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

John T. Cunningham, Joseph T. Rodgers, Daniel H. Arlow, Francisca Vazquez, Vamsi K. Mootha, Pere Puigserver

    Research output: Contribution to journalArticle

    Abstract

    Transcriptional complexes that contain peroxisome-proliferator-activated receptor coactivator (PGC)-1α 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-1α, oestrogen-related receptor α 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-1α. 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-1α. 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.

    Original languageEnglish (US)
    Pages (from-to)736-740
    Number of pages5
    JournalNature
    Volume450
    Issue number7170
    DOIs
    StatePublished - Nov 29 2007

    ASJC Scopus subject areas

    • General

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