【原】mTOR通过PGC1α 来促进线粒体的合成

GCTA 2022-06-11 发布于贵州

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mTOR controls mitochondrial oxidative function through a YY1-PGC-1alpha transcriptional complex.

|核心内容：

过氧化物酶体-增殖物激活受体辅激活剂(PGC)-1 α 转录复合物控制线粒体氧化功能，以维持能量稳态对营养和激素信号的反应。能量和营养途径中的一个重要组成部分是哺乳动物雷帕霉素靶蛋白(mTOR) ，这是一种调节细胞生长、大小和存活的激酶。然而，mTOR 是否以及如何控制线粒体氧化活性尚不清楚。在这里，我们表明 mTOR 是维持线粒体氧化功能s所必要的。在骨骼肌组织和细胞中，mTOR 抑制剂雷帕霉素降低了线粒体转录调节因子 PGC-1α、雌激素相关受体 α 和核呼吸因子的基因表达，导致线粒体基因表达和耗氧量降低。使用计算基因组学，我们确定转录因子阴-阳1(YY1)作为 mTOR 和 PGC-1alpha 的共同靶点。YY1基因的敲除导致线粒体基因表达和呼吸功能显著下降，雷帕霉素需要通过YY1基因才能对这些基因的抑制作用。此外，mTOR 和 Raptor 与 YY1相互作用，mTOR 的抑制会导致 YY1不能与 PGC-1alpha 相互作用或被 PGC-1alpha 共激活。因此，我们确定了一个机制，营养传感器(mTOR)平衡能量代谢的方式是通过转录控制线粒体氧化功能。这些结果对于我们理解这些通路在代谢性疾病和癌症中是如何改变的具有重要意义。

mTOR通过PGC1α 来促进线粒体的合成

原文摘要：

Transcriptional complexes that contain peroxisome-proliferator-activated receptor coactivator (PGC)-1alpha control mitochondrial oxidative function to maintain energy homeostasis in response to nutrient and hormonal signals. An important component in the energy and nutrient pathways is mammalian target of rapamycin (mTOR), a kinase that regulates cell growth, size and survival. However, it is unknown whether and how mTOR controls mitochondrial oxidative activities. Here we show that mTOR is necessary for the maintenance of mitochondrial oxidative function. In skeletal muscle tissues and cells, the mTOR inhibitor rapamycin decreased the gene expression of the mitochondrial transcriptional regulators PGC-1alpha, oestrogen-related receptor alpha and nuclear respiratory factors, resulting in a decrease in mitochondrial gene expression and oxygen consumption. Using computational genomics, we identified the transcription factor yin-yang 1 (YY1) as a common target of mTOR and PGC-1alpha. Knockdown of YY1 caused a significant decrease in mitochondrial gene expression and in respiration, and YY1 was required for rapamycin-dependent repression of those genes. Moreover, mTOR and raptor interacted with YY1, and inhibition of mTOR resulted in a failure of YY1 to interact with and be coactivated by PGC-1alpha. We have therefore identified a mechanism by which a nutrient sensor (mTOR) balances energy metabolism by means of the transcriptional control of mitochondrial oxidative function. These results have important implications for our understanding of how these pathways might be altered in metabolic diseases and cancer.