Cyb5r3 links FoxO1-dependent mitochondrial dysfunction with β-cell failure

Objective: Diabetes is characterized by pancreatic beta-cell dedifferentiation. Dedifferentiating beta cells inappropriately metabolize lipids over carbohydrates and exhibit impaired mitochondrial oxidative phosphorylation. However, the mechanism linking the beta-cell's response to an adverse metabolic environment with impaired mitochondrial function remains unclear. Methods: Here we report that the oxidoreductase cytochrome b5 reductase 3 (Cyb5r3) links FoxO1 signaling to beta-cell stimulus/secretion coupling by regulating mitochondrial function, reactive oxygen species generation, and nicotinamide actin dysfunction (NAD)/reduced nicotinamide actin dysfunction (NADH) ratios. Results: The expression of Cyb5r3 is decreased in FoxO1-deficient beta cells. Mice with beta-cell-specific deletion of Cyb5r3 have impaired insulin secretion, resulting in glucose intolerance and diet-induced hyperglycemia. Cyb5r3-deficient beta cells have a blunted respiratory response to glucose and display extensive mitochondrial and secretory granule abnormalities, consistent with altered differentiation. Moreover, FoxO1 is unable to maintain expression of key differentiation markers in Cyb5r3-deficient beta cells, suggesting that Cyb5r3 is required for FoxO1-dependent lineage stability. Conclusions: The findings highlight a pathway linking FoxO1 to mitochondrial dysfunction that can mediate beta-cell failure. (C) 2020 The Author(s). Published by Elsevier GmbH.