Abstract
Mitochondrial metabolism and oxidative respiration are crucial for pancreatic β-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 β-cell function is unknown. We generated β-cell-specific, inducible OxPhos complex knock-out (KO) mouse models to investigate the effects of disrupting complex I, complex III, or complex IV on β-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 β-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 present study highlights that defects in individual OxPhos complexes lead to different pathogenic outcomes. ARTICLE HIGHLIGHTS: Mitochondrial metabolism is critical for β-cell insulin secretion, and mitochondrial dysfunction is involved in type 2 diabetes pathogenesis. We determined whether individual oxidative phosphorylation complexes contribute uniquely to β-cell function. Compared with loss of complex I and IV, loss of complex III resulted in severe in vivo hyperglycemia and altered β-cell redox status. Loss of complex III altered cytosolic and mitochondrial Ca2+ signaling and increased expression of glycolytic enzymes. Individual complexes contribute differently to β-cell function. This underscores the role of mitochondrial oxidative phosphorylation complex defects in diabetes pathogenesis.