| First Author | Fan J | Year | 2020 |
| Journal | Mol Metab | Volume | 34 |
| Pages | 97-111 | PubMed ID | 32180563 |
| Mgi Jnum | J:287369 | Mgi Id | MGI:6416062 |
| Doi | 10.1016/j.molmet.2019.12.008 | Citation | Fan J, et al. (2020) Cyb5r3 links FoxO1-dependent mitochondrial dysfunction with beta-cell failure. Mol Metab 34:97-111 |
| abstractText | 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. |
