Department of Agricultural, Food and Nutritional Science, University of Alberta, Edmonton, AB T6G 2E1, Canada.
Faculty Saint-Jean, Department of Medicine, University of Alberta, Edmonton, AB T6C 4G9, Canada.
Cells. 2020 Jan 9;9(1):168. doi: 10.3390/cells9010168.
Nor1, the third member of the Nr4a subfamily of nuclear receptor, is garnering increased interest in view of its role in the regulation of glucose homeostasis. Our previous study highlighted a proapoptotic role of Nor1 in pancreatic beta cells and showed that Nor1 expression was increased in islets isolated from type 2 diabetic individuals, suggesting that Nor1 could mediate the deterioration of islet function in type 2 diabetes. However, the mechanism remains incompletely understood. We herein investigated the subcellular localization of Nor1 in INS832/13 cells and dispersed human beta cells. We also examined the consequences of Nor1 overexpression on mitochondrial function and morphology. Our results show that, surprisingly, Nor1 is mostly cytoplasmic in beta cells and undergoes mitochondrial translocation upon activation by proinflammatory cytokines. Mitochondrial localization of Nor1 reduced glucose oxidation, lowered ATP production rates, and inhibited glucose-stimulated insulin secretion. Western blot and microscopy images revealed that Nor1 could provoke mitochondrial fragmentation via mitophagy. Our study unveils a new mode of action for Nor1, which affects beta-cell viability and function by disrupting mitochondrial networks.
Nor1 是核受体 Nr4a 亚家族的第三个成员，鉴于其在葡萄糖稳态调节中的作用，它越来越受到关注。我们之前的研究强调了 Nor1 在胰岛β细胞中的促凋亡作用，并表明 2 型糖尿病个体分离的胰岛中 Nor1 的表达增加，这表明 Nor1 可能介导 2 型糖尿病中胰岛功能的恶化。然而，其机制尚不完全清楚。我们在此研究了 Nor1 在 INS832/13 细胞和分散的人β细胞中的亚细胞定位。我们还检查了 Nor1 过表达对线粒体功能和形态的影响。我们的结果表明，令人惊讶的是，Nor1 在β细胞中主要位于细胞质中，并在受到促炎细胞因子激活时发生线粒体易位。Nor1 的线粒体定位减少了葡萄糖氧化，降低了 ATP 产生速率，并抑制了葡萄糖刺激的胰岛素分泌。Western blot 和显微镜图像显示，Nor1 可以通过线粒体自噬引发线粒体碎片化。我们的研究揭示了 Nor1 的一种新作用模式，它通过破坏线粒体网络影响β细胞的活力和功能。
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