Author:
Karlstaedt Anja,Zhang Xiaotian,Vitrac Heidi,Harmancey Romain,Vasquez Hernan,Wang Jing Han,Goodell Margaret A.,Taegtmeyer Heinrich
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.
Funder
HHS | NIH | National Heart, Lung, and Blood Institute
Adrienne Helis Malvin Medical Research Foundation
Friede Springer Herz Stiftung
Roderick MacDonald Research Fund
Publisher
Proceedings of the National Academy of Sciences
Cited by
108 articles.
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