Molecular Metabolism ( IF 7.0 ) Pub Date : 2020-02-04 , DOI: 10.1016/j.molmet.2019.12.008 Jason Fan 1 , Wen Du 1 , Ja Young Kim-Muller 1 , Jinsook Son 1 , Taiyi Kuo 1 , Delfina Larrea 2 , Christian Garcia 3 , Takumi Kitamoto 1 , Michael J Kraakman 1 , Edward Owusu-Ansah 3 , Vincenzo Cirulli 4 , Domenico Accili 1
Objective
Diabetes 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.
Methods
Here 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 nicotinamide actin dysfunction (NAD)/reduced nicotinamide actin dysfunction (NADH) ratios.
Results
The expression 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.
Conclusions
The findings highlight a pathway linking FoxO1 to mitochondrial dysfunction that can mediate β-cell failure.
中文翻译:
Cyb5r3 将 FoxO1 依赖性线粒体功能障碍与 β 细胞衰竭联系起来。
客观的
糖尿病的特点是胰腺β细胞去分化。去分化的β细胞不恰当地代谢脂质而不是碳水化合物,并表现出线粒体氧化磷酸化受损。然而,β细胞对不利代谢环境的反应与线粒体功能受损之间的联系机制仍不清楚。
方法
在这里,我们报道氧化还原酶细胞色素 b5 还原酶 3 (Cyb5r3) 通过调节线粒体功能、活性氧生成和烟酰胺肌动蛋白功能障碍 (NAD)/减少的烟酰胺肌动蛋白功能障碍 (NADH) 比率,将 FoxO1 信号传导与 β 细胞刺激/分泌耦合联系起来。
结果
FoxO1 缺陷的 β 细胞中 Cyb5r3 的表达降低。 β细胞特异性缺失 Cyb5r3 的小鼠胰岛素分泌受损,导致葡萄糖不耐受和饮食引起的高血糖。 Cyb5r3 缺陷的 β 细胞对葡萄糖的呼吸反应减弱,并表现出广泛的线粒体和分泌颗粒异常,与分化改变一致。此外,FoxO1 无法在 Cyb5r3 缺陷的 β 细胞中维持关键分化标记物的表达,这表明 Cyb5r3 是 FoxO1 依赖性谱系稳定性所必需的。
结论
这些发现强调了 FoxO1 与线粒体功能障碍之间的联系,可介导 β 细胞衰竭。