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Oncometabolite d-2-hydroxyglutarate impairs α-ketoglutarate dehydrogenase and contractile function in rodent heart.
Karlstaedt, Anja; Zhang, Xiaotian; Vitrac, Heidi; Harmancey, Romain; Vasquez, Hernan; Wang, Jing Han; Goodell, Margaret A; Taegtmeyer, Heinrich.
Afiliación
  • Karlstaedt A; Department of Internal Medicine, Division of Cardiology, McGovern Medical School, The University of Texas Health Science Center, Houston, TX 77030;
  • Zhang X; 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 Col
  • Vitrac H; Department of Biochemistry and Molecular Biology, McGovern Medical School, The University of Texas Health Science Center, Houston, TX 77030;
  • Harmancey R; 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 3921
  • Vasquez H; Department of Internal Medicine, Division of Cardiology, McGovern Medical School, The University of Texas Health Science Center, Houston, TX 77030;
  • Wang JH; Department of Hematology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China.
  • Goodell MA; 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 Col
  • Taegtmeyer H; 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.
Proc Natl Acad Sci U S A ; 113(37): 10436-41, 2016 09 13.
Article en En | MEDLINE | ID: mdl-27582470
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.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: ATP Citrato (pro-S)-Liasa / Neoplasias Hematológicas / Isocitrato Deshidrogenasa / Complejo Cetoglutarato Deshidrogenasa / Cardiomiopatías / Miocardio Límite: Animals / Humans Idioma: En Revista: Proc Natl Acad Sci U S A Año: 2016 Tipo del documento: Article Pais de publicación: Estados Unidos
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: ATP Citrato (pro-S)-Liasa / Neoplasias Hematológicas / Isocitrato Deshidrogenasa / Complejo Cetoglutarato Deshidrogenasa / Cardiomiopatías / Miocardio Límite: Animals / Humans Idioma: En Revista: Proc Natl Acad Sci U S A Año: 2016 Tipo del documento: Article Pais de publicación: Estados Unidos