mTOR controls mitochondrial oxidative function through a YY1-PGC-1α transcriptional complex
mTOR controls mitochondrial oxidative function through a YY1-PGC-1α transcriptional complex
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DOI：
10.1038/nature06322
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发表时间：
2007-11-29
期刊：
影响因子：
64.8
通讯作者：
Puigserver, Pere
中科院分区：
文献类型：
--
作者：
Cunningham, John T.;Rodgers, Joseph T.;Puigserver, Pere
含有过氧化物酶体增殖物激活受体辅激活因子（PGC）-1 α的转录复合物控制线粒体氧化功能，以维持能量稳态，从而响应营养和激素信号（1，2）。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（3-5）。然而，目前尚不清楚mTOR是否以及如何控制线粒体氧化活性。在这里，我们表明，mTOR是必要的线粒体氧化功能的维护。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-1 α、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，我们确定了转录因子阴阳1（YY 1）作为mTOR和PGC-1 α的共同靶点。YY 1的敲低导致线粒体基因表达和呼吸显著降低，并且YY 1是雷帕霉素依赖性抑制这些基因所必需的。此外，mTOR和raptor与YY 1相互作用，抑制mTOR导致YY 1无法与PGC-1 α相互作用并被其共激活。因此，我们已经确定了一种机制，营养传感器（mTOR）平衡能量代谢的线粒体氧化功能的转录控制的手段。这些结果对于我们理解这些途径如何在代谢疾病和癌症中改变具有重要意义。
Transcriptional complexes that contain peroxisome-proliferator-activated receptor coactivator (PGC)-1 alpha control mitochondrial oxidative function to maintain energy homeostasis in response to nutrient and hormonal signals(1,2). An important component in the energy and nutrient pathways is mammalian target of rapamycin (mTOR), a kinase that regulates cell growth, size and survival(3-5). 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-1 alpha, oestrogen-related receptor a 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-1 alpha. 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-1 alpha. 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.