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 ({Delta}mtDNA) that loses six tRNA genes and seven structural genes essential for mitochondrial respiration. Compared with non-diabetic mice carrying {Delta}mtDNA, diabetic mice carrying {Delta}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 {Delta}mtDNA. In addition, diabetic culture conditions intensified the pathogenicity of human mtDNA with an A3243G point mutation in the tRNALue (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.\n\nAuthor SummaryIt has been reported that accumulation of pathogenic mutant mitochondrial DNA (mtDNA) and the resultant mitochondrial metabolic dysfunction are associated with a wide variety of disorders, such as mitochondrial diseases, diabetes, neuo-degenerative disorders, and cancers. Considering that most mitochondrial function is regulated by nuclear-genome-encoded polypeptides, it is very important to focus on cooperation between mutant mtDNA, nuclear genetic background, and vital conditions for understanding precise pathogeneses of mtDNA-mediated disorders. By using model cells and mice carrying pathogenic mtDNAs, we report here that diabetic conditions are a modifier for the pathogenic regulation of mutant mtDNAs. Because the onset and progression of diabetes are often associated with aging, our finding suggests that some age-associated disorders with mutant mtDNAs and diabetic complications might be induced partly by enhancement of the pathogenicity of mutant mtDNAs by diabetic conditions.