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<p>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&gt;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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年7月1日

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  • Ekaterina Korotkevich,
  • Daniel N. Conrad,
  • Zev J. Gartner,
  • Patrick H. O’Farrell

摘要

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.