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 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-1α, oestrogen-related receptor

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. Access through your institution Buy or subscribe This

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IS A GATE-KEEPER OF CELLULAR AMPK ACTIVITY AND FUNCTION Article 24 September 2021 EMERGING ROLES OF TFE3 IN METABOLIC REGULATION Article Open access 11 March 2023 TRANSCRIPTIONAL CONTROL OF

ENERGY METABOLISM BY NUCLEAR RECEPTORS Article 16 May 2022 ACCESSION CODES PRIMARY ACCESSIONS GENE EXPRESSION OMNIBUS * GSE5332 DATA DEPOSITS Microarray data is available online through the

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insulin-regulated inhibitor of the mTORC1 protein kinase. _Mol. Cell_ 25, 903–915 (2007) Article  CAS  PubMed  Google Scholar  Download references ACKNOWLEDGEMENTS We thank members of the

Puigserver laboratory for helpful comments and discussions on this work; S.-H. Kim for technical assistance; M. Montminy for the anti-PGC-1α polyclonal antibody; D. Kwiatkowski for the

_TSC2_-/- and _TSC2_+/+ murine embryonic fibroblasts; R. Abraham for the AU1-mTOR expression plasmid; and D. Sabatini for HA–raptor and Myc–rictor expression constructs. These studies were

supported by a National Institutes of Health R21 grant (P.P.), a grant from the American Diabetes Association/Smith Family Foundation (V.K.M.) and a Burroughs Wellcome Career Award in the

Biomedical Sciences (V.K.M.). AUTHOR INFORMATION AUTHORS AND AFFILIATIONS * Dana-Farber Cancer Institute and Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115,

USA, Massachusetts John T. Cunningham, Joseph T. Rodgers, Francisca Vazquez & Pere Puigserver * Department of Cell Biology, Johns Hopkins University School of Medicine, Baltimore,

Maryland 21205, USA, Maryland John T. Cunningham & Pere Puigserver * 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, Massachusetts Daniel H. Arlow & Vamsi K. Mootha

Authors * John T. Cunningham View author publications You can also search for this author inPubMed Google Scholar * Joseph T. Rodgers View author publications You can also search for this

author inPubMed Google Scholar * Daniel H. Arlow View author publications You can also search for this author inPubMed Google Scholar * Francisca Vazquez View author publications You can

also search for this author inPubMed Google Scholar * Vamsi K. Mootha View author publications You can also search for this author inPubMed Google Scholar * Pere Puigserver View author

publications You can also search for this author inPubMed Google Scholar CORRESPONDING AUTHORS Correspondence to Vamsi K. Mootha or Pere Puigserver. SUPPLEMENTARY INFORMATION SUPPLEMENTARY

INFORMATION This file contains Supplementary Figures1-7 with Legends. A referenced Supplementary Methods are also contained as well as a list of oligonucleotide primers used in the text.

(PDF 1195 kb) SUPPLEMENTARY TABLE 1 This file contains Supplementary Table 1 which is an Excel Spreadsheet of microarray data containing Affymetrix Probe Set ID, gene title, and expression

values for 3 vehicle treated samples and 3 rapamycin treated samples. (XLS 8257 kb) SUPPLEMENTARY TABLE 2 This file contains Supplementary Table 2 which is an Excel Spreadsheet of microarray

data containing Affymetrix Probe Set ID, gene title, and expression values for 3 GFP-infected samples and 3 PGC-1α-infected samples. (XLS 8272 kb) RIGHTS AND PERMISSIONS Reprints and

permissions ABOUT THIS ARTICLE CITE THIS ARTICLE Cunningham, J., Rodgers, J., Arlow, D. _et al._ mTOR controls mitochondrial oxidative function through a YY1–PGC-1α transcriptional complex.

_Nature_ 450, 736–740 (2007). https://doi.org/10.1038/nature06322 Download citation * Received: 05 August 2007 * Accepted: 25 September 2007 * Published: 29 November 2007 * Issue Date: 29

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