A defect in mitochondrial complex iii but not in complexes i or iv causes early beta cell dysfunction and hyperglycemia in mice.

Mitochondrial metabolism and oxidative respiration are crucial for pancreatic beta cell function and stimulus secretion coupling. Oxidative phosphorylation (OxPhos) produces ATP and other metabolites that potentiate insulin secretion. However, the contribution of individual OxPhos complexes to beta cell function is unknown. We generated beta cell specific, inducible OxPhos complex KO mouse models to investigate the effects of disrupting Complex I, Complex III, or Complex IV on beta cell function. Although all KO models had similar mitochondrial respiratory defects, Complex III caused early hyperglycemia, glucose intolerance, and loss of glucose-stimulated insulin secretion in vivo. However, ex vivo insulin secretion did not change. Complex I and IV KO models showed diabetic phenotypes much later. Mitochondrial Ca2+ responses to glucose stimulation 3 weeks after gene deletion ranged from not affected to severely disrupted depending on the complex targeted, supporting the unique roles of each complex in beta cell signaling. Mitochondrial antioxidant enzyme immunostaining increased in islets from Complex III KO, but not from Complex I or IV KO mice, indicating that severe diabetic phenotype in the Complex III deficient mice is causing alterations in cellular redox status. The current study highlights that defects in individual OxPhos complexes lead to different pathogenic outcomes.