Oncometabolite D-2-hydroxyglutarate impairs α-ketoglutarate dehydrogenase and contractile function in rodent heart
Oncometabolite D-2-hydroxyglutarate impairs α-ketoglutarate dehydrogenase and contractile function in rodent heart
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DOI：
10.1073/pnas.1601650113
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发表时间：
2016-09-13
影响因子：
11.1
通讯作者：
Taegtmeyer, Heinrich
中科院分区：
文献类型：
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作者：
Karlstaedt, Anja;Zhang, Xiaotian;Taegtmeyer, Heinrich
血液系统恶性肿瘤常常与心脏病相关。部分急性髓系白血病患者中存在异柠檬酸脱氢酶 1 和 2 (IDH1/2) 突变，导致代谢和表观遗传紊乱。我们现在发现白血病细胞代谢的改变对心脏代谢具有深远的影响。结合数学模型和体内及离体研究，我们发现 IDH2 突变白血病细胞产生的致癌代谢物 D-2-羟基戊二酸 (D2-HG) 量增加，会导致心脏收缩功能障碍。这种收缩功能障碍与 α-酮戊二酸氧化脱羧受损、三羧酸循环中间体重定向以及 ATP 柠檬酸裂解酶 (ACL) 活性增加有关。 D2-HG 可用性的增加也会导致心脏中组蛋白甲基化和乙酰化的改变。我们认为 D2-HG 通过损害 α-酮戊二酸脱氢酶促进心脏功能障碍，并以 ACL 依赖性方式诱导组蛋白修饰。总的来说，我们的结果强调了癌细胞代谢对心脏功能和代谢的影响。
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 alpha-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 alpha-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.