Profiling the effects of isocitrate dehydrogenase 1 and 2 mutations on the cellular metabolome
Profiling the effects of isocitrate dehydrogenase 1 and 2 mutations on the cellular metabolome
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DOI：
10.1073/pnas.1019393108
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发表时间：
2011-02-22
影响因子：
11.1
通讯作者：
Yan, Hai
中科院分区：
文献类型：
--
作者：
Reitman, Zachary J.;Jin, Genglin;Yan, Hai
NADP+ 依赖性异柠檬酸脱氢酶 1 和 2（IDH1 和 IDH2）的点突变发生在神经胶质瘤发病机制的早期。突变后，IDH1 和 IDH2 获得产生代谢物 (R)-2-羟基戊二酸 (2HG) 的能力，但突变 IDH1 和 IDH2 蛋白或 2HG 对细胞代谢的下游影响尚不清楚。我们分析了人少突神经胶质瘤 (HOG) 细胞中超过 200 种代谢物，以确定 IDH1 和 IDH2 突变体表达的影响。在表达突变 IDH1 和 IDH2 的细胞中，氨基酸、谷胱甘肽代谢物、胆碱衍生物和三羧酸 (TCA) 循环中间体的水平发生了变化。这些变化与用 2HG 处理细胞后发现的变化相似。值得注意的是，N-乙酰基-天冬氨酰-谷氨酸（NAAG）是大脑中常见的二肽，在表达 IDH1 突变体的细胞中减少了 50 倍，在表达 IDH2 突变体的细胞中减少了 8.3 倍。含有 IDH 突变的人神经胶质瘤组织中的 NAAG 也显着低于没有此类突变的神经胶质瘤。这些代谢变化为与 IDH 基因突变相关的肿瘤的发病机制提供了线索。
Point mutations of the NADP+-dependent isocitrate dehydrogenases 1 and 2 (IDH1 and IDH2) occur early in the pathogenesis of gliomas. When mutated, IDH1 and IDH2 gain the ability to produce the metabolite (R)-2-hydroxyglutarate (2HG), but the downstream effects of mutant IDH1 and IDH2 proteins or of 2HG on cellular metabolism are unknown. We profiled >200 metabolites in human oligodendroglioma (HOG) cells to determine the effects of expression of IDH1 and IDH2 mutants. Levels of amino acids, glutathione metabolites, choline derivatives, and tricarboxylic acid (TCA) cycle intermediates were altered in mutant IDH1- and IDH2-expressing cells. These changes were similar to those identified after treatment of the cells with 2HG. Remarkably, N-acetyl-aspartyl-glutamate (NAAG), a common dipeptide in brain, was 50-fold reduced in cells expressing IDH1 mutants and 8.3-fold reduced in cells expressing IDH2 mutants. NAAG also was significantly lower in human glioma tissues containing IDH mutations than in gliomas without such mutations. These metabolic changes provide clues to the pathogenesis of tumors associated with IDH gene mutations.