analogous metricthe time of maturation (Methods).…”

“…1c, Supplementary Mat.). Keeping in mind the increased AH>GH in long-versus shortlived mammals (Mikhaylova et al 2019) we tested a potential association of STG-SAC with both temperature and the time of maturation of fishes. The result of the multiple linear regression is the following: We see that both factors affect the STG-SAC positively, but temperature has a higher impact on the STG-SAC as compared to the time of maturation (all coefficients are standardized, Fig.…”

“…which might shape the mtDNA spectrum. Previously we demonstrated an increase in AH>GH in long-lived mammals which makes their genomes AH poor and GH rich (Mikhaylova et al 2019). Here in order to deconvolute the effects of temperature and lifespan on mtDNA mutational spectrum we analysed mammalian species with known complete mitochondrial genomes, generation lengths and body temperatures (Methods).…”