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Nat Commun. 2015 Jul 16;6:7768. doi: 10.1038/ncomms8768.

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

Author information

1
Division of Hematology and Medical Oncology, Department of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, Texas 78229, USA.
2
Department of Pediatrics, Children's Medical Center Research Institute, University of Texas Southwestern, Dallas, Texas 75390, USA.
3
Division of Hematology, Medical University of Graz, A-8036 Graz, Austria.
4
Institute of Human Genetics, Medical University of Graz, A-8036 Graz, Austria.
5
1] Department of Pediatrics, Children's Medical Center Research Institute, University of Texas Southwestern, Dallas, Texas 75390, USA [2] Department of Pathology and Pediatrics, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.
6
Department of Biochemistry, University of Texas Health Science Center at San Antonio, San Antonio, Texas 78229, USA.
7
1] Division of Hematology and Medical Oncology, Department of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, Texas 78229, USA [2] Greehey Children's Cancer Research Institute, University of Texas Health Sciences Center at San Antonio, San Antonio, Texas 78229, USA [3] Cancer Therapy and Research Center, University of Texas Health Science Center at San Antonio, San Antonio, Texas 78229, USA.
8
1] Division of Hematology and Medical Oncology, Department of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, Texas 78229, USA [2] Greehey Children's Cancer Research Institute, University of Texas Health Sciences Center at San Antonio, San Antonio, Texas 78229, USA [3] Cancer Therapy and Research Center, University of Texas Health Science Center at San Antonio, San Antonio, Texas 78229, USA [4] South Texas Veterans Health Care System, Audie Murphy VA Hospital, San Antonio, Texas 78229, USA.

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.

PMID:
26178471
PMCID:
PMC4515030
DOI:
10.1038/ncomms8768
[Indexed for MEDLINE]
Free PMC Article

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