Abstract
Abstract Deleterious and intact mitochondrial DNA (mtDNA) mutations frequently co-exist in cells (heteroplasmy). Such mutations likely survive and are inherited due to complementation via the intra-cellular mitochondrial network. Hence, we hypothesized that compromised mitochondrial fusion would hamper such complementation, thereby affecting heteroplasmy inheritance. To test this hypothesis, we assessed heteroplasmic patterns in three Charcot-Marie-Tooth disease type 2A pedigrees, which carry a mutated mitofusin 2 (MFN2). We found reduced prevalence of a potentially functional mtDNA heteroplasmic mutation in these patients, as compared to healthy maternal relatives, while neutral heteroplasmic mutations fluctuated randomly. Secondly, we found that MFN2 dysfunction in a Caenorhabditis elegans model carrying a large heteroplasmic mtDNA deletion (ΔmtDNA) led to a severe developmental delay and embryonic lethality. Strikingly, these phenotypes were relieved during subsequent generations in association with complete ΔmtDNA removal. Such ΔmtDNA loss occurred during both gametogenesis and embryogenesis. Therefore, mitochondrial fusion is essential for inheritance of mtDNA heteroplasmy.