Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Letter
  • Published:

Reductive glutamine metabolism by IDH1 mediates lipogenesis under hypoxia

Nature volume 481, pages 380–384 (2012)Cite this article

Subjects

Abstract

Acetyl coenzyme A (AcCoA) is the central biosynthetic precursor for fatty-acid synthesis and protein acetylation. In the conventional view of mammalian cell metabolism, AcCoA is primarily generated from glucose-derived pyruvate through the citrate shuttle and ATP citrate lyase in the cytosol1,2,3. However, proliferating cells that exhibit aerobic glycolysis and those exposed to hypoxia convert glucose to lactate at near-stoichiometric levels, directing glucose carbon away from the tricarboxylic acid cycle and fatty-acid synthesis4. Although glutamine is consumed at levels exceeding that required for nitrogen biosynthesis5, the regulation and use of glutamine metabolism in hypoxic cells is not well understood. Here we show that human cells use reductive metabolism of α-ketoglutarate to synthesize AcCoA for lipid synthesis. This isocitrate dehydrogenase-1 (IDH1)-dependent pathway is active in most cell lines under normal culture conditions, but cells grown under hypoxia rely almost exclusively on the reductive carboxylation of glutamine-derived α-ketoglutarate for de novo lipogenesis. Furthermore, renal cell lines deficient in the von Hippel–Lindau tumour suppressor protein preferentially use reductive glutamine metabolism for lipid biosynthesis even at normal oxygen levels. These results identify a critical role for oxygen in regulating carbon use to produce AcCoA and support lipid synthesis in mammalian cells.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Reductive carboxylation is the primary route of glutamine to lipids.
Figure 2: Hypoxia reprograms cells to rely on reductive glutamine metabolism for lipid synthesis.
Figure 3: Reductive TCA metabolism increases under hypoxia.
Figure 4: HIF/ARNT/VHL signalling regulate carbon use for lipogenesis.

Similar content being viewed by others

References

  1. Hatzivassiliou, G. et al. ATP citrate lyase inhibition can suppress tumor cell growth. Cancer Cell 8, 311–321 (2005)

    Article  CAS  Google Scholar 

  2. Wellen, K. E. et al. ATP-citrate lyase links cellular metabolism to histone acetylation. Science 324, 1076–1080 (2009)

    Article  ADS  CAS  Google Scholar 

  3. Migita, T. et al. ATP citrate lyase: activation and therapeutic implications in non-small cell lung cancer. Cancer Res. 68, 8547–8554 (2008)

    Article  CAS  Google Scholar 

  4. Semenza, G. L. HIF-1: upstream and downstream of cancer metabolism. Curr. Opin. Genet. Dev. 20, 51–56 (2010)

    Article  CAS  Google Scholar 

  5. DeBerardinis, R. J. et al. Beyond aerobic glycolysis: transformed cells can engage in glutamine metabolism that exceeds the requirement for protein and nucleotide synthesis. Proc. Natl Acad. Sci. USA 104, 19345–19350 (2007)

    Article  ADS  CAS  Google Scholar 

  6. Weinberg, F. et al. Mitochondrial metabolism and ROS generation are essential for Kras-mediated tumorigenicity. Proc. Natl Acad. Sci. USA 107, 8788–8793 (2010)

    Article  ADS  CAS  Google Scholar 

  7. Des Rosiers, C. et al. Isotopomer analysis of citric acid cycle and gluconeogenesis in rat liver. Reversibility of isocitrate dehydrogenase and involvement of ATP-citrate lyase in gluconeogenesis. J. Biol. Chem. 270, 10027–10036 (1995)

    Article  CAS  Google Scholar 

  8. Yoo, H., Antoniewicz, M. R., Stephanopoulos, G. & Kelleher, J. K. Quantifying reductive carboxylation flux of glutamine to lipid in a brown adipocyte cell line. J. Biol. Chem. 283, 20621–20627 (2008)

    Article  CAS  Google Scholar 

  9. Metallo, C. M., Walther, J. L. & Stephanopoulos, G. Evaluation of 13C isotopic tracers for metabolic flux analysis in mammalian cells. J. Biotechnol. 144, 167–174 (2009)

    Article  CAS  Google Scholar 

  10. Lemons, J. M. et al. Quiescent fibroblasts exhibit high metabolic activity. PLoS Biol. 8, e1000514 (2010)

    Article  Google Scholar 

  11. Ward, P. S. et al. The common feature of leukemia-associated IDH1 and IDH2 mutations is a neomorphic enzyme activity converting α-ketoglutarate to 2-hydroxyglutarate. Cancer Cell 17, 225–234 (2010)

    Article  CAS  Google Scholar 

  12. Boros, L. G. et al. Defective RNA ribose synthesis in fibroblasts from patients with thiamine-responsive megaloblastic anemia (TRMA). Blood 102, 3556–3561 (2003)

    Article  CAS  Google Scholar 

  13. Munger, J. et al. Systems-level metabolic flux profiling identifies fatty acid synthesis as a target for antiviral therapy. Nature Biotechnol. 26, 1179–1186 (2008)

    Article  CAS  Google Scholar 

  14. Maier, K., Hofmann, U., Reuss, M. & Mauch, K. Identification of metabolic fluxes in hepatic cells from transient 13C-labeling experiments: part II. Flux estimation. Biotechnol. Bioeng. 100, 355–370 (2008)

    Article  CAS  Google Scholar 

  15. Kharroubi, A. T., Masterson, T. M., Aldaghlas, T. A., Kennedy, K. A. & Kelleher, J. K. Isotopomer spectral analysis of triglyceride fatty acid synthesis in 3T3–L1 cells. Am. J. Physiol. 263, E667–E675 (1992)

    Article  CAS  Google Scholar 

  16. Siebert, G., Carsiotis, M. & Plaut, G. W. The enzymatic properties of isocitric dehydrogenase. J. Biol. Chem. 226, 977–991 (1957)

    CAS  PubMed  Google Scholar 

  17. Sauer, U. Metabolic networks in motion: 13C-based flux analysis. Mol. Syst. Biol. 2, 62 (2006)

    Article  Google Scholar 

  18. Young, J. D., Walther, J. L., Antoniewicz, M. R., Yoo, H. & Stephanopoulos, G. An elementary metabolite unit (EMU) based method of isotopically nonstationary flux analysis. Biotechnol. Bioeng. 99, 686–699 (2008)

    Article  CAS  Google Scholar 

  19. Hartong, D. T. et al. Insights from retinitis pigmentosa into the roles of isocitrate dehydrogenases in the Krebs cycle. Nature Genet. 40, 1230–1234 (2008)

    Article  CAS  Google Scholar 

  20. Cheng, T. et al. Pyruvate carboxylase is required for glutamine-independent growth of tumor cells. Proc. Natl Acad. Sci. USA 108, 8674–8679 (2011)

    Article  ADS  CAS  Google Scholar 

  21. Bonnet, S. et al. A mitochondria-K+ channel axis is suppressed in cancer and its normalization promotes apoptosis and inhibits cancer growth. Cancer Cell 11, 37–51 (2007)

    Article  CAS  Google Scholar 

  22. Kim, J. W., Tchernyshyov, I., Semenza, G. L. & Dang, C. V. HIF-1-mediated expression of pyruvate dehydrogenase kinase: a metabolic switch required for cellular adaptation to hypoxia. Cell Metab. 3, 177–185 (2006)

    Article  Google Scholar 

  23. Papandreou, I., Cairns, R. A., Fontana, L., Lim, A. L. & Denko, N. C. HIF-1 mediates adaptation to hypoxia by actively downregulating mitochondrial oxygen consumption. Cell Metab. 3, 187–197 (2006)

    Article  CAS  Google Scholar 

  24. Kaelin, W. G., Jr Molecular basis of the VHL hereditary cancer syndrome. Nature Rev. Cancer 2, 673–682 (2002)

    Article  CAS  Google Scholar 

  25. Ivan, M. et al. HIFα targeted for VHL-mediated destruction by proline hydroxylation: implications for O2 sensing. Science 292, 464–468 (2001)

    Article  ADS  CAS  Google Scholar 

  26. Jaakkola, P. et al. Targeting of HIF-α to the von Hippel-Lindau ubiquitylation complex by O2-regulated prolyl hydroxylation. Science 292, 468–472 (2001)

    Article  ADS  CAS  Google Scholar 

  27. Zimmer, M. et al. Small-molecule inhibitors of HIF-2a translation link its 5′UTR iron-responsive element to oxygen sensing. Mol. Cell 32, 838–848 (2008)

    Article  CAS  Google Scholar 

  28. Gordan, J. D., Bertout, J. A., Hu, C. J., Diehl, J. A. & Simon, M. C. HIF-2α promotes hypoxic cell proliferation by enhancing c-myc transcriptional activity. Cancer Cell 11, 335–347 (2007)

    Article  CAS  Google Scholar 

  29. Gao, P. et al. c-Myc suppression of miR-23a/b enhances mitochondrial glutaminase expression and glutamine metabolism. Nature 458, 762–765 (2009)

    Article  ADS  CAS  Google Scholar 

  30. Sutherland, R. M. Cell and environment interactions in tumor microregions: the multicell spheroid model. Science 240, 177–184 (1988)

    Article  ADS  CAS  Google Scholar 

  31. Zimmer, M., Doucette, D., Siddiqui, N. & Iliopoulos, O. Inhibition of hypoxia-inducible factor is sufficient for growth suppression of VHL−/− tumors. Mol. Cancer Res. 2, 89–95 (2004)

    CAS  PubMed  Google Scholar 

  32. Iliopoulos, O., Kibel, A., Gray, S. & Kaelin, W. G., Jr Tumour suppression by the human von Hippel-Lindau gene product. Nature Med. 1, 822–826 (1995)

    Article  CAS  Google Scholar 

  33. Hogquist, K. A. et al. T cell receptor antagonist peptides induce positive selection. Cell 76, 17–27 (1994)

    Article  CAS  Google Scholar 

  34. Sarbassov, D. D., Guertin, D. A., Ali, S. M. & Sabatini, D. M. Phosphorylation and regulation of Akt/PKB by the rictor-mTOR complex. Science 307, 1098–1101 (2005)

    Article  ADS  CAS  Google Scholar 

  35. Fernandez, C. A., Des Rosiers, C., Previs, S. F., David, F. & Brunengraber, H. Correction of 13C mass isotopomer distributions for natural stable isotope abundance. J. Mass Spectrom. 31, 255–262 (1996)

    Article  ADS  CAS  Google Scholar 

  36. Antoniewicz, M. R., Kelleher, J. K. & Stephanopoulos, G. Determination of confidence intervals of metabolic fluxes estimated from stable isotope measurements. Metab. Eng. 8, 324–337 (2006)

    Article  CAS  Google Scholar 

  37. Antoniewicz, M. R., Kelleher, J. K. & Stephanopoulos, G. Elementary metabolite units (EMU): a novel framework for modeling isotopic distributions. Metab. Eng. 9, 68–86 (2007)

    Article  CAS  Google Scholar 

  38. Noguchi, Y. et al. Effect of anaplerotic fluxes and amino acid availability on hepatic lipoapoptosis. J. Biol. Chem. 284, 33425–33436 (2009)

    Article  CAS  Google Scholar 

  39. Gaglio, D. et al. Oncogenic K-Ras decouples glucose and glutamine metabolism to support cancer cell growth. Mol. Syst. Biol. 7, 523 (2011)

    Article  Google Scholar 

  40. Grassian, A. R., Metallo, C. M., Coloff, J. L., Stephanopoulos, G. & Brugge, J. S. Erk regulation of pyruvate dehydrogenase flux through PDK4 modulates cell proliferation. Genes Dev. 25, 1716–1733 (2011)

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank N. Vokes and P. Ward for discussions. We also thank S. Gross and Agios Pharmaceuticals for providing the IDH1 construct. We acknowledge support from National Institutes of Health grant R01 DK075850-01. C.M.M. is supported by a postdoctoral fellowship from the American Cancer Society. K.H. is supported by the German Research Foundation (DFG) grant HI1400. L.G. is supported by the NIH and the Glenn Foundation for Medical Research. M.G.V.H. is supported by the Burrough’s Wellcome Fund, the Smith Family, the Damon Runyon Cancer Research Foundation and the National Cancer Institute. D.J.I. is an investigator of the Howard Hughes Medical Institute. O.I. is supported by R01 CA122591 and the Dana Farber/Harvard Cancer Center Kidney SPORE Grant Developmental Award.

Author information

Author notes

  1. Christian M. Metallo & Karsten Hiller

    Present address: Present addresses: Department of Bioengineering, University of California at San Diego, La Jolla, California 92093, USA (C.M.M.); Luxembourg Centre for Systems Biomedicine, University of Luxembourg, L-1511, Luxembourg (K.H.).,

Authors and Affiliations

  1. Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, 02139, Massachusetts, USA

    Christian M. Metallo, Paulo A. Gameiro, Karsten Hiller, Joanne K. Kelleher & Gregory Stephanopoulos

  2. Department of Life Sciences, University of Coimbra, 3004-517 Coimbra, Portugal,

    Paulo A. Gameiro

  3. Massachusetts General Hospital Cancer Center, Boston, 02114, Massachusetts, USA

    Paulo A. Gameiro, Juanjuan Yang & Othon Iliopoulos

  4. Massachusetts General Hospital Center for Cancer Research, Charlestown, 02129, Massachusetts, USA

    Paulo A. Gameiro, Juanjuan Yang & Othon Iliopoulos

  5. Department of Biology, Massachusetts Institute of Technology, Cambridge, 02139, Massachusetts, USA

    Eric L. Bell, Katherine R. Mattaini, Leonard Guarente & Matthew G. Vander Heiden

  6. Koch Institute for Cancer Research, Massachusetts Institute of Technology, Cambridge, 02139, Massachusetts, USA

    Katherine R. Mattaini, Christopher M. Jewell, Zachary R. Johnson, Darrell J. Irvine & Matthew G. Vander Heiden

  7. Howard Hughes Medical Institute, Chevy Chase, 20815, Maryland, USA

    Darrell J. Irvine

  8. Dana-Farber Cancer Institute, Boston, 02115, Massachusetts, USA

    Matthew G. Vander Heiden

Authors
  1. Christian M. Metallo
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Paulo A. Gameiro
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Eric L. Bell
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Katherine R. Mattaini
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Juanjuan Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Karsten Hiller
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Christopher M. Jewell
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Zachary R. Johnson
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Darrell J. Irvine
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Leonard Guarente
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Joanne K. Kelleher
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Matthew G. Vander Heiden
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Othon Iliopoulos
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Gregory Stephanopoulos
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

C.M.M., P.A.G., E.L.B., K.R.M., J.Y., K.H. and C.M.J. performed cellular experiments and isotope tracing. C.M.M. and P.A.G. performed metabolite profiling and analysed data. K.R.M. and M.G.V.H. performed enzyme assays and 14C experiments. E.L.B., J.Y. and Z.R.J. generated western blots. D.J.I. and L.G. provided support and reagents. J.K.K., M.G.V.H., O.I. and G.S. provided conceptual advice. C.M.M., J.K.K., M.G.V.H., O.I. and G.S. wrote and edited the paper.

Corresponding authors

Correspondence to Othon Iliopoulos or Gregory Stephanopoulos.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Information

This file contains Supplementary Figures 1-23 with legends, Supplementary Text on the subject of Metabolic flux analysis (MFA), Supplementary Tables 1-14 and additional references. (PDF 1175 kb)

PowerPoint slides

Rights and permissions

Reprints and permissions

About this article

Cite this article

Metallo, C., Gameiro, P., Bell, E. et al. Reductive glutamine metabolism by IDH1 mediates lipogenesis under hypoxia. Nature 481, 380–384 (2012). https://doi.org/10.1038/nature10602

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nature10602

This article is cited by

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing