title: Oncometabolite d-2-hydroxyglutarate impairs α-ketoglutarate dehydrogenase and contractile function in rodent heart.
abstract: Hematologic malignancies are frequently associated with cardiac pathologies. Mutations of isocitrate dehydrogenase 1 and 2 (IDH1/2) occur in a subset of acute myeloid leukemia patients, causing metabolic and epigenetic derangements. We have now discovered that altered metabolism in leukemic cells has a profound effect on cardiac metabolism. Combining mathematical modeling and in vivo as well as ex vivo studies, we found that increased amounts of the oncometabolite d-2-hydroxyglutarate (D2-HG), produced by IDH2 mutant leukemic cells, cause contractile dysfunction in the heart. This contractile dysfunction is associated with impaired oxidative decarboxylation of α-ketoglutarate, a redirection of Krebs cycle intermediates, and increased ATP citrate lyase (ACL) activity. Increased availability of D2-HG also leads to altered histone methylation and acetylation in the heart. We propose that D2-HG promotes cardiac dysfunction by impairing α-ketoglutarate dehydrogenase and induces histone modifications in an ACL-dependent manner. Collectively, our results highlight the impact of cancer cell metabolism on function and metabolism of the heart.
authors: Department of Internal Medicine, Division of Cardiology, McGovern Medical School, The University of Texas Health Science Center, Houston, TX 77030;
authors: Anja
authors: A
authors: Karlstaedt
authors: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030; Center for Cell and Gene Therapy, Baylor College of Medicine, Houston, TX 77030; Stem Cells and Regenerative Medicine Center, Baylor College of Medicine, Houston, TX 77030; Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030;
authors: Xiaotian
authors: X
authors: Zhang
authors: Department of Biochemistry and Molecular Biology, McGovern Medical School, The University of Texas Health Science Center, Houston, TX 77030;
authors: Heidi
authors: H
authors: Vitrac
authors: Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, MS 39216; Mississippi Center for Obesity Research, University of Mississippi Medical Center, Jackson, MS 39216; Cardiovascular-Renal Research Center, University of Mississippi Medical Center, Jackson, MS 39216;
authors: Romain
authors: R
authors: Harmancey
authors: Department of Internal Medicine, Division of Cardiology, McGovern Medical School, The University of Texas Health Science Center, Houston, TX 77030;
authors: Hernan
authors: H
authors: Vasquez
authors: Department of Hematology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China.
authors: Jing Han
authors: JH
authors: Wang
authors: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030; Center for Cell and Gene Therapy, Baylor College of Medicine, Houston, TX 77030; Stem Cells and Regenerative Medicine Center, Baylor College of Medicine, Houston, TX 77030; Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030;
authors: Margaret A
authors: MA
authors: Goodell
authors: Department of Internal Medicine, Division of Cardiology, McGovern Medical School, The University of Texas Health Science Center, Houston, TX 77030; Heinrich.Taegtmeyer@uth.tmc.edu.
authors: Heinrich
authors: H
authors: Taegtmeyer
mesh_terms: D001275:ATP Citrate (pro-S)-Lyase / Q000235:genetics* / Q000378:metabolism; D000107:Acetylation; D000818:Animals; D009202:Cardiomyopathies / Q000150:complications / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D005977:Glutarates / Q000378:metabolism; D019337:Hematologic Neoplasms / Q000150:complications / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D006657:Histones / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007521:Isocitrate Dehydrogenase / Q000235:genetics* / Q000378:metabolism; D007655:Ketoglutarate Dehydrogenase Complex / Q000235:genetics*; D008745:Methylation; D051379:Mice; D009154:Mutation; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology
chemical_list: D005977:Glutarates; D006657:Histones; C019417:alpha-hydroxyglutarate; D007521:Isocitrate Dehydrogenase; C000599591:isocitrate dehydrogenase 2, mouse; C543588:IDH1 protein, human; D007655:Ketoglutarate Dehydrogenase Complex; D001275:ATP Citrate (pro-S)-Lyase
keywords: IDH2; cardiomyopathy; d-2-hydroxyglutarate; flux rate analysis; metabolism