Loss of prohibitin induces mitochondrial damages altering β-cell function and survival and is responsible for gradual diabetes development.
Loss of prohibitin induces mitochondrial damages altering β-cell function and survival and is responsible for gradual diabetes development.
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DOI：
10.2337/db13-0152
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发表时间：
2013-10
期刊：
影响因子：
7.7
通讯作者：
Maechler P
中科院分区：
文献类型：
--
作者：
Supale S;Thorel F;Merkwirth C;Gjinovci A;Herrera PL;Scorrano L;Meda P;Langer T;Maechler P
抑制素是高度保守的蛋白质，主要参与线粒体功能和结构的维持。它们的功能障碍与衰老、癌症、肥胖和炎症有关。然而，它们在胰腺β细胞中的可能作用仍然未知。目前的研究记录了人和啮齿动物胰岛中的阿比汀表达及其对β细胞功能和存活的关键作用。小鼠β细胞中Phb 2的消融依次导致线粒体功能和胰岛素分泌受损、β细胞损失、葡萄糖稳态的进行性改变，并最终导致严重的糖尿病。值得注意的是，这些事件在断奶后3周内发生。β-Phb 2 −/−小鼠的胰岛素供应缺陷是由β细胞功能障碍和细胞凋亡造成的，暂时由β细胞增殖增加补偿。在分子水平上，我们观察到Phb 2的缺失导致线粒体异常，包括线粒体DNA拷贝数和呼吸链复合物IV水平的减少，线粒体活性的改变，L-视神经萎缩1的裂解和线粒体片段化。总体而言，我们的数据表明，Phb 2对于线粒体的代谢活化是必不可少的，因此，对于β细胞的功能和存活是必不可少的。
Prohibitins are highly conserved proteins mainly implicated in the maintenance of mitochondrial function and architecture. Their dysfunctions are associated with aging, cancer, obesity, and inflammation. However, their possible role in pancreatic β-cells remains unknown. The current study documents the expression of prohibitins in human and rodent islets and their key role for β-cell function and survival. Ablation of Phb2 in mouse β-cells sequentially resulted in impairment of mitochondrial function and insulin secretion, loss of β-cells, progressive alteration of glucose homeostasis, and, ultimately, severe diabetes. Remarkably, these events progressed over a 3-week period of time after weaning. Defective insulin supply in β-Phb2−/− mice was contributed by both β-cell dysfunction and apoptosis, temporarily compensated by increased β-cell proliferation. At the molecular level, we observed that deletion of Phb2 caused mitochondrial abnormalities, including reduction of mitochondrial DNA copy number and respiratory chain complex IV levels, altered mitochondrial activity, cleavage of L-optic atrophy 1, and mitochondrial fragmentation. Overall, our data demonstrate that Phb2 is essential for metabolic activation of mitochondria and, as a consequence, for function and survival of β-cells.
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影响因子：
7.8
作者：
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