Are low-frequency mitochondrial mutations transmitted in both mice and humans?

Mitochondrial disorders, which are most commonly caused by pathogenic mutations in mitochondrial DNA, constitute a significant and rapidly growing threat to human health. It remains unclear whether mitochondrial DNA mutations, especially these with low-frequency, can be effectively purged in mice or humans. In this study, we employed the DddA-derived cytosine base editor (DdCBE) to generate a mouse model carrying a defined mtDNA point mutation in the mitochondrial ND1 gene. We observed that when F0 females harboring low-level mtDNA mutations (7.71%) were bred, the mean mutation load in their descendants fell to just 0.6% by the F3 generation. This decline was progressive: offspring born to mothers with low initial mutation burdens exhibited lower loads with increasing maternal age, and no mutations were detectable in any pups delivered after maternal week 20. Importantly, the phenomenon was recapitulated in human embryos: 94.59% of oocytes from mothers carrying <10 % mutant mtDNA displayed mutation loads below the maternal level. Our findings collectively offer deeper insight into the transmission of mitochondrial disease.