D2HGDH Regulates Alpha-ketoglutarate Levels and Dioxygenase Function by Modulating IDH2

Overview

Journal Nat Commun

Specialty Biology

Date 2015 Jul 17

PMID 26178471

Citations 52

Authors

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

Ricardo C T Aguiar

Affiliations

Soon will be listed here.

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.

Citing Articles

IRF8-mutant B cell lymphoma evades immunity through a CD74-dependent deregulation of antigen processing and presentation in MHCII complexes.

Qiu Z, Khalife J, Ethiraj P, Jaafar C, Lin A, Holder K Sci Adv. 2024; 10(28):eadk2091.

PMID: 38996030 PMC: 11244530. DOI: 10.1126/sciadv.adk2091.

Prenatal 1-Nitropyrene Exposure Causes Autism-Like Behavior Partially by Altering DNA Hydroxymethylation in Developing Brain.

Zhao T, Huang C, Zhang Y, Zhu Y, Chen X, Wang T Adv Sci (Weinh). 2024; 11(28):e2306294.

PMID: 38757379 PMC: 11267330. DOI: 10.1002/advs.202306294.

Insights into the role of RNA mA modification in the metabolic process and related diseases.

Hu H, Li Z, Xie X, Liao Q, Hu Y, Gong C Genes Dis. 2024; 11(4):101011.

PMID: 38560499 PMC: 10978549. DOI: 10.1016/j.gendis.2023.04.038.

Epigenetic modulators link mitochondrial redox homeostasis to cardiac function in a sex-dependent manner.

Elbeck Z, Hossain M, Siga H, Oskolkov N, Karlsson F, Lindgren J Nat Commun. 2024; 15(1):2358.

PMID: 38509128 PMC: 10954618. DOI: 10.1038/s41467-024-46384-8.

Metabolic basis of cardiac dysfunction in cancer patients.

Figueiredo J, Bhowmick N, Karlstaedt A Curr Opin Cardiol. 2024; 39(3):138-147.

PMID: 38386340 PMC: 11185275. DOI: 10.1097/HCO.0000000000001118.

References

Pettersen E, Goddard T, Huang C, Couch G, Greenblatt D, Meng E . UCSF Chimera--a visualization system for exploratory research and analysis. J Comput Chem. 2004; 25(13):1605-12. DOI: 10.1002/jcc.20084. View

Achouri Y, Noel G, Vertommen D, Rider M, Veiga-da-Cunha M, Van Schaftingen E . Identification of a dehydrogenase acting on D-2-hydroxyglutarate. Biochem J. 2004; 381(Pt 1):35-42. PMC: 1133759. DOI: 10.1042/BJ20031933. View

Rzem R, Veiga-da-Cunha M, Noel G, Goffette S, Nassogne M, Tabarki B . A gene encoding a putative FAD-dependent L-2-hydroxyglutarate dehydrogenase is mutated in L-2-hydroxyglutaric aciduria. Proc Natl Acad Sci U S A. 2004; 101(48):16849-54. PMC: 534725. DOI: 10.1073/pnas.0404840101. View

Contreras-Shannon V, Lin A, McCammon M, McAlister-Henn L . Kinetic properties and metabolic contributions of yeast mitochondrial and cytosolic NADP+-specific isocitrate dehydrogenases. J Biol Chem. 2004; 280(6):4469-75. DOI: 10.1074/jbc.M410140200. View

Soding J, Biegert A, Lupas A . The HHpred interactive server for protein homology detection and structure prediction. Nucleic Acids Res. 2005; 33(Web Server issue):W244-8. PMC: 1160169. DOI: 10.1093/nar/gki408. View

Arnold K, Bordoli L, Kopp J, Schwede T . The SWISS-MODEL workspace: a web-based environment for protein structure homology modelling. Bioinformatics. 2005; 22(2):195-201. DOI: 10.1093/bioinformatics/bti770. View

Struys E . D-2-Hydroxyglutaric aciduria: unravelling the biochemical pathway and the genetic defect. J Inherit Metab Dis. 2006; 29(1):21-9. DOI: 10.1007/s10545-006-0317-9. View

Loenarz C, Schofield C . Expanding chemical biology of 2-oxoglutarate oxygenases. Nat Chem Biol. 2008; 4(3):152-6. DOI: 10.1038/nchembio0308-152. View

Kim S, Rai D, McKeller M, Aguiar R . Rational combined targeting of phosphodiesterase 4B and SYK in DLBCL. Blood. 2009; 113(24):6153-60. PMC: 2699235. DOI: 10.1182/blood-2009-02-206128. View

10.

Li C, Kim S, Rai D, Bolla A, Adhvaryu S, Kinney M . Copy number abnormalities, MYC activity, and the genetic fingerprint of normal B cells mechanistically define the microRNA profile of diffuse large B-cell lymphoma. Blood. 2009; 113(26):6681-90. PMC: 3401058. DOI: 10.1182/blood-2009-01-202028. View

11.

Gross S, Cairns R, Minden M, Driggers E, Bittinger M, Jang H . Cancer-associated metabolite 2-hydroxyglutarate accumulates in acute myelogenous leukemia with isocitrate dehydrogenase 1 and 2 mutations. J Exp Med. 2010; 207(2):339-44. PMC: 2822606. DOI: 10.1084/jem.20092506. View

12.

Rai D, Kim S, McKeller M, Dahia P, Aguiar R . Targeting of SMAD5 links microRNA-155 to the TGF-beta pathway and lymphomagenesis. Proc Natl Acad Sci U S A. 2010; 107(7):3111-6. PMC: 2840369. DOI: 10.1073/pnas.0910667107. View

13.

Qin Y, Yao L, King E, Buddavarapu K, Lenci R, Chocron E . Germline mutations in TMEM127 confer susceptibility to pheochromocytoma. Nat Genet. 2010; 42(3):229-33. PMC: 2998199. DOI: 10.1038/ng.533. View

14.

Kranendijk M, Struys E, Gibson K, Wickenhagen W, Abdenur J, Buechner J . Evidence for genetic heterogeneity in D-2-hydroxyglutaric aciduria. Hum Mutat. 2009; 31(3):279-83. DOI: 10.1002/humu.21186. View

15.

Ward P, Patel J, Wise D, Abdel-Wahab O, Bennett B, Coller H . The common feature of leukemia-associated IDH1 and IDH2 mutations is a neomorphic enzyme activity converting alpha-ketoglutarate to 2-hydroxyglutarate. Cancer Cell. 2010; 17(3):225-34. PMC: 2849316. DOI: 10.1016/j.ccr.2010.01.020. View

16.

Steenweg M, Jakobs C, Errami A, van Dooren S, Adeva Bartolome M, Aerssens P . An overview of L-2-hydroxyglutarate dehydrogenase gene (L2HGDH) variants: a genotype-phenotype study. Hum Mutat. 2010; 31(4):380-90. DOI: 10.1002/humu.21197. View

17.

Dang L, White D, Gross S, Bennett B, Bittinger M, Driggers E . Cancer-associated IDH1 mutations produce 2-hydroxyglutarate. Nature. 2010; 465(7300):966. PMC: 3766976. DOI: 10.1038/nature09132. View

18.

Kranendijk M, Struys E, Van Schaftingen E, Gibson K, Kanhai W, van der Knaap M . IDH2 mutations in patients with D-2-hydroxyglutaric aciduria. Science. 2010; 330(6002):336. DOI: 10.1126/science.1192632. View

19.

Rakheja D, Mitui M, Boriack R, DeBerardinis R . Isocitrate dehydrogenase 1/2 mutational analyses and 2-hydroxyglutarate measurements in Wilms tumors. Pediatr Blood Cancer. 2011; 56(3):379-83. DOI: 10.1002/pbc.22697. View

20.

Xu W, Yang H, Liu Y, Yang Y, Wang P, Kim S . Oncometabolite 2-hydroxyglutarate is a competitive inhibitor of α-ketoglutarate-dependent dioxygenases. Cancer Cell. 2011; 19(1):17-30. PMC: 3229304. DOI: 10.1016/j.ccr.2010.12.014. View