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

Fan, J.; Du, W.; Kim-Muller, J.-Y.; Kuo, T.; Son, J.; Larrea, D.; Garcia, C. J.; Kitamoto, T.; Kraakman, M. J.; Owusu-Ansah, E.; Cirulli, V.; Accili, D.

doi:10.1101/774364

bioRxiv · 10.1101/774364

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

Fan, J.·Du, W.·Kim-Muller, J.-Y.·Kuo, T.·Son, J.·Larrea, D.·Garcia, C. J.·Kitamoto, T.·Kraakman, M. J.·Owusu-Ansah, E.·Cirulli, V.·Accili, D.

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Abstract

ObjectiveDiabetes 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}-cells response to an adverse metabolic environment with impaired mitochondrial function remains unclear.\n\nMethodsHere 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 NAD/NADH ratios.\n\nResultsExpression 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.\n\nConclusionsThe findings highlight a pathway linking FoxO1 to mitochondrial dysfunction that can mediate {beta}-cell failure.

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Fan, J., Du, W., Kim-Muller, J.-Y., Kuo, T., Son, J., Larrea, D., Garcia, C. J., Kitamoto, T., Kraakman, M. J., Owusu-Ansah, E., Cirulli, V., Accili, D.. 2019-09-19. Cyb5r3 links FoxO1-dependent mitochondrial dysfunction with β-cell failure. https://doi.org/10.1101/774364

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