Mtor controls mitochondrial oxidative function through a yy1–pgc-1α transcriptional complex

Mtor controls mitochondrial oxidative function through a yy1–pgc-1α transcriptional complex

Play all audios:

Loading...

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


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. Access through your institution Buy or subscribe This


is a preview of subscription content, access via your institution ACCESS OPTIONS Access through your institution Subscribe to this journal Receive 51 print issues and online access $199.00


per year only $3.90 per issue Learn more Buy this article * Purchase on SpringerLink * Instant access to full article PDF Buy now Prices may be subject to local taxes which are calculated


during checkout ADDITIONAL ACCESS OPTIONS: * Log in * Learn about institutional subscriptions * Read our FAQs * Contact customer support SIMILAR CONTENT BEING VIEWED BY OTHERS NUCLEAR UHRF1


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


Gene Expression Omnibus (GEO accession number GSE5332). REFERENCES * Finck, B. N. & Kelly, D. P. PGC-1 coactivators: inducible regulators of energy metabolism in health and disease. _J.


Clin. Invest._ 116, 615–622 (2006) Article  CAS  PubMed  PubMed Central  Google Scholar  * Lin, J., Handschin, C. & Spiegelman, B. M. Metabolic control through the PGC-1 family of


transcription coactivators. _Cell Metab._ 1, 361–370 (2005) Article  PubMed  Google Scholar  * Wullschleger, S., Loewith, R. & Hall, M. N. TOR signaling in growth and metabolism. _Cell_


124, 471–484 (2006) Article  CAS  PubMed  Google Scholar  * Dann, S. G. & Thomas, G. The amino acid sensitive TOR pathway from yeast to mammals. _FEBS Lett._ 580, 2821–2829 (2006)


Article  CAS  PubMed  Google Scholar  * Sarbassov, D. D., Ali, S. M. & Sabatini, D. M. Growing roles for the mTOR pathway. _Curr. Opin. Cell Biol._ 17, 596–603 (2005) Article  CAS 


PubMed  Google Scholar  * Inoki, K., Li, Y., Xu, T. & Guan, K. L. Rheb GTPase is a direct target of TSC2 GAP activity and regulates mTOR signaling. _Genes Dev._ 17, 1829–1834 (2003)


Article  CAS  PubMed  PubMed Central  Google Scholar  * Long, X., Lin, Y., Ortiz-Vega, S., Yonezawa, K. & Avruch, J. Rheb binds and regulates the mTOR kinase. _Curr. Biol._ 15, 702–713


(2005) Article  CAS  PubMed  Google Scholar  * Nobukini, T. et al. Amino acids mediate mTOR/raptor signaling through activation of class 3 phosphatidylinositol 3OH-kinase. _Proc. Natl Acad.


Sci. USA_ 102, 14238–14243 (2005) Article  ADS  Google Scholar  * Peng, T., Golub, T. R. & Sabatini, D. M. The immunosuppressant rapamycin mimics a starvation-like signal distinct from


amino acid and glucose deprivation. _Mol. Cell. Biol._ 22, 5575–5584 (2002) Article  CAS  PubMed  PubMed Central  Google Scholar  * Schieke, S. M. et al. The mammalian target of rapamycin


(mTOR) pathway regulates mitochondrial oxygen consumption and oxidative capacity. _J. Biol. Chem._ 281, 27643–27652 (2006) Article  CAS  PubMed  Google Scholar  * Mootha, V. K. et al. Errα


and Gabpa/b specify PGC-1α-dependent oxidative phosphorylation gene expression that is altered in diabetic muscle. _Proc. Natl Acad. Sci. USA_ 101, 6570–6575 (2004) Article  ADS  CAS  PubMed


  PubMed Central  Google Scholar  * Mootha, V. K. et al. PGC-1α-responsive genes involved in oxidative phosphorylation are coordinately downregulated in human diabetes. _Nature Genet._ 34,


267–273 (2003) Article  ADS  CAS  PubMed  Google Scholar  * Patti, M. E. et al. Coordinated reduction of genes of oxidative metabolism in humans with insulin resistance and diabetes:


Potential role of PGC1 and NRF1. _Proc. Natl Acad. Sci. USA_ 100, 8466–8471 (2003) Article  ADS  CAS  PubMed  PubMed Central  Google Scholar  * Zhang, H. et al. Loss of Tsc1/Tsc2 activates


mTOR and disrupts PI3K–Akt signaling through downregulation of PDGFR. _J. Clin. Invest._ 112, 1223–1233 (2003) Article  CAS  PubMed  PubMed Central  Google Scholar  * Shah, O. J., Wang, Z.


& Hunter, T. Inappropriate activation of the TSC/Rheb/mTOR/S6K cassette induces IRS1/2 depletion, insulin resistance, and cell survival deficiencies. _Curr. Biol._ 14, 1650–1656 (2004)


Article  CAS  PubMed  Google Scholar  * Sarbassov, D. D. et al. Prolonged rapamycin treatment inhibits mTORC2 assembly and Akt/PKB. _Mol. Cell_ 22, 159–168 (2006) Article  CAS  PubMed 


Google Scholar  * Tusher, V. G., Tibshirani, R. & Chu, G. Significance analysis of microarrays applied to the ionizing radiation response. _Proc. Natl Acad. Sci. USA_ 98, 5116–5121


(2001) Article  ADS  CAS  PubMed  PubMed Central  Google Scholar  * Calvo, S. et al. Systematic identification of human mitochondrial disease genes through integrative genomics. _Nature


Genet._ 38, 576–582 (2006) Article  CAS  PubMed  Google Scholar  * Yant, S. R. et al. High affinity YY1 binding motifs: identification of two core types (ACAT and CCAT) and distribution of


potential binding sites within the human beta globin cluster. _Nucleic Acids Res._ 23, 4353–4362 (1995) Article  CAS  PubMed  PubMed Central  Google Scholar  * Wilkinson, F. H., Park, K.


& Atchison, M. L. Polycomb recruitment to DNA _in vivo_ by the YY1 REPO domain. _Proc. Natl Acad. Sci. USA_ 103, 19296–19301 (2006) Article  ADS  CAS  PubMed  PubMed Central  Google


Scholar  * Schreiber, S. N. et al. The estrogen-related receptor α (ERRα) functions in PPARγ coactivator 1α (PGC-1α)-induced mitochondrial biogenesis. _Proc. Natl Acad. Sci. USA_ 101,


6472–6477 (2004) Article  ADS  CAS  PubMed  PubMed Central  Google Scholar  * Ribes, D., Kamar, N., Esposito, L. & Rostaing, L. Combined use of tacrolimus and sirolimus in _de novo_


renal transplant patients: current data. _Transplant. Proc._ 37, 2813–2816 (2005) Article  CAS  PubMed  Google Scholar  * Morrisett, J. D. et al. Effects of sirolimus on plasma lipids,


lipoprotein levels, and fatty acid metabolism in renal transplant patients. _J. Lipid Res._ 43, 1170–1180 (2002) Article  CAS  PubMed  Google Scholar  * Leone, T. C. et al. PGC-1α deficiency


causes multi-system energy metabolic derangements: muscle dysfunction, abnormal weight control and hepatic steatosis. _PLoS Biol._ 3, e101 (2005) Article  PubMed  PubMed Central  Google


Scholar  * Saks, V. A. et al. Permeabilized cell and skinned fiber techniques in studies of mitochondrial function _in vivo_ . _Mol. Cell. Biochem._ 184, 81–100 (1998) Article  CAS  PubMed 


Google Scholar  * Irizarry, R. A. et al. Summaries of Affymetrix GeneChip probe level data. _Nucleic Acids Res._ 31, e15 (2003) Article  PubMed  PubMed Central  Google Scholar  * Andersson,


U. & Scarpulla, R. C. Pgc-1-related coactivator, a novel, serum-inducible coactivator of nuclear respiratory factor 1-dependent transcription in mammalian cells. _Mol. Cell. Biol._ 21,


3738–3749 (2001) Article  CAS  PubMed  PubMed Central  Google Scholar  * Pierce, S. B. et al. Regulation of DAF-2 receptor signaling by human insulin and _ins-1_, a member of the unusually


large and diverse _C. _ _elegans_ insulin gene family. _Genes Dev._ 15, 672–686 (2001) Article  CAS  PubMed  PubMed Central  Google Scholar  * Kim, D. H. et al. mTOR interacts with raptor to


form a nutrient-sensitive complex that signals to the cell growth machinery. _Cell_ 110, 163–175 (2002) Article  CAS  PubMed  Google Scholar  * Sancak, Y. et al. PRAS40 is an


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


November 2007 * DOI: https://doi.org/10.1038/nature06322 SHARE THIS ARTICLE Anyone you share the following link with will be able to read this content: Get shareable link Sorry, a shareable


link is not currently available for this article. Copy to clipboard Provided by the Springer Nature SharedIt content-sharing initiative