title: Inter-mitochondrial complementation: Mitochondria-specific system preventing mice from expression of disease phenotypes by mutant mtDNA.
abstract: Here we investigated the pathogenesis of deletion mutant mitochondrial (mt)DNA by generating mice with mutant mtDNA carrying a 4696-basepair deletion (DeltamtDNA4696), and by using cytochrome c oxidase (COX) electron micrographs to identify COX activity at the individual mitochondrial level. All mitochondria in tissues with DeltamtDNA4696 showed normal COX activity until DeltamtDNA4696 accumulated predominantly; this prevented mice from expressing disease phenotypes. Moreover, we did not observe coexistence of COX-positive and -negative mitochondria within single cells. These results indicate the occurrence of inter-mitochondrial complementation through exchange of genetic contents between exogenously introduced mitochondria with DeltamtDNA4696 and host mitochondria with normal mtDNA. This complementation shows a mitochondria-specific mechanism for avoiding expression of deletion-mutant mtDNA, and opens the possibility of a gene therapy in which mitochondria possessing full-length DNA are introduced.
authors.affiliation: Institute of Biological Sciences, University of Tsukuba, Ibaraki, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Nakada
authors.forename: K
authors.initials: K
authors.lastname: Inoue
authors.forename: T
authors.initials: T
authors.lastname: Ono
authors.forename: K
authors.initials: K
authors.lastname: Isobe
authors.forename: A
authors.initials: A
authors.lastname: Ogura
authors.forename: Y I
authors.initials: YI
authors.lastname: Goto
authors.forename: I
authors.initials: I
authors.lastname: Nonaka
authors.forename: J I
authors.initials: JI
authors.lastname: Hayashi
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D004272:DNA, Mitochondrial / Q000235:genetics*; D003576:Electron Transport Complex IV / Q000378:metabolism; D005816:Genetic Complementation Test; D008297:Male; D051379:Mice; D008854:Microscopy, Electron; D008928:Mitochondria / Q000201:enzymology / Q000235:genetics*; D010641:Phenotype
chemical_list: D004272:DNA, Mitochondrial; D003576:Electron Transport Complex IV