Inter-mitochondrial complementation: Mitochondria-specific system preventing mice from expression of disease phenotypes by mutant mtDNA

Here we investigated the pathogenesis of deletion mutant mitochondrial (mt) DNA by generating mice with mutant mtDNA carrying a 4696-basepair deletion (Delta mtDNA4696), and by using cytochrome c oxidase (COX) electron microgr aphs to identify COX activity at the individual mitochondrial level. All mi tochondria in tissues with Delta mtDNA4696 showed normal COX activity until Delta mtDNA4696 accumulated predominantly; this prevented mice from expres sing disease phenotypes. Moreover, we did not observe coexistence of COX-po sitive and -negative mitochondria within single cells. These results indica te the occurrence of inter-mitochondrial complementation through exchange o f genetic contents between exogenously introduced mitochondria with Delta m tDNA4696 and host mitochondria with normal mtDNA. This complementation show s a mitochondria-specific mechanism for avoiding expression of deletion-mut ant mtDNA, and opens the possibility of a gene therapy in which mitochondri a possessing full-length DNA are introduced.