Ischemic accumulation of succinate induces Cdc42 succinylation and inhibits neural stem cell proliferation after cerebral ischemia/reperfusion

作     者：Lin-Yan Huang Ju-Yun Ma Jin-Xiu Song Jing-Jing Xu Rui Hong Hai-Di Fan Heng Cai Wan Wang Yan-Ling Wang Zhao-Li Hu Jian-Gang Shen Su-Hua Qi Lin-Yan Huang;Ju-Yun Ma;Jin-Xiu Song;Jing-Jing Xu;Rui Hong;Hai-Di Fan;Heng Cai;Wan Wang;Yan-Ling Wang;Zhao-Li Hu;Jian-Gang Shen;Su-Hua Qi

作者机构：School of Medical TechnologyXuzhou Key Laboratory of Laboratory DiagnosticsXuzhou Medical UniversityXuzhouJiangsu ProvinceChina College of PharmacologyXuzhou Medical UniversityXuzhouJiangsu ProvinceChina Research Center for Biochemistry and Molecular Biology and Jiangsu Key Laboratory of Brain Disease BioinformationXuzhou Medical UniversityXuzhouJiangsu ProvinceChina School of Chinese MedicineThe University of Hong KongHong Kong Special Administrative RegionChina 

出 版 物：《Neural Regeneration Research》 (中国神经再生研究（英文版）)

年 卷 期：2023年第18卷第5期

页      面：1040-1045页

核心收录：

学科分类：0710[理学-生物学] 1002[医学-临床医学] 1001[医学-基础医学(可授医学、理学学位)] 100204[医学-神经病学] 10[医学] 

基　　金：supported by the National Natural Science Foundation of China,No. 81671164 (to SHQ) the Natural Science Foundation of Jiangsu Province of China,No. BK20211348 (to SHQ) Xuzhou Basic Research Program,No. KC21030 (to LYH)。 

主　　题：Cdc42 cerebral ischemia/reperfusion injury GPR91 neural stem cells neurogenesis proliferation SIRT5 succinate succinylation 

摘      要：Ischemic accumulation of succinate causes cerebral damage by excess production of reactive oxygen species. However, it is unknown whether ischemic accumulation of succinate affects neural stem cell proliferation. In this study, we established a rat model of cerebral ischemia/reperfusion injury by occlusion of the middle cerebral artery. We found that succinate levels increased in serum and brain tissue(cortex and hippocampus) after ischemia/reperfusion injury. Oxygen-glucose deprivation and reoxygenation stimulated primary neural stem cells to produce abundant succinate. Succinate can be converted into diethyl succinate in cells. Exogenous diethyl succinate inhibited the proliferation of mouse-derived C17.2 neural stem cells and increased the infarct volume in the rat model of cerebral ischemia/reperfusion injury. Exogenous diethyl succinate also increased the succinylation of the Rho family GTPase Cdc42 but repressed Cdc42 GTPase activity in C17.2 cells. Increasing Cdc42 succinylation by knockdown of the desuccinylase Sirt5 also inhibited Cdc42 GTPase activity in C17.2 cells. Our findings suggest that ischemic accumulation of succinate decreases Cdc42 GTPase activity by induction of Cdc42 succinylation, which inhibits the proliferation of neural stem cells and aggravates cerebral ischemia/reperfusion injury.