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 (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.
Nakada
K
K
Institute of Biological Sciences, University of Tsukuba, Ibaraki, Japan.
Inoue
K
K
Ono
T
T
Isobe
K
K
Ogura
A
A
Goto
Y I
YI
Nonaka
I
I
Hayashi
J I
JI
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
D004272:DNA, Mitochondrial; D003576:Electron Transport Complex IV