Cyb5r3 links FoxO1-dependent mitochondrial dysfunction with β-cell failure
Cyb5r3 links FoxO1-dependent mitochondrial dysfunction with β-cell failure
Abstract ObjectiveDiabetes is characterized by pancreatic β-cell dedifferentiation. Dedifferentiating β-cells inappropriately metabolize lipids over carbohydrates and exhibit impaired mitochondrial oxidative phosphorylation. However, the mechanism linking the β-cell’s response to an adverse metabolic environment with impaired mitochondrial function remains unclear. MethodsHere we report that the oxidoreductase cytochrome b5 reductase 3 (Cyb5r3) links FoxO1 signaling to β-cell stimulus/secretion coupling by regulating mitochondrial function, reactive oxygen species generation, and NAD/NADH ratios. ResultsExpression of Cyb5r3 is decreased in FoxO1-deficient β-cells. Mice with β-cell-specific deletion of Cyb5r3 have impaired insulin secretion resulting in glucose intolerance and diet-induced hyperglycemia. Cyb5r3-deficient β-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 β-cells, suggesting that Cyb5r3 is required for FoxO1-dependent lineage stability. ConclusionsThe findings highlight a pathway linking FoxO1 to mitochondrial dysfunction that can mediate β-cell failure.
Kraakman Michael J.、Fan Jason、Kitamoto Takumi、Owusu-Ansah Edward、Cirulli Vincenzo、Larrea Delfina、Garcia Christian、Du Wen、Kim-Muller Ja Young、Accili Domenico、Son Jinsook、Kuo Taiyi
Naomi Berrie Diabetes Center and Departments of Medicine, Columbia UniversityNaomi Berrie Diabetes Center and Departments of Medicine, Columbia UniversityNaomi Berrie Diabetes Center and Departments of Medicine, Columbia UniversityPhysiology and Cellular Biophysics, Columbia UniversityDepartment of Medicine, UW-Diabetes Institute, Institute for Stem Cell and Regenerative Medicine, University of WashingtonGenetics and Development, Columbia UniversityPhysiology and Cellular Biophysics, Columbia UniversityNaomi Berrie Diabetes Center and Departments of Medicine, Columbia UniversityNaomi Berrie Diabetes Center and Departments of Medicine, Columbia UniversityNaomi Berrie Diabetes Center and Departments of Medicine, Columbia UniversityNaomi Berrie Diabetes Center and Departments of Medicine, Columbia UniversityNaomi Berrie Diabetes Center and Departments of Medicine, Columbia University
基础医学生理学分子生物学
Kraakman Michael J.,Fan Jason,Kitamoto Takumi,Owusu-Ansah Edward,Cirulli Vincenzo,Larrea Delfina,Garcia Christian,Du Wen,Kim-Muller Ja Young,Accili Domenico,Son Jinsook,Kuo Taiyi.Cyb5r3 links FoxO1-dependent mitochondrial dysfunction with β-cell failure[EB/OL].(2025-03-28)[2025-05-08].https://www.biorxiv.org/content/10.1101/774364.点此复制
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