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. GraeberDaniel Braas, Heather R. Christofk, Michael E. Jung, Karen Reue, Jing Huang

Research output: Contribution to journalArticle

85 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)508-515
Number of pages8
JournalCell Metabolism
Volume22
Issue number3
DOIs
StatePublished - Sep 1 2015

ASJC Scopus subject areas

  • Physiology
  • Molecular Biology
  • Cell Biology

Fingerprint Dive into the research topics of '2-hydroxyglutarate inhibits ATP synthase and mTOR Signaling'. Together they form a unique fingerprint.

  • Cite this

    Fu, X., Chin, R. M., Vergnes, L., Hwang, H., Deng, G., Xing, Y., Pai, M. Y., Li, S., Ta, L., Fazlollahi, F., Chen, C., Prins, R. M., Teitell, M. A., Nathanson, D. A., Lai, A., Faull, K. F., Jiang, M., Clarke, S. G., Cloughesy, T. F., ... Huang, J. (2015). 2-hydroxyglutarate inhibits ATP synthase and mTOR Signaling. Cell Metabolism, 22(3), 508-515. https://doi.org/10.1016/j.cmet.2015.06.009