Nucleic Acids Res.: co-auth.: A.Reymond

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Nucleic Acids Res. 2022 Sep 21;gkac779. doi: 10.1093/nar/gkac779. Online ahead of print.

A mitochondria-specific mutational signature of aging: increased rate of A > G substitutions on the heavy strand

Alina G Mikhailova 1 2, Alina A Mikhailova 1, Kristina Ushakova 1, Evgeny O Tretiakov 1 3, Dmitrii Iliushchenko 1, Victor Shamansky 1, Valeria Lobanova 1, Ivan Kozenkov 1, Bogdan Efimenko 1, Andrey A Yurchenko 4, Elena Kozenkova 5, Evgeny M Zdobnov 6 7, Vsevolod Makeev 2 8, Valerian Yurov 5, Masashi Tanaka 9, Irina Gostimskaya 10, Zoe Fleischmann 11, Sofia Annis 11, Melissa Franco 11, Kevin Wasko 11, Stepan Denisov 1 12, Wolfram S Kunz 13, Dmitry Knorre 14, Ilya Mazunin 15 16 17, Sergey Nikolaev 4, Jacques Fellay 7 18, Alexandre Reymond 19, Konstantin Khrapko 11, Konstantin Gunbin 1 20, Konstantin Popadin 1 7 18

Abstract

The mutational spectrum of the mitochondrial DNA (mtDNA) does not resemble any of the known mutational signatures of the nuclear genome and variation in mtDNA mutational spectra between different organisms is still incomprehensible. Since mitochondria are responsible for aerobic respiration, it is expected that mtDNA mutational spectrum is affected by oxidative damage. Assuming that oxidative damage increases with age, we analyse mtDNA mutagenesis of different species in regards to their generation length. Analysing, (i) dozens of thousands of somatic mtDNA mutations in samples of different ages (ii) 70053 polymorphic synonymous mtDNA substitutions reconstructed in 424 mammalian species with different generation lengths and (iii) synonymous nucleotide content of 650 complete mitochondrial genomes of mammalian species we observed that the frequency of AH > GH substitutions (H: heavy strand notation) is twice bigger in species with high versus low generation length making their mtDNA more AH poor and GH rich. Considering that AH > GH substitutions are also sensitive to the time spent single-stranded (TSSS) during asynchronous mtDNA replication we demonstrated that AH > GH substitution rate is a function of both species-specific generation length and position-specific TSSS. We propose that AH > GH is a mitochondria-specific signature of oxidative damage associated with both aging and TSSS.