This study determined pathogenicity of an A11181G mtDNA mutation found in a senescence-accelerated mouse strain, SAMP8. The mutation was at a highly conserved site of the mt-Nd4 gene, which encodes one of the respiratory complex I subunits. The young SAMP8 expressed reduced complex I activity, which is controlled by both nuclear and mitochondrial DNA (mtDNA). To exclude the nuclear effects, we isolated transmitochondrial cybrids that share the same nuclear background, but possess mtDNA with or without the mutation. The cybrids showed normal respiratory function irrespective of whether their...