Medizinische Universität Graz Austria/Österreich - Forschungsportal - Medical University of Graz

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Gewählte Publikation:

SHR Neuro Krebs Kardio Lipid

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, ST; DeBerardinis, RJ; Sill, H; Dahia, PL; Aguiar, RC.
D2HGDH regulates alpha-ketoglutarate levels and dioxygenase function by modulating IDH2.
Nat Commun. 2015; 6(7):7768-7768 [OPEN ACCESS]
Web of Science PubMed PUBMED Central FullText FullText_MUG

 

Autor/innen der Med Uni Graz:
Deutsch Alexander
Mohan Sumitra
Neumeister Peter
Schulz Eduard
Sill Heinz
Ulz Peter
Gendermonitor:
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Number of Figures: 7
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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.
Find related publications in this database (using NLM MeSH Indexing)
Alcohol Oxidoreductases - genetics
Blotting, Western -
Cell Line, Tumor -
DNA Methylation - genetics
Dioxygenases - metabolism
Epigenesis, Genetic -
Gene Expression Regulation, Neoplastic -
HEK293 Cells -
Histones - metabolism
Humans -
Hydroxylation - genetics
Hypoxia-Inducible Factor 1, alpha Subunit - metabolism
Isocitrate Dehydrogenase - genetics
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Lymphoma, Large B-Cell, Diffuse - genetics
Methylation -
Real-Time Polymerase Chain Reaction -

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