Mitochondrial oxidative phosphorylation is impaired in TALLYHO mice, a new obesity and type 2 diabetes animal model

•Mitochondrial oxidative phosphorylation is impaired in TALLYHO/Jng mice.•Expression and activities of complex I and IV are diminished in TALLYHO/Jng mice.•Impaired mitochondrial protein synthesis is one of the contributing factors.•Mitochondrial sequence variants may contribute to mitochondrial biogenesis defects. Type 2 diabetes has become an epidemic disease largely explained by the dramatic increase in obesity in recent years. Mitochondrial dysfunction is suggested as an underlying factor in obesity and type 2 diabetes. In this study, we evaluated changes in oxidative phosphorylation and mitochondrial biogenesis in a new human obesity and type 2 diabetes model, TALLYHO/Jng mice. We hypothesized that the sequence variants identified in the whole genome analysis of TALLYHO/Jng mice would affect oxidative phosphorylation and contribute to obesity and insulin resistant phenotypes. To test this hypothesis, we investigated differences in the expression and activity of oxidative phosphorylation complexes, including the transcription and translation of nuclear- and mitochondrial-encoded subunits and enzymatic activities, in the liver and kidney of TALLYHO/Jng and C57BL/6 J mice. A significant decrease was observed in the expression of nuclear- and mitochondrial-encoded subunits of complex I and IV, respectively, in TALLYHO/Jng mice, which coincided with significant reductions in their enzymatic activities. Furthermore, sequence variants were identified in oxidative phosphorylation complex subunits, a mitochondrial tRNA synthetase, and mitochondrial ribosomal proteins. Our data suggested that the lower expression and activity of oxidative phosphorylation complexes results in the diminished energy metabolism observed in TALLYHO/Jng mice. Sequence variants identified in mitochondrial proteins accentuated a defect in mitochondrial protein synthesis which also contributes to impaired biogenesis and oxidative phosphorylation in TALLYHO/Jng mice. These results demonstrated that the identification of factors contributing to mitochondrial dysfunction will allow us to improve the disease prognosis and treatment of obesity and type 2 diabetes in humans.