A mouse model of mitochondrial disease reveals germline selection against severe mtDNA mutations

Science. 2008 Feb 15;319(5865):958-62. doi: 10.1126/science.1147786.


The majority of mitochondrial DNA (mtDNA) mutations that cause human disease are mild to moderately deleterious, yet many random mtDNA mutations would be expected to be severe. To determine the fate of the more severe mtDNA mutations, we introduced mtDNAs containing two mutations that affect oxidative phosphorylation into the female mouse germ line. The severe ND6 mutation was selectively eliminated during oogenesis within four generations, whereas the milder COI mutation was retained throughout multiple generations even though the offspring consistently developed mitochondrial myopathy and cardiomyopathy. Thus, severe mtDNA mutations appear to be selectively eliminated from the female germ line, thereby minimizing their impact on population fitness.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cardiomyopathies / genetics
  • Cardiomyopathies / pathology
  • Cell Line
  • Crosses, Genetic
  • DNA, Mitochondrial / genetics*
  • Electron Transport Complex I / metabolism
  • Electron Transport Complex IV / genetics*
  • Electron Transport Complex IV / metabolism
  • Embryonic Stem Cells
  • Female
  • Frameshift Mutation
  • Germ-Line Mutation*
  • Litter Size
  • Male
  • Mice
  • Mitochondria / physiology
  • Mitochondrial Myopathies / genetics*
  • Mitochondrial Myopathies / pathology
  • Mutation, Missense
  • Myocardium / pathology
  • NADH Dehydrogenase / genetics*
  • Oocytes / physiology*
  • Oogenesis
  • Oxidative Phosphorylation
  • Oxygen Consumption
  • Point Mutation
  • Selection, Genetic*


  • DNA, Mitochondrial
  • NADH Dehydrogenase
  • NADH dehydrogenase subunit 6, mouse
  • Electron Transport Complex IV
  • cytochrome c oxidase subunit I, mouse
  • Electron Transport Complex I