title: 2-Hydroxyglutarate Inhibits ATP Synthase and mTOR Signaling.
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.
authors.affiliation: Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA 90095, USA.
authors.forename: Xudong
authors.initials: X
authors.lastname: Fu
authors.affiliation: Molecular Biology Institute, University of California Los Angeles, Los Angeles, CA 90095, USA.
authors.forename: Randall M
authors.initials: RM
authors.lastname: Chin
authors.affiliation: Department of Human Genetics, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA 90095, USA.
authors.forename: Laurent
authors.initials: L
authors.lastname: Vergnes
authors.affiliation: Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA 90095, USA.
authors.forename: Heejun
authors.initials: H
authors.lastname: Hwang
authors.affiliation: Department of Chemistry and Biochemistry, University of California Los Angeles, Los Angeles, CA 90095, USA.
authors.forename: Gang
authors.initials: G
authors.lastname: Deng
authors.affiliation: Department of Chemistry and Biochemistry, University of California Los Angeles, Los Angeles, CA 90095, USA.
authors.forename: Yanpeng
authors.initials: Y
authors.lastname: Xing
authors.affiliation: Molecular Biology Institute, University of California Los Angeles, Los Angeles, CA 90095, USA.
authors.forename: Melody Y
authors.initials: MY
authors.lastname: Pai
authors.affiliation: Department of Neurology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA 90095, USA.
authors.forename: Sichen
authors.initials: S
authors.lastname: Li
authors.affiliation: Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA 90095, USA.
authors.forename: Lisa
authors.initials: L
authors.lastname: Ta
authors.affiliation: 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.
authors.forename: Farbod
authors.initials: F
authors.lastname: Fazlollahi
authors.affiliation: Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Chuo
authors.initials: C
authors.lastname: Chen
authors.affiliation: Department of Neurosurgery, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA 90095, USA.
authors.forename: Robert M
authors.initials: RM
authors.lastname: Prins
authors.affiliation: 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.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Teitell
authors.affiliation: Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA 90095, USA.
authors.forename: David A
authors.initials: DA
authors.lastname: Nathanson
authors.affiliation: Department of Neurology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA 90095, USA.
authors.forename: Albert
authors.initials: A
authors.lastname: Lai
authors.affiliation: 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.
authors.forename: Kym F
authors.initials: KF
authors.lastname: Faull
authors.affiliation: Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA 90095, USA.
authors.forename: Meisheng
authors.initials: M
authors.lastname: Jiang
authors.affiliation: 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.
authors.forename: Steven G
authors.initials: SG
authors.lastname: Clarke
authors.affiliation: 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.
authors.forename: Timothy F
authors.initials: TF
authors.lastname: Cloughesy
authors.affiliation: 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.
authors.forename: Thomas G
authors.initials: TG
authors.lastname: Graeber
authors.affiliation: 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.
authors.forename: Daniel
authors.initials: D
authors.lastname: Braas
authors.affiliation: 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.
authors.forename: Heather R
authors.initials: HR
authors.lastname: Christofk
authors.affiliation: 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.
authors.forename: Michael E
authors.initials: ME
authors.lastname: Jung
authors.affiliation: 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.
authors.forename: Karen
authors.initials: K
authors.lastname: Reue
authors.affiliation: 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.
authors.forename: Jing
authors.initials: J
authors.lastname: Huang
mesh_terms: D000251:Adenosine Triphosphatases / Q000378:metabolism*; D000818:Animals; D017173:Caenorhabditis elegans / Q000502:physiology*; D049109:Cell Proliferation; D005909:Glioblastoma / Q000235:genetics / Q000378:metabolism*; D005977:Glutarates / Q000378:metabolism*; D006801:Humans; D007521:Isocitrate Dehydrogenase / Q000235:genetics / Q000378:metabolism; D008136:Longevity; D009154:Mutation; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*
chemical_list: D005977:Glutarates; C019417:alpha-hydroxyglutarate; D007521:Isocitrate Dehydrogenase; C543588:IDH1 protein, human; D058570:TOR Serine-Threonine Kinases; D000251:Adenosine Triphosphatases