MitoNEET-Parkin Effects in Pancreatic α- and β-Cells, Cellular Survival, and Intrainsular Cross Talk.
MitoNEET-Parkin Effects in Pancreatic α- and β-Cells, Cellular Survival, and Intrainsular Cross Talk.
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DOI：
10.2337/db15-1323
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发表时间：
2016-06
期刊：
影响因子：
7.7
通讯作者：
Scherer PE
中科院分区：
文献类型：
--
作者：
Kusminski CM;Chen S;Ye R;Sun K;Wang QA;Spurgin SB;Sanders PE;Brozinick JT;Geldenhuys WJ;Li WH;Unger RH;Scherer PE
线粒体代谢在β细胞葡萄糖刺激胰岛素分泌（GSIS）中起着不可或缺的作用。此外，α-细胞释放的胰高血糖素的致糖尿病作用在1型和2型糖尿病的病因学中都起着重要作用，因为非对抗性高胰高血糖素血症是糖尿病高血糖的相关因素。滴定线粒体蛋白mitoNEET的表达水平是一种微调细胞线粒体能力的有效方法。从机制上说，β细胞特异性mitoNEET诱导引起高血糖和葡萄糖耐受不良，这是由于激活了帕金森依赖的有丝分裂途径，导致液泡和结构独特的有丝分裂体的形成。α-细胞mitoNEET的诱导导致GSIS期间空腹诱导的低血糖和胰岛素高分泌。mitoNEET激发的α-细胞对β-细胞具有有效的抗凋亡作用，可预防β-细胞中mitoNEET过表达引起的细胞功能障碍。这些观察结果表明，α-细胞线粒体功能的降低对β-细胞具有潜在的保护作用，可以保持β细胞的活力和质量。
Mitochondrial metabolism plays an integral role in glucose-stimulated insulin secretion (GSIS) in β-cells. In addition, the diabetogenic role of glucagon released from α-cells plays a major role in the etiology of both type 1 and type 2 diabetes because unopposed hyperglucagonemia is a pertinent contributor to diabetic hyperglycemia. Titrating expression levels of the mitochondrial protein mitoNEET is a powerful approach to fine-tune mitochondrial capacity of cells. Mechanistically, β-cell–specific mitoNEET induction causes hyperglycemia and glucose intolerance due to activation of a Parkin-dependent mitophagic pathway, leading to the formation of vacuoles and uniquely structured mitophagosomes. Induction of mitoNEET in α-cells leads to fasting-induced hypoglycemia and hypersecretion of insulin during GSIS. MitoNEET-challenged α-cells exert potent antiapoptotic effects on β-cells and prevent cellular dysfunction associated with mitoNEET overexpression in β-cells. These observations identify that reduced mitochondrial function in α-cells exerts potently protective effects on β-cells, preserving β-cell viability and mass.