The oncometabolite 2-hydroxyglutarate produced by mutant IDH1 sensitizes cells to ferroptosis
The oncometabolite 2-hydroxyglutarate produced by mutant IDH1 sensitizes cells to ferroptosis
复制标题
突变 IDH1 产生的致癌代谢物 2-羟基戊二酸使细胞对铁死亡敏感
DOI：
10.1038/s41419-019-1984-4
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发表时间：
2019-10-07
影响因子：
9
通讯作者：
Yuan, Hai-Xin
中科院分区：
文献类型：
--
作者：
Wang, Tian-Xiang;Liang, Jun-Yun;Yuan, Hai-Xin
铁凋亡是一种以铁依赖性脂质过氧化为特征的非凋亡形式的细胞死亡，并与多种人类病理学有关，如组织缺血、神经变性和癌症。铁凋亡似乎是高度细胞环境依赖性和生理或病理条件下的铁凋亡的调节是不清楚的。在这里，我们报告说，肿瘤衍生IDH 1突变敏感细胞铁凋亡。在IDH 1杂合子肿瘤细胞中缺失突变IDH 1等位基因或药理学抑制突变IDH 1产生癌代谢产物D-2-羟基戊二酸（D-2-HG）可抵抗erastin诱导的铁凋亡。相反，突变IDH 1的异位表达或用细胞可渗透的D-2-HG处理细胞促进脂质活性氧（ROS）的积累和随后的铁凋亡。从机制上讲，突变体IDH 1降低了谷胱甘肽过氧化物酶4（GPX 4）的蛋白质水平，这是清除脂质ROS和铁凋亡的关键酶，并促进谷胱甘肽的消耗。我们的研究结果揭示了一个新的作用，muplastin IDH 1和2-HG在铁凋亡。
Ferroptosis is a non-apoptotic form of cell death characterized by the iron-dependent lipid peroxidation and is implicated in several human pathologies, such as tissue ischemia, neurodegeneration, and cancer. Ferroptosis appears to be high cell-context dependent and the regulation of ferroptosis by physiological or pathological conditions are unclear. Here, we report that tumor-derivedIDH1mutation sensitizes cells to ferroptosis. Deletion of the mutantIDH1allele inIDH1heterozygous tumor cells or pharmacological inhibition of mutant IDH1 to produce the oncometabolite D-2-hydroxyglutarate (D-2-HG) confers resistance to erastin-induced ferroptosis. Conversely, ectopic expression of mutant IDH1 or treatment of cells with cell-permeable D-2-HG promotes the accumulation of lipid reactive oxygen species (ROS) and subsequently ferroptosis. Mechanistically, mutant IDH1 reduces the protein level of the glutathione peroxidase 4 (GPX4), a key enzyme in removing lipid ROS and ferroptosis, and promotes depletion of glutathione. Our results uncover a new role of mutantIDH1and 2-HG in ferroptosis.