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: Feng Li, Xiadi He, Dingwei Ye, Yan Lin, Hongxiu Yu, Cuifang Yao, Lei Huang, Jianong Zhang, Fang Wang, Sha Xu, Xiaohui Wu, Lixia Liu, Chen Yang, Jiaqi Shi, Xiaoyang He, Jie Liu, Yuanyuan Qu, Fushen Guo, Jianyuan Zhao, Wei Xu, Shimin Zhao
• Journal: Molecular cell (Mol Cell) Vol. 60 Issue 4 Pg. 661-75 (Nov 19 2015) ISSN: 1097-4164 [Electronic] United States
• PMID: 26585387 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2015 Elsevier Inc. All rights reserved.

Chemical References

• Glutarates
• alpha-hydroxyglutarate
• Succinic Acid
• IDH2 protein, human
• Isocitrate Dehydrogenase
• IDH1 protein, human
• Succinate Dehydrogenase

Topics

• Animals
• Apoptosis (drug effects)
• Cell Line, Tumor
• Glutarates (pharmacology)
• HEK293 Cells
• Humans
• Isocitrate Dehydrogenase (genetics)
• Mice
• Mitochondria (drug effects, metabolism)
• Mutation
• Neoplasms, Experimental (genetics, metabolism)
• Succinate Dehydrogenase (antagonists & inhibitors)
• Succinic Acid (metabolism)