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

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Version: Final published version
License: CC BY-NC 4.0
Serval ID
serval:BIB_AC322A4B5E86
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
A mitochondria-specific mutational signature of aging: increased rate of A > G substitutions on the heavy strand.
Journal
Nucleic acids research
Author(s)
Mikhailova A.G., Mikhailova A.A., Ushakova K., Tretiakov E.O., Iliushchenko D., Shamansky V., Lobanova V., Kozenkov I., Efimenko B., Yurchenko A.A., Kozenkova E., Zdobnov E.M., Makeev V., Yurov V., Tanaka M., Gostimskaya I., Fleischmann Z., Annis S., Franco M., Wasko K., Denisov S., Kunz W.S., Knorre D., Mazunin I., Nikolaev S., Fellay J., Reymond A., Khrapko K., Gunbin K., Popadin K.
ISSN
1362-4962 (Electronic)
ISSN-L
0305-1048
Publication state
Published
Issued date
14/10/2022
Peer-reviewed
Oui
Volume
50
Number
18
Pages
10264-10277
Language
english
Notes
Publication types: Journal Article
Publication Status: ppublish
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.
Keywords
Aging/genetics, Animals, DNA, Mitochondrial/genetics, Mammals/genetics, Mitochondria/genetics, Mutation, Nucleotides
Pubmed
Web of science
Open Access
Yes
Create date
26/09/2022 12:57
Last modification date
25/01/2024 7:42
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