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Mol Cell. 2015 Nov 19;60(4):661-75. doi: 10.1016/j.molcel.2015.10.017. Epub 2015 Nov 12.

NADP(+)-IDH Mutations Promote Hypersuccinylation that Impairs Mitochondria Respiration and Induces Apoptosis Resistance.

Author information

1
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.
2
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.
3
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.
4
Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, P.R. China.
5
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.
6
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.
7
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.
8
Institute of Plant Physiology and Ecology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, P.R. China.
9
Department of Urology, Affiliated Hospital of Guiyang Medical College, Guiyang 550004, P.R. China.
10
Guizhou Cancer Hospital, Guiyang 550001, P.R. China.
11
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.
12
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.
13
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.
14
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.

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.

PMID:
26585387
DOI:
10.1016/j.molcel.2015.10.017
[Indexed for MEDLINE]
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