2-Hydroxyglutarate Inhibits ATP Synthase and mTOR Signaling

Xudong Fu; Randall M Chin; Laurent Vergnes; Heejun Hwang; Gang Deng; Yanpeng Xing; Melody Y Pai; Sichen Li; Lisa Ta; Farbod Fazlollahi; Chuo Chen; Robert M Prins; Michael A Teitell; David A Nathanson; Albert Lai; Kym F Faull; Meisheng Jiang; Steven G Clarke; Timothy F Cloughesy; Thomas G Graeber; Daniel Braas; Heather R Christofk; Michael E Jung; Karen Reue; Jing Huang

doi:10.1016/j.cmet.2015.06.009

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. Epub 2015 Jul 16.

Authors

Xudong Fu¹, Randall M Chin², Laurent Vergnes³, Heejun Hwang¹, Gang Deng⁴, Yanpeng Xing⁴, Melody Y Pai², Sichen Li⁵, Lisa Ta¹, Farbod Fazlollahi⁶, Chuo Chen⁷, Robert M Prins⁸, Michael A Teitell⁹, David A Nathanson¹, Albert Lai⁵, Kym F Faull⁶, Meisheng Jiang¹, Steven G Clarke¹⁰, Timothy F Cloughesy¹¹, Thomas G Graeber¹², Daniel Braas¹³, Heather R Christofk¹⁴, Michael E Jung¹⁵, Karen Reue¹⁶, Jing Huang¹⁷

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: jinghuang.ucla@gmail.com.

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Adenosine Triphosphatases / metabolism*
Animals
Caenorhabditis elegans / physiology*
Cell Proliferation
Glioblastoma / genetics
Glioblastoma / metabolism*
Glutarates / metabolism*
Humans
Isocitrate Dehydrogenase / genetics
Isocitrate Dehydrogenase / metabolism
Longevity
Mutation
Signal Transduction*
TOR Serine-Threonine Kinases / metabolism*

Substances

Glutarates
alpha-hydroxyglutarate
Isocitrate Dehydrogenase
IDH1 protein, human
TOR Serine-Threonine Kinases
Adenosine Triphosphatases

Abstract

Publication types

MeSH terms

Substances

Grants and funding