Selfish mutations promote age-associated erosion of mtDNA integrity in mammals

Ekaterina Korotkevich (), Daniel N. Conrad, Zev J. Gartner and Patrick H. O’Farrell ()
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Ekaterina Korotkevich: San Francisco
Daniel N. Conrad: San Francisco
Zev J. Gartner: San Francisco
Patrick H. O’Farrell: San Francisco

Nature Communications, 2025, vol. 16, issue 1, 1-14

Abstract: Abstract Mutations in mitochondrial DNA (mtDNA) accumulate during aging and contribute to age-related conditions. High mtDNA copy number masks newly emerged recessive mutations; however, phenotypes develop when cellular levels of a mutant mtDNA rise above a critical threshold. The process driving this increase is unknown. Single-cell DNA sequencing of mouse and human hepatocytes detected increases in abundance of mutant alleles in sequences governing mtDNA replication. These alleles provided a replication advantage (drive) leading to accumulation of the affected genome along with a wide variety of associated passenger mutations, some of which are detrimental. The most prevalent human mtDNA disease variant, the 3243A>G allele, behaved as a driver, suggesting that drive underlies prevalence. We conclude that replicative drive amplifies linked mtDNA mutations to a threshold at which phenotypes are seen thereby promoting age-associated erosion of the mtDNA and influencing the transmission and progression of mitochondrial diseases.

Date: 2025
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DOI: 10.1038/s41467-025-60477-y

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