A Mouse Model of Mitochondrial Disease Reveals Germline Selection Against Severe mtDNA Mutations
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.
Author contributions ::: ::: GH helped design the study, establish the animal model, collect and analyze samples, and write the manuscript. YY and DH helped establish the animal model, performed Western blotting, immunohistochemistry analyses. YY and DH also helped analyse data and revise the manuscript. QYW and JK contributed to study planning, analyse and interpret data, review and revise the manuscript. All authors have approved the final version of this article to be published and agreed to be accountable for all aspects of the work in ensuring the questions related to the accuracy or integrity of any part of the work. ::: ::: ::: ::: Disclosure ::: ::: The authors report no conflicts of interest in this work.