NADP+-IDH Mutations Promote Hypersuccinylation that Impairs Mitochondria Respiration and Induces Apoptosis Resistance
NADP+-IDH Mutations Promote Hypersuccinylation that Impairs Mitochondria Respiration and Induces Apoptosis Resistance
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NADP( )-IDH 突变促进过度琥珀酰化，从而损害线粒体呼吸并诱导细胞凋亡抵抗。
DOI：
10.1016/j.molcel.2015.10.017
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发表时间：
2015-11-19
期刊：
影响因子：
16
通讯作者：
Zhao, Shimin
中科院分区：
文献类型：
--
作者：
Li, Feng;He, Xiadi;Zhao, Shimin
阐明R-2-羟基戊二酸（R-2 HG）的致瘤机制对于确定NADP（+）-IDH突变如何导致癌症至关重要。本文报道R-2 HG通过促进琥珀酰化诱导肿瘤代谢和凋亡抵抗。通过竞争性抑制线粒体三羧酸循环酶琥珀酸脱氢酶（SDH），R-2 HG优先诱导线粒体中琥珀酰辅酶A积累和过度琥珀酰化。携带IDH 1突变的胶质瘤样品和细胞在线粒体中高度琥珀酰化。IDH 1突变或SDH失活导致琥珀酰化过度，引起呼吸抑制，并诱导癌性代谢和线粒体去极化。这些线粒体功能障碍诱导BCL-2在线粒体膜上积累，导致过度琥珀酰化细胞的凋亡抗性。通过过度表达脱琥珀酰酶SIRT 5或补充甘氨酸来缓解过度琥珀酰化，挽救了线粒体功能障碍，逆转了BCL-2的积累，并减缓了过度琥珀酰化IDH 1（R132 C）-携带HT 1080细胞的致癌生长。因此，R-2 HG诱导的过度琥珀酰化有助于NADP（+）-IDH突变的致瘤性，表明过度琥珀酰化抑制作为过度琥珀酰化相关肿瘤的干预的潜力。
Elucidating the tumorigenic mechanism of R-2-hydroxyglutarate (R-2HG) is critical for determining how NADP(+)-IDH mutations cause cancer. Here we report that R-2HG induces cancerous metabolism and apoptosis resistance through promoting hypersuccinylation. By competitive inhibition of the mitochondrial tricarboxylic acid cycle enzyme succinate dehydrogenase (SDH), R-2HG preferentially induced succinyl-CoA accumulation and hypersuccinylation in the mitochondria. IDH1 mutation-bearing glioma samples and cells were hypersuccinylated in the mitochondria. IDH1 mutation or SDH inactivation resulted in hypersuccinylation, causing respiration inhibition and inducing cancerous metabolism and mitochondrial depolarization. These mitochondrial dysfunctions induced BCL-2 accumulation at the mitochondrial membrane, leading to apoptosis resistance of hypersuccinylated cells. Relief of hypersuccinylation by overexpressing the desuccinylase SIRT5 or supplementing glycine rescued mitochondrial dysfunctions, reversed BCL-2 accumulation, and slowed the oncogenic growth of hypersuccinylated IDH1 (R132C)-harboring HT1080 cells. Thus, R-2HG-induced hypersuccinylation contributes to the tumorigenicity of NADP(+)-IDH mutations, suggesting the potential of hypersuccinylation inhibition as an intervention for hypersuccinylation- related tumors.