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

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 journal › Article › peer-review

167 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 language	English (US)
Pages (from-to)	508-515
Number of pages	8
Journal	Cell Metabolism
Volume	22
Issue number	3
DOIs	https://doi.org/10.1016/j.cmet.2015.06.009
State	Published - Sep 1 2015

ASJC Scopus subject areas

Physiology
Molecular Biology
Cell Biology

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10.1016/j.cmet.2015.06.009

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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

Fu, X, Chin, RM, Vergnes, L, Hwang, H, Deng, G, Xing, Y, Pai, MY, Li, S, Ta, L, Fazlollahi, F, Chen, C, Prins, RM, Teitell, MA, Nathanson, DA, Lai, A, Faull, KF, Jiang, M, Clarke, SG, Cloughesy, TF, Graeber, TG, Braas, D, Christofk, HR, Jung, ME, Reue, K & Huang, J 2015, '2-hydroxyglutarate inhibits ATP synthase and mTOR Signaling', Cell Metabolism, vol. 22, no. 3, pp. 508-515. https://doi.org/10.1016/j.cmet.2015.06.009

@article{99ff9bc3331a495f88ee55117caa40c0,

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.",

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

note = "Funding Information: We thank Chris Walsh for insightful suggestions and advice. This work was supported by the Oppenheimer Program, NIH grants R01 AT006889 and P01 HL028481, and UCLA Jonsson Cancer Center Foundation and National Center for Advancing Translational Sciences UCLA Clinical and Translational Science Institute (CTSI) Grant UL1TR000124. X.F. is a recipient of a China Scholarship Council scholarship. R.M.C. is a postdoctoral fellow supported by the UCLA Tumor Immunology Training Program (NIH T32 CA009120). M.Y.P. was a trainee of the UCLA C&MB training grant (NIH T32 GM007185). Support for L.V. and K.R. was from the Leducq Foundation. This paper is dedicated to Dr. Judith Gasson in honor of her 20 years as Director of the Jonsson Comprehensive Cancer Center. Publisher Copyright: {\textcopyright} 2015 Elsevier Inc.",

year = "2015",

month = sep,

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doi = "10.1016/j.cmet.2015.06.009",

language = "English (US)",

volume = "22",

pages = "508--515",

journal = "Cell Metabolism",

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T1 - 2-hydroxyglutarate inhibits ATP synthase and mTOR Signaling

AU - Fu, Xudong

AU - Chin, Randall M.

AU - Vergnes, Laurent

AU - Hwang, Heejun

AU - Deng, Gang

AU - Xing, Yanpeng

AU - Pai, Melody Y.

AU - Li, Sichen

AU - Ta, Lisa

AU - Fazlollahi, Farbod

AU - Chen, Chuo

AU - Prins, Robert M.

AU - Teitell, Michael A.

AU - Nathanson, David A.

AU - Lai, Albert

AU - Faull, Kym F.

AU - Jiang, Meisheng

AU - Clarke, Steven G.

AU - Cloughesy, Timothy F.

AU - Graeber, Thomas G.

AU - Braas, Daniel

AU - Christofk, Heather R.

AU - Jung, Michael E.

AU - Reue, Karen

AU - Huang, Jing

N1 - Funding Information: We thank Chris Walsh for insightful suggestions and advice. This work was supported by the Oppenheimer Program, NIH grants R01 AT006889 and P01 HL028481, and UCLA Jonsson Cancer Center Foundation and National Center for Advancing Translational Sciences UCLA Clinical and Translational Science Institute (CTSI) Grant UL1TR000124. X.F. is a recipient of a China Scholarship Council scholarship. R.M.C. is a postdoctoral fellow supported by the UCLA Tumor Immunology Training Program (NIH T32 CA009120). M.Y.P. was a trainee of the UCLA C&MB training grant (NIH T32 GM007185). Support for L.V. and K.R. was from the Leducq Foundation. This paper is dedicated to Dr. Judith Gasson in honor of her 20 years as Director of the Jonsson Comprehensive Cancer Center. Publisher Copyright: © 2015 Elsevier Inc.

PY - 2015/9/1

Y1 - 2015/9/1

N2 - 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.

AB - 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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U2 - 10.1016/j.cmet.2015.06.009

DO - 10.1016/j.cmet.2015.06.009

M3 - Article

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AN - SCOPUS:84940726154

SN - 1550-4131

VL - 22

SP - 508

EP - 515

JO - Cell Metabolism

JF - Cell Metabolism

IS - 3

ER -

2-hydroxyglutarate inhibits ATP synthase and mTOR Signaling

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