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Li, Feng; He, Xiadi; Ye, Dingwei; Lin, Yan; Yu, Hongxiu; Yao, Cuifang; Huang, Lei; Zhang, Jianong; Wang, Fang; Xu, Sha; Wu, Xiaohui; Liu, Lixia; Yang, Chen; Shi, Jiaqi; He, Xiaoyang; Liu, Jie; Qu, Yuanyuan; Guo, Fushen; Zhao, Jianyuan; Xu, Wei; Zhao, Shimin
Molecular cell, 11/2015, Letnik: 60, Številka: 4Journal Article
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 IDH1R132C-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. Display omitted •R-2HG competitively inhibits SDH and induces hypersuccinylation•IDH1 mutations preferentially induce hypersuccinylation in mitochondria•Hypersuccinylation impairs mitochondrial functions and induces apoptosis resistance•Relief of hypersuccinylation inhibits oncogenic growth of hypersuccinylated cells NADP+-IDH mutation-produced R-2-hydroxyglutarate induces mitochondrial hypersuccinylation that induces cancerous metabolism and apoptosis resistance. Relief of hypersuccinylation inhibits tumorigenic growth of IDH mutant-harboring cells. Thus, hypersuccinylation contributes to oncogenicity of R-2-hydroxyglutarate.
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