Diabetic conditions induce intolerance to accumulation of pathogenic mitochondrial DNAs

Marked accumulation of mitochondrial DNA (mtDNA) with a particular pathogenic mutation is necessary for the mutant mtDNA to express its pathogenicity as mitochondrial respiration defects. However, the nuclear genome background, or the physiological status, or both, might also be important for the pathogenic regulation of mutant mtDNAs, because most mitochondrial function is controlled by polypeptides encoded in the nuclear genome. To test this, we generated diabetic mice carrying pathogenic mtDNA with a large-scale deletion (?mtDNA) that loses six tRNA genes and seven structural genes essential for mitochondrial respiration. Compared with non-diabetic mice carrying ?mtDNA, diabetic mice carrying ?mtDNA showed a decrease in mitochondrial biogenesis regulated by nuclear-encoded genes, and mitochondrial respiration defects and the resultant mitochondrial disease phenotypes were induced even in the case of low loads of ?mtDNA. In addition, diabetic culture conditions intensified the pathogenicity of human mtDNA with an A3243G point mutation in the tRNA Lue (UUR) gene. Our results indicated that the diabetic conditions are a modifier that exacerbates mitochondrial respiration defects due to mutant mtDNAs. The finding suggests the possibility that recovery from diabetic conditions might be an effective treatment strategy for some disorders involving both mutant mtDNAs and diabetic signs.