Oncometabolite D-2-hydroxyglutarate impairs α-ketoglutarate dehydrogenase and contractile function in rodent heart

Proceedings of the National Academy of Sciences of the United States of America

Volumn 113, Issue 37, 2016, Pages 10436-10441

  Karlstaedt, Anja ^a   Zhang, Xiaotian ^b,c   Vitrac, Heidi ^a   Harmancey, Romain ^d,e   Vasquez, Hernan ^a   Wang, Jing Han ^f   Goodell, Margaret A ^b,c   Taegtmeyer, Heinrich ^a  

^a UNIVERSITY OF TEXAS MEDICAL SCHOOL   (United States)

^b BAYLOR COLLEGE OF MEDICINE   (United States)

^c CENTER FOR CELL AND GENE THERAPY   (United States)

^d UNIVERSITY OF MISSISSIPPI SCHOOL OF MEDICINE   (United States)

^e UNIVERSITY OF MISSISSIPPI MEDICAL CENTER   (United States)

^f ZHEJIANG UNIVERSITY SCHOOL OF MEDICINE   (China)

Author keywords

Cardiomyopathy; D 2 hydroxyglutarate; Flux rate analysis; IDH2; Metabolism

Indexed keywords

2 HYDROXYGLUTARIC ACID; ADENOSINE TRIPHOSPHATE CITRATE SYNTHASE; DEXTRO 2 HYDROXYGLUTARIC ACID; ISOCITRATE DEHYDROGENASE 1; ISOCITRATE DEHYDROGENASE 2; OXOGLUTARATE DEHYDROGENASE; UNCLASSIFIED DRUG; ALPHA-HYDROXYGLUTARATE; GLUTARIC ACID DERIVATIVE; HISTONE; IDH1 PROTEIN, HUMAN; ISOCITRATE DEHYDROGENASE; ISOCITRATE DEHYDROGENASE 2, MOUSE;

ACUTE MYELOBLASTIC LEUKEMIA; ANIMAL CELL; CANCER PATIENT; CELL ENERGY; CITRIC ACID CYCLE; CONFERENCE PAPER; DECARBOXYLATION; ENZYME ACTIVITY; EPIGENETICS; EX VIVO STUDY; GLUCOSE OXIDATION; HEART MUSCLE CONTRACTILITY; HEART MUSCLE METABOLISM; HISTONE ACETYLATION; HISTONE METHYLATION; HISTONE MODIFICATION; IN VITRO STUDY; IN VIVO STUDY; LEUKEMIA CELL; MALE; MOUSE; NONHUMAN; PRIORITY JOURNAL; RAT; ACETYLATION; ANIMAL; CARDIAC MUSCLE; CARDIOMYOPATHY; COMPLICATION; GENETICS; HEMATOLOGIC DISEASE; HUMAN; METABOLISM; METHYLATION; MUTATION; PATHOLOGY;

ACETYLATION; ANIMALS; ATP CITRATE (PRO-S)-LYASE; CARDIOMYOPATHIES; GLUTARATES; HEMATOLOGIC NEOPLASMS; HISTONES; HUMANS; ISOCITRATE DEHYDROGENASE; KETOGLUTARATE DEHYDROGENASE COMPLEX; METHYLATION; MICE; MUTATION; MYOCARDIUM;

EID: 84987607019     PISSN: 00278424     EISSN: 10916490     Source Type: Journal    
DOI: 10.1073/pnas.1601650113     Document Type: Article

References (42)

1. Ward PS, et al. (2010) The common feature of leukemia-associated IDH1 and IDH2 mutations is a neomorphic enzyme activity converting alpha-ketoglutarate to 2-hydroxyglutarate. Cancer Cell 17(3):225-234.
2. Figueroa ME, et al. (2010) Leukemic IDH1 and IDH2 mutations result in a hypermethylation phenotype, disrupt TET2 function, and impair hematopoietic differentiation. Cancer Cell 18(6):553-567.
3. Lawrence MS, et al. (2014) Discovery and saturation analysis of cancer genes across 21 tumour types. Nature 505(7484):495-501.
4. Xu W, et al. (2011) Oncometabolite 2-hydroxyglutarate is a competitive inhibitor of α-ketoglutarate-dependent dioxygenases. Cancer Cell 19(1):17-30.
5. Xiao M, et al. (2012) Inhibition of α-KG-dependent histone and DNA demethylases by fumarate and succinate that are accumulated in mutations of FH and SDH tumor suppressors. Genes Dev 26(12):1326-1338.
6. Mullen AR, et al. (2014) Oxidation of alpha-ketoglutarate is required for reductive carboxylation in cancer cells with mitochondrial defects. Cell Reports 7(5):1679-1690.
7. Jaiswal S, et al. (2014) Age-related clonal hematopoiesis associated with adverse outcomes. N Engl J Med 371(26):2488-2498.
8. Akbay EA, et al. (2014) D-2-hydroxyglutarate produced by mutant IDH2 causes cardiomyopathy and neurodegeneration in mice. Genes Dev 28(5):479-490.
9. Kranendijk M, et al. (2010) IDH2 mutations in patients with D-2-hydroxyglutaric aciduria. Science 330(6002):336.
10. Depre C, et al. (1998) Unloaded heart in vivo replicates fetal gene expression of cardiac hypertrophy. Nat Med 4(11):1269-1275.
11. Razeghi P, et al. (2001) Metabolic gene expression in fetal and failing human heart. Circulation 104(24):2923-2931.
12. Harada K, Sugaya T, Murakami K, Yazaki Y, Komuro I (1999) Angiotensin II type 1A receptor knockout mice display less left ventricular remodeling and improved survival after myocardial infarction. Circulation 100(20):2093-2099.
13. Miyata S, Minobe W, Bristow MR, Leinwand LA (2000) Myosin heavy chain isoform expression in the failing and nonfailing human heart. Circ Res 86(4):386-390.
14. Karlstädt A, et al. (2012) CardioNet: A human metabolic network suited for the study of cardiomyocyte metabolism. BMC Syst Biol 6:114.
15. DiNardo CD, et al. (2013) Serum 2-hydroxyglutarate levels predict isocitrate dehydrogenase mutations and clinical outcome in acute myeloid leukemia. Blood 121(24):4917-4924.
16. Janin M, et al. (2014) Serum 2-hydroxyglutarate production in IDH1- and IDH2-mutated de novo acute myeloid leukemia: A study by the Acute Leukemia French Association group. J Clin Oncol 32(4):297-305.
17. Borger DR, et al. (2014) Circulating oncometabolite 2-hydroxyglutarate is a potential surrogate biomarker in patients with isocitrate dehydrogenase-mutant intrahepatic cholangiocarcinoma. Clin Cancer Res 20(7):1884-1890.
18. Latini A, et al. (2005) Mitochondrial energy metabolism is markedly impaired by D-2-hydroxyglutaric acid in rat tissues. Mol Genet Metab 86(1-2):188-199.
19. Goodwin GW, Ahmad F, Doenst T, Taegtmeyer H (1998) Energy provision from glycogen, glucose, and fatty acids on adrenergic stimulation of isolated working rat hearts. Am J Physiol 274(4 Pt 2):H1239-H1247.
20. Fu X, et al. (2015) 2-Hydroxyglutarate inhibits ATP synthase and mTOR signaling. Cell Metab 22(3):508-515.
21. Lomenick B, et al. (2009) Target identification using drug affinity responsive target stability (DARTS). Proc Natl Acad Sci USA 106(51):21984-21989.
22. Korshunov SS, Skulachev VP, Starkov AA (1997) High protonic potential actuates a mechanism of production of reactive oxygen species in mitochondria. FEBS Lett 416(1):15-18.
23. Holzhütter H-G (2004) The principle of flux minimization and its application to estimate stationary fluxes in metabolic networks. Eur J Biochem 271(14):2905-2922.
24. Ogata H, et al. (1999) KEGG: Kyoto Encyclopedia of Genes and Genomes. Nucleic Acids Res 27(1):29-34.
25. Williamson DH, Lund P, Krebs HA (1967) The redox state of free nicotinamide-adenine dinucleotide in the cytoplasm and mitochondria of rat liver. Biochem J 103(2): 514-527.
26. Kauppinen RA, Hiltunen JK, Hassinen IE (1982) Compartmentation of citrate in relation to the regulation of glycolysis and the mitochondrial transmembrane proton electrochemical potential gradient in isolated perfused rat heart. Biochim Biophys Acta 681(2):286-291.
27. Wang Q, et al. (2010) Acetylation of metabolic enzymes coordinates carbon source utilization and metabolic flux. Science 327(5968):1004-1007.
28. Wellen KE, et al. (2009) ATP-citrate lyase links cellular metabolism to histone acetylation. Science 324(5930):1076-1080.
29. Gottlieb E, Armour SM, Harris MH, Thompson CB (2003) Mitochondrial membrane potential regulates matrix configuration and cytochrome c release during apoptosis. Cell Death Differ 10(6):709-717.
30. Chacon E, Acosta D (1991) Mitochondrial regulation of superoxide by Ca2+: An alternate mechanism for the cardiotoxicity of doxorubicin. Toxicol Appl Pharmacol 107(1):117-128.
31. Kaneda R, et al. (2009) Genome-wide histone methylation profile for heart failure. Genes Cells 14(1):69-77.
32. Haberland M, Montgomery RL, Olson EN (2009) The many roles of histone deacetylases in development and physiology: Implications for disease and therapy. Nat Rev Genet 10(1):32-42.
33. McKinsey TA (2012) Therapeutic potential for HDAC inhibitors in the heart. Annu Rev Pharmacol Toxicol 52:303-319.
34. Starkov AA, et al. (2004) Mitochondrial alpha-ketoglutarate dehydrogenase complex generates reactive oxygen species. J Neurosci 24(36):7779-7788.
35. Srere PA (1959) The citrate cleavage enzyme. I. Distribution and purification. J Biol Chem 234:2544-2547.
36. Challen GA, et al. (2011) Dnmt3a is essential for hematopoietic stem cell differentiation. Nat Genet 44(1):23-31.
37. Taegtmeyer H, Hems R, Krebs HA (1980) Utilization of energy-providing substrates in the isolated working rat heart. Biochem J 186(3):701-711.
38. Wu SP, et al. (2015) Increased COUP-TFII expression in adult hearts induces mitochondrial dysfunction resulting in heart failure. Nat Commun 6:8245.
39. Harmancey R, Wilson CR, Wright NR, Taegtmeyer H (2010) Western diet changes cardiac acyl-CoA composition in obese rats: A potential role for hepatic lipogenesis. J Lipid Res 51(6):1380-1393.
40. Farrelly E, Amaral MC, Marshall L, Huang SG (2001) A high-throughput assay for mitochondrial membrane potential in permeabilized yeast cells. Anal Biochem 293(2): 269-276.
41. Swanton EM, Saggerson ED (1997) Effects of adrenaline on triacylglycerol synthesis and turnover in ventricular myocytes from adult rats. Biochem J 328(Pt 3):913-922.
42. Chua BH, Siehl DL, Morgan HE (1980) A role for leucine in regulation of protein turnover in working rat hearts. Am J Physiol 239(6):E510-E514.