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D2HGDH regulates alpha-ketoglutarate levels and dioxygenase function by modulating IDH2

Author

Listed:
  • An-Ping Lin

    (University of Texas Health Science Center at San Antonio)

  • Saman Abbas

    (University of Texas Health Science Center at San Antonio)

  • Sang-Woo Kim

    (University of Texas Health Science Center at San Antonio
    Present address: Department of Biological Sciences, Pusan National University, 63 Beon-gil 2, Busandaehag-ro, Geumjeong-gu, Pusan 609 735, Republic of Korea)

  • Manoela Ortega

    (University of Texas Health Science Center at San Antonio)

  • Hakim Bouamar

    (University of Texas Health Science Center at San Antonio)

  • Yissela Escobedo

    (University of Texas Health Science Center at San Antonio)

  • Prakash Varadarajan

    (University of Texas Health Science Center at San Antonio)

  • Yuejuan Qin

    (University of Texas Health Science Center at San Antonio)

  • Jessica Sudderth

    (Children’s Medical Center Research Institute, University of Texas Southwestern)

  • Eduard Schulz

    (Medical University of Graz)

  • Alexander Deutsch

    (Medical University of Graz)

  • Sumitra Mohan

    (Institute of Human Genetics, Medical University of Graz)

  • Peter Ulz

    (Institute of Human Genetics, Medical University of Graz)

  • Peter Neumeister

    (Medical University of Graz)

  • Dinesh Rakheja

    (Children’s Medical Center Research Institute, University of Texas Southwestern
    University of Texas Southwestern Medical Center)

  • Xiaoli Gao

    (University of Texas Health Science Center at San Antonio)

  • Andrew Hinck

    (University of Texas Health Science Center at San Antonio)

  • Susan T. Weintraub

    (University of Texas Health Science Center at San Antonio)

  • Ralph J. DeBerardinis

    (Children’s Medical Center Research Institute, University of Texas Southwestern)

  • Heinz Sill

    (Medical University of Graz)

  • Patricia L. M. Dahia

    (University of Texas Health Science Center at San Antonio
    Greehey Children’s Cancer Research Institute, University of Texas Health Sciences Center at San Antonio
    Cancer Therapy and Research Center, University of Texas Health Science Center at San Antonio)

  • Ricardo C. T. Aguiar

    (University of Texas Health Science Center at San Antonio
    Greehey Children’s Cancer Research Institute, University of Texas Health Sciences Center at San Antonio
    Cancer Therapy and Research Center, University of Texas Health Science Center at San Antonio
    South Texas Veterans Health Care System, Audie Murphy VA Hospital)

Abstract

Isocitrate dehydrogenases (IDH) convert isocitrate to alpha-ketoglutarate (α-KG). In cancer, mutant IDH1/2 reduces α-KG to D2-hydroxyglutarate (D2-HG) disrupting α-KG-dependent dioxygenases. However, the physiological relevance of controlling the interconversion of D2‐HG into α‐KG, mediated by D2‐hydroxyglutarate dehydrogenase (D2HGDH), remains obscure. Here we show that wild-type D2HGDH elevates α-KG levels, influencing histone and DNA methylation, and HIF1α hydroxylation. Conversely, the D2HGDH mutants that we find in diffuse large B-cell lymphoma are enzymatically inert. D2-HG is a low-abundance metabolite, but we show that it can meaningfully elevate α-KG levels by positively modulating mitochondrial IDH activity and inducing IDH2 expression. Accordingly, genetic depletion of IDH2 abrogates D2HGDH effects, whereas ectopic IDH2 rescues D2HGDH-deficient cells. Our data link D2HGDH to cancer and describe an additional role for the enzyme: the regulation of IDH2 activity and α-KG-mediated epigenetic remodelling. These data further expose the intricacies of mitochondrial metabolism and inform on the pathogenesis of D2HGDH-deficient diseases.

Suggested Citation

  • An-Ping Lin & Saman Abbas & Sang-Woo Kim & Manoela Ortega & Hakim Bouamar & Yissela Escobedo & Prakash Varadarajan & Yuejuan Qin & Jessica Sudderth & Eduard Schulz & Alexander Deutsch & Sumitra Mohan , 2015. "D2HGDH regulates alpha-ketoglutarate levels and dioxygenase function by modulating IDH2," Nature Communications, Nature, vol. 6(1), pages 1-14, November.
    • Handle: RePEc:nat:natcom:v:6:y:2015:i:1:d:10.1038_ncomms8768
    DOI: 10.1038/ncomms8768
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    Cited by:

    1. Zaher ElBeck & Mohammad Bakhtiar Hossain & Humam Siga & Nikolay Oskolkov & Fredrik Karlsson & Julia Lindgren & Anna Walentinsson & Dominique Koppenhöfer & Rebecca Jarvis & Roland Bürli & Tanguy Jamier, 2024. "Epigenetic modulators link mitochondrial redox homeostasis to cardiac function in a sex-dependent manner," Nature Communications, Nature, vol. 15(1), pages 1-23, December.

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