title: NADP(+)-IDH Mutations Promote Hypersuccinylation that Impairs Mitochondria Respiration and Induces Apoptosis Resistance.
abstract: 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.
authors.affiliation: State Key Lab of Genetic Engineering and the Obstetrics & Gynecology Hospital of Fudan University, Fudan University, Shanghai 200032, P.R. China; Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, P.R. China; State Key Laboratory of Biotherapy/Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, P.R. China.
authors.forename: Feng
authors.initials: F
authors.lastname: Li
authors.affiliation: State Key Lab of Genetic Engineering and the Obstetrics & Gynecology Hospital of Fudan University, Fudan University, Shanghai 200032, P.R. China; School of Life Sciences and Collaborative Innovation Center for Genetics and Development, Fudan University, Shanghai 200032, P.R. China; State Key Laboratory of Biotherapy/Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, P.R. China.
authors.forename: Xiadi
authors.initials: X
authors.lastname: He
authors.affiliation: Department of Urology, Fudan University Shanghai Cancer Center, Fudan University, Shanghai 200032, P.R. China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, P.R. China.
authors.forename: Dingwei
authors.initials: D
authors.lastname: Ye
authors.affiliation: State Key Lab of Genetic Engineering and the Obstetrics & Gynecology Hospital of Fudan University, Fudan University, Shanghai 200032, P.R. China; Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, P.R. China; State Key Laboratory of Biotherapy/Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, P.R. China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Lin
authors.affiliation: Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, P.R. China.
authors.forename: Hongxiu
authors.initials: H
authors.lastname: Yu
authors.affiliation: State Key Lab of Genetic Engineering and the Obstetrics & Gynecology Hospital of Fudan University, Fudan University, Shanghai 200032, P.R. China; Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, P.R. China.
authors.forename: Cuifang
authors.initials: C
authors.lastname: Yao
authors.affiliation: State Key Lab of Genetic Engineering and the Obstetrics & Gynecology Hospital of Fudan University, Fudan University, Shanghai 200032, P.R. China; School of Life Sciences and Collaborative Innovation Center for Genetics and Development, Fudan University, Shanghai 200032, P.R. China.
authors.forename: Lei
authors.initials: L
authors.lastname: Huang
authors.affiliation: State Key Lab of Genetic Engineering and the Obstetrics & Gynecology Hospital of Fudan University, Fudan University, Shanghai 200032, P.R. China; School of Life Sciences and Collaborative Innovation Center for Genetics and Development, Fudan University, Shanghai 200032, P.R. China.
authors.forename: Jianong
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, P.R. China.
authors.forename: Fang
authors.initials: F
authors.lastname: Wang
authors.affiliation: State Key Lab of Genetic Engineering and the Obstetrics & Gynecology Hospital of Fudan University, Fudan University, Shanghai 200032, P.R. China; Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, P.R. China.
authors.forename: Sha
authors.initials: S
authors.lastname: Xu
authors.affiliation: State Key Lab of Genetic Engineering and the Obstetrics & Gynecology Hospital of Fudan University, Fudan University, Shanghai 200032, P.R. China; Institute of Developmental Biology and Molecular Medicine, Fudan University, Shanghai 200032, P.R. China.
authors.forename: Xiaohui
authors.initials: X
authors.lastname: Wu
authors.affiliation: Institute of Plant Physiology and Ecology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, P.R. China.
authors.forename: Lixia
authors.initials: L
authors.lastname: Liu
authors.affiliation: Institute of Plant Physiology and Ecology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, P.R. China.
authors.forename: Chen
authors.initials: C
authors.lastname: Yang
authors.affiliation: Department of Urology, Affiliated Hospital of Guiyang Medical College, Guiyang 550004, P.R. China.
authors.forename: Jiaqi
authors.initials: J
authors.lastname: Shi
authors.affiliation: Guizhou Cancer Hospital, Guiyang 550001, P.R. China.
authors.forename: Xiaoyang
authors.initials: X
authors.lastname: He
authors.affiliation: Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, P.R. China; Institute of Digestive Medicine, Affiliated Huashan Hospital, Fudan University, Shanghai 200032, P.R. China; Department of Urology, Affiliated Hospital of Guiyang Medical College, Guiyang 550004, P.R. China.
authors.forename: Jie
authors.initials: J
authors.lastname: Liu
authors.affiliation: Department of Urology, Fudan University Shanghai Cancer Center, Fudan University, Shanghai 200032, P.R. China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, P.R. China.
authors.forename: Yuanyuan
authors.initials: Y
authors.lastname: Qu
authors.affiliation: State Key Lab of Genetic Engineering and the Obstetrics & Gynecology Hospital of Fudan University, Fudan University, Shanghai 200032, P.R. China; Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, P.R. China; School of Life Sciences and Collaborative Innovation Center for Genetics and Development, Fudan University, Shanghai 200032, P.R. China.
authors.forename: Fushen
authors.initials: F
authors.lastname: Guo
authors.affiliation: State Key Lab of Genetic Engineering and the Obstetrics & Gynecology Hospital of Fudan University, Fudan University, Shanghai 200032, P.R. China; School of Life Sciences and Collaborative Innovation Center for Genetics and Development, Fudan University, Shanghai 200032, P.R. China.
authors.forename: Jianyuan
authors.initials: J
authors.lastname: Zhao
authors.affiliation: State Key Lab of Genetic Engineering and the Obstetrics & Gynecology Hospital of Fudan University, Fudan University, Shanghai 200032, P.R. China; Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, P.R. China; State Key Laboratory of Biotherapy/Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, P.R. China. Electronic address: xuwei_0706@fudan.edu.cn.
authors.forename: Wei
authors.initials: W
authors.lastname: Xu
authors.affiliation: State Key Lab of Genetic Engineering and the Obstetrics & Gynecology Hospital of Fudan University, Fudan University, Shanghai 200032, P.R. China; Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, P.R. China; School of Life Sciences and Collaborative Innovation Center for Genetics and Development, Fudan University, Shanghai 200032, P.R. China; Institute of Digestive Medicine, Affiliated Huashan Hospital, Fudan University, Shanghai 200032, P.R. China; State Key Laboratory of Biotherapy/Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, P.R. China. Electronic address: zhaosm@fudan.edu.cn.
authors.forename: Shimin
authors.initials: S
authors.lastname: Zhao
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D005977:Glutarates / Q000494:pharmacology*; D057809:HEK293 Cells; D006801:Humans; D007521:Isocitrate Dehydrogenase / Q000235:genetics*; D051379:Mice; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D009154:Mutation; D009374:Neoplasms, Experimental / Q000235:genetics / Q000378:metabolism*; D013385:Succinate Dehydrogenase / Q000037:antagonists & inhibitors; D019802:Succinic Acid / Q000378:metabolism*
chemical_list: D005977:Glutarates; C019417:alpha-hydroxyglutarate; D019802:Succinic Acid; C538784:IDH2 protein, human; D007521:Isocitrate Dehydrogenase; C543588:IDH1 protein, human; D013385:Succinate Dehydrogenase