2-Hydroxyglutarate Inhibits ATP Synthase and mTOR Signaling

  • Cell Metab. 2015 Sep 1;22(3):508-15. doi: 10.1016/j.cmet.2015.06.009.
Xudong Fu  1 ,  Randall M Chin  2 ,  Laurent Vergnes  3 ,  Heejun Hwang  1 ,  Gang Deng  4 ,  Yanpeng Xing  4 ,  Melody Y Pai  2 ,  Sichen Li  5 ,  Lisa Ta  1 ,  Farbod Fazlollahi  6 ,  Chuo Chen  7 ,  Robert M Prins  8 ,  Michael A Teitell  9 ,  David A Nathanson  1 ,  Albert Lai  5 ,  Kym F Faull  6 ,  Meisheng Jiang  1 ,  Steven G Clarke  10 ,  Timothy F Cloughesy  11 ,  Thomas G Graeber  12 ,  Daniel Braas  13 ,  Heather R Christofk  14 ,  Michael E Jung  15 ,  Karen Reue  16 ,  Jing Huang  17
Affiliations
  • 1. Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA 90095, USA.
  • 2. Molecular Biology Institute, University of California Los Angeles, Los Angeles, CA 90095, USA.
  • 3. Department of Human Genetics, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA 90095, USA.
  • 4. Department of Chemistry and Biochemistry, University of California Los Angeles, Los Angeles, CA 90095, USA.
  • 5. Department of Neurology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA 90095, USA.
  • 6. Pasarow Mass Spectrometry Laboratory, Department of Psychiatry and Biobehavioral Sciences, and Semel Institute for Neuroscience and Human Behavior, University of California Los Angeles, Los Angeles, CA 90095, USA.
  • 7. Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
  • 8. Department of Neurosurgery, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA 90095, USA.
  • 9. Molecular Biology Institute, University of California Los Angeles, Los Angeles, CA 90095, USA; Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA 90095, USA; Jonsson Comprehensive Cancer Center, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA 90095, USA.
  • 10. Molecular Biology Institute, University of California Los Angeles, Los Angeles, CA 90095, USA; Department of Chemistry and Biochemistry, University of California Los Angeles, Los Angeles, CA 90095, USA.
  • 11. Department of Neurology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA 90095, USA; Jonsson Comprehensive Cancer Center, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA 90095, USA.
  • 12. Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA 90095, USA; Jonsson Comprehensive Cancer Center, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA 90095, USA; UCLA Metabolomics Center, University of California Los Angeles, Los Angeles, CA 90095, USA; Crump Institute for Molecular Imaging, University of California Los Angeles, Los Angeles, CA 90095, USA.
  • 13. Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA 90095, USA; UCLA Metabolomics Center, University of California Los Angeles, Los Angeles, CA 90095, USA.
  • 14. Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA 90095, USA; Jonsson Comprehensive Cancer Center, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA 90095, USA; UCLA Metabolomics Center, University of California Los Angeles, Los Angeles, CA 90095, USA.
  • 15. Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA 90095, USA; Molecular Biology Institute, University of California Los Angeles, Los Angeles, CA 90095, USA; Department of Chemistry and Biochemistry, University of California Los Angeles, Los Angeles, CA 90095, USA; Jonsson Comprehensive Cancer Center, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA 90095, USA.
  • 16. Molecular Biology Institute, University of California Los Angeles, Los Angeles, CA 90095, USA; Department of Human Genetics, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA 90095, USA.
  • 17. Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA 90095, USA; Molecular Biology Institute, University of California Los Angeles, Los Angeles, CA 90095, USA; Jonsson Comprehensive Cancer Center, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA 90095, USA. Electronic address: [email protected].
PMID: 26190651 DOI: 10.1016/j.cmet.2015.06.009
Abstract

We discovered recently that the central metabolite α-ketoglutarate (α-KG) extends the lifespan of C. elegans through inhibition of ATP Synthase and TOR signaling. Here we find, unexpectedly, that (R)-2-hydroxyglutarate ((R)-2HG), an oncometabolite that interferes with various α-KG-mediated processes, similarly extends worm lifespan. (R)-2HG accumulates in human cancers carrying neomorphic mutations in the isocitrate dehydrogenase (IDH) 1 and 2 genes. We show that, like α-KG, both (R)-2HG and (S)-2HG bind and inhibit ATP Synthase and inhibit mTOR signaling. These effects are mirrored in IDH1 mutant cells, suggesting a growth-suppressive function of (R)-2HG. Consistently, inhibition of ATP Synthase by 2-HG or α-KG in glioblastoma cells is sufficient for growth arrest and tumor cell killing under conditions of glucose limitation, e.g., when ketone bodies (instead of glucose) are supplied for energy. These findings inform therapeutic strategies and open avenues for investigating the roles of 2-HG and metabolites in biology and disease.

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