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

Author

Listed:
  • Ekaterina Korotkevich

    (San Francisco)

  • Daniel N. Conrad

    (San Francisco)

  • Zev J. Gartner

    (San Francisco)

  • Patrick H. O’Farrell

    (San Francisco)

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.

Suggested Citation

  • Ekaterina Korotkevich & Daniel N. Conrad & Zev J. Gartner & Patrick H. O’Farrell, 2025. "Selfish mutations promote age-associated erosion of mtDNA integrity in mammals," Nature Communications, Nature, vol. 16(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-60477-y
    DOI: 10.1038/s41467-025-60477-y
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