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西亞試劑：mTOR controls mitochondrial oxidative function through a YY

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

John T. Cunningham1,2, Joseph T. Rodgers1, Daniel H. Arlow3, Francisca Vazquez1, Vamsi K. Mootha3 & Pere Puigserver1,2

  1. Dana-Farber Cancer Institute and Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115, USA
  2. Department of Cell Biology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA
  3. 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)-1alpha 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-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.