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

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.

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Figure 1: mTOR controls mitochondrial gene expression and oxygen consumption.
Figure 2: Genomic analysis reveals that mitochondrial genes are regulated by PGC-1α and mTOR pathways by means of the transcription factor YY1.
Figure 3: YY1 regulates mitochondrial gene expression and oxygen consumption.
Figure 4: Rapamycin-dependent coactivation and interaction between PGC-1α, YY1 and mTORC1.

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Gene Expression Omnibus

Data deposits

Microarray data is available online through the Gene Expression Omnibus (GEO accession number GSE5332).

References

  1. 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 

  2. 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 

  3. Wullschleger, S., Loewith, R. & Hall, M. N. TOR signaling in growth and metabolism. Cell 124, 471–484 (2006)

    Article  CAS  PubMed  Google Scholar 

  4. 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 

  5. 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 

  6. 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 

  7. 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 

  8. 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 

  9. 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 

  10. 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 

  11. 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 

  12. 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 

  13. 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 

  14. 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 

  15. 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 

  16. 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 

  17. 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 

  18. 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 

  19. 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 

  20. 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 

  21. 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 

  22. 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 

  23. 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 

  24. 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 

  25. 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 

  26. Irizarry, R. A. et al. Summaries of Affymetrix GeneChip probe level data. Nucleic Acids Res. 31, e15 (2003)

    Article  PubMed  PubMed Central  Google Scholar 

  27. 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 

  28. 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 

  29. 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 

  30. 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 

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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.).

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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)

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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

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