营养物传感分子mTOR（雷帕霉素的哺乳动物目标）是参与调控细胞生长和增殖的一种激酶。它与细胞能量的密切联系表明，它也许能够与线粒体发生相互作用。现在一项计算遗传学研究证实了这一点。mTOR通过对线粒体基因表达的转录控制及氧化功能来平衡能量代谢，以转录调控物质PGC-1alpha 和YY1为调控因子。这一通道为线粒体活性受损的代谢疾病的治疗干预提供了新的可能性。
原始出处:
Nature 450, 736-740 (29 November 2007) | doi:10.1038/nature06322; Received 5 August 2007; Accepted 25 September 2007
mTOR controls mitochondrial oxidative function through a YY1–PGC-1 transcriptional complex
John T. Cunningham1,2, Joseph T. Rodgers1, Daniel H. Arlow3, Francisca Vazquez1, Vamsi K. Mootha3 & Pere Puigserver1,2
Dana-Farber Cancer Institute and Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115, USA
Department of Cell Biology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA
Departments of Systems Biology and Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114, USA and Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, Massachusetts 02139, USA
Correspondence to: Vamsi K. Mootha3Pere Puigserver1,2 Correspondence and requests for materials should be addressed to P.P. (Email: pere_puigserver@dfci.harvard.edu) or V.K.M.
Transcriptional complexes that contain peroxisome-proliferator-activated receptor coactivator (PGC)-1 control mitochondrial oxidative function to maintain energy homeostasis in response to nutrient and hormonal signals1, 2. An important component in the energy and nutrient pathways is mammalian target of rapamycin (mTOR), a kinase that regulates cell growth, size and survival3, 4, 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, oestrogen-related receptor 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. 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. 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.
