Medizinische Universität Graz Austria/Österreich - Forschungsportal - Medical University of Graz
Gewählte Publikation:
SHR Neuro Krebs Kardio Lipid Stoffw Microb
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
Doi: 10.1038/ncomms8768
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- Co-Autor*innen der Med Uni Graz
- Deutsch Alexander
- Mohan Sumitra
- Neumeister Peter
- Schulz Eduard
- Sill Heinz
- Ulz Peter
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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.
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- Alcohol Oxidoreductases - genetics
- Blotting, Western -
- Cell Line, Tumor -
- DNA Methylation - genetics
- Dioxygenases - metabolism
- Epigenesis, Genetic -
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- Histones - metabolism
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- Hydroxylation - genetics
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- Lymphoma, Large B-Cell, Diffuse - genetics
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