The MDM2-p53-pyruvate carboxylase signalling axis couples mitochondrial metabolism to glucose-stimulated insulin secretion in pancreatic β-cells.
The MDM2-p53-pyruvate carboxylase signalling axis couples mitochondrial metabolism to glucose-stimulated insulin secretion in pancreatic β-cells.
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MDM2-p53-丙酮酸羧化酶信号轴将线粒体代谢与胰腺 β 细胞中葡萄糖刺激的胰岛素分泌结合起来。
DOI：
10.1038/ncomms11740
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发表时间：
2016-06-06
影响因子：
16.6
通讯作者：
Xu A
中科院分区：
文献类型：
--
作者：
Li X;Cheng KKY;Liu Z;Yang JK;Wang B;Jiang X;Zhou Y;Hallenborg P;Hoo RLC;Lam KSL;Ikeda Y;Gao X;Xu A
线粒体代谢对于胰腺β细胞中葡萄糖刺激的胰岛素分泌（GSIS）是关键的。然而，很少有人知道的分子机制，控制线粒体中的中间代谢产物的稳态。在这里，我们表明β细胞中的p53的激活，通过基因缺失或其负调节因子MDM 2的药理学抑制，损害GSIS，导致小鼠葡萄糖耐受不良。从机制上讲，p53激活抑制线粒体酶丙酮酸羧化酶（PC）的表达，导致TCA循环中间体草酰乙酸和NADPH的产生减少，耗氧量受损。MDM 2缺失胰岛中有缺陷的GSIS和线粒体代谢可以通过恢复PC表达来挽救。在致糖尿病条件下，小鼠β细胞中MDM 2和p53上调，而PC减少。p53的药理学抑制通过恢复PC表达来消除糖尿病胰岛中的缺陷GSIS。因此，MDM 2-p53-PC信号传导轴将线粒体代谢与胰岛素分泌和葡萄糖稳态联系起来，并且可以代表糖尿病的治疗靶点。 缺乏肿瘤抑制因子p53的小鼠部分免于患糖尿病。在此，作者表明，p53在糖尿病小鼠的胰腺中上调，其中它通过抑制线粒体丙酮酸羧化酶的表达来损害β细胞功能，从而抑制胰岛素分泌。
Mitochondrial metabolism is pivotal for glucose-stimulated insulin secretion (GSIS) in pancreatic β-cells. However, little is known about the molecular machinery that controls the homeostasis of intermediary metabolites in mitochondria. Here we show that the activation of p53 in β-cells, by genetic deletion or pharmacological inhibition of its negative regulator MDM2, impairs GSIS, leading to glucose intolerance in mice. Mechanistically, p53 activation represses the expression of the mitochondrial enzyme pyruvate carboxylase (PC), resulting in diminished production of the TCA cycle intermediates oxaloacetate and NADPH, and impaired oxygen consumption. The defective GSIS and mitochondrial metabolism in MDM2-null islets can be rescued by restoring PC expression. Under diabetogenic conditions, MDM2 and p53 are upregulated, whereas PC is reduced in mouse β-cells. Pharmacological inhibition of p53 alleviates defective GSIS in diabetic islets by restoring PC expression. Thus, the MDM2–p53–PC signalling axis links mitochondrial metabolism to insulin secretion and glucose homeostasis, and could represent a therapeutic target in diabetes. Mice lacking the tumour suppressor p53 are partially protected from developing diabetes. Here the authors show that p53 is upregulated in the pancreas of diabetic mice where it impairs β cell function by repressing expression of mitochondrial pyruvate carboxylase, thereby inhibiting insulin secretion.