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 E Weintraub, Ralph J. DeBerardinis, Heinz Sill & 2 others Patricia L Dahia, Ricardo C Aguiar

Research output: Contribution to journalArticle

16 Citations (Scopus)

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.

Original languageEnglish (US)
Article number7768
JournalNature Communications
Volume6
DOIs
StatePublished - Jul 16 2015

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Ketoglutarate Dehydrogenase Complex
Dioxygenases
dehydrogenases
Oxidoreductases
Isocitrate Dehydrogenase
Hydroxylation
cancer
Lymphoma, Large B-Cell, Diffuse
DNA Methylation
Metabolites
alpha-ketoglutaric acid
disrupting
data links
pathogenesis
Metabolism
Epigenomics
Histones
methylation
metabolites
Neoplasms

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Chemistry(all)
  • Physics and Astronomy(all)

Cite this

D2HGDH regulates alpha-ketoglutarate levels and dioxygenase function by modulating IDH2. / Lin, An Ping; Abbas, Saman; Kim, Sang Woo; Ortega, Manoela; Bouamar, Hakim; Escobedo, Yissela; Varadarajan, Prakash; Qin, Yuejuan; Sudderth, Jessica; Schulz, Eduard; Deutsch, Alexander; Mohan, Sumitra; Ulz, Peter; Neumeister, Peter; Rakheja, Dinesh; Gao, Xiaoli; Hinck, Andrew; Weintraub, Susan E; DeBerardinis, Ralph J.; Sill, Heinz; Dahia, Patricia L; Aguiar, Ricardo C.

In: Nature Communications, Vol. 6, 7768, 16.07.2015.

Research output: Contribution to journalArticle

Lin, AP, Abbas, S, Kim, SW, Ortega, M, Bouamar, H, Escobedo, Y, Varadarajan, P, Qin, Y, Sudderth, J, Schulz, E, Deutsch, A, Mohan, S, Ulz, P, Neumeister, P, Rakheja, D, Gao, X, Hinck, A, Weintraub, SE, DeBerardinis, RJ, Sill, H, Dahia, PL & Aguiar, RC 2015, 'D2HGDH regulates alpha-ketoglutarate levels and dioxygenase function by modulating IDH2', Nature Communications, vol. 6, 7768. https://doi.org/10.1038/ncomms8768
Lin, An Ping ; Abbas, Saman ; Kim, Sang Woo ; Ortega, Manoela ; Bouamar, Hakim ; Escobedo, Yissela ; Varadarajan, Prakash ; Qin, Yuejuan ; Sudderth, Jessica ; Schulz, Eduard ; Deutsch, Alexander ; Mohan, Sumitra ; Ulz, Peter ; Neumeister, Peter ; Rakheja, Dinesh ; Gao, Xiaoli ; Hinck, Andrew ; Weintraub, Susan E ; DeBerardinis, Ralph J. ; Sill, Heinz ; Dahia, Patricia L ; Aguiar, Ricardo C. / D2HGDH regulates alpha-ketoglutarate levels and dioxygenase function by modulating IDH2. In: Nature Communications. 2015 ; Vol. 6.
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AU - Abbas, Saman

AU - Kim, Sang Woo

AU - Ortega, Manoela

AU - Bouamar, Hakim

AU - Escobedo, Yissela

AU - Varadarajan, Prakash

AU - Qin, Yuejuan

AU - Sudderth, Jessica

AU - Schulz, Eduard

AU - Deutsch, Alexander

AU - Mohan, Sumitra

AU - Ulz, Peter

AU - Neumeister, Peter

AU - Rakheja, Dinesh

AU - Gao, Xiaoli

AU - Hinck, Andrew

AU - Weintraub, Susan E

AU - DeBerardinis, Ralph J.

AU - Sill, Heinz

AU - Dahia, Patricia L

AU - Aguiar, Ricardo C

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N2 - 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.

AB - 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.

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