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

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, Peter Ulz, Peter Neumeister, Dinesh Rakheja, Xiaoli Gao, Andrew Hinck, Susan T. Weintraub, Ralph J. DeBerardinis, Heinz Sill, Patricia L. M. Dahia and Ricardo C. T. Aguiar ()
Additional contact information
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
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
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
Ricardo C. T. Aguiar: University of Texas Health Science Center at San Antonio

Nature Communications, 2015, vol. 6, issue 1, 1-14

Abstract: 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.

Date: 2015
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DOI: 10.1038/ncomms8768

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