Neural Regeneration Research ›› 2023, Vol. 18 ›› Issue (5): 1040-1045.doi: 10.4103/1673-5374.355821

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

Lin-Yan Huang1, #, Ju-Yun Ma2, #, Jin-Xiu Song2, #, Jing-Jing Xu1, Rui Hong1, Hai-Di Fan2, Heng Cai2, Wan Wang1, Yan-Ling Wang1, #br# Zhao-Li Hu3, Jian-Gang Shen1, 4, Su-Hua Qi1, 2, 3, *#br#   

  1. 1School of Medical Technology, Xuzhou Key Laboratory of Laboratory Diagnostics, Xuzhou Medical University, Xuzhou, Jiangsu Province, China;  2College of Pharmacology, Xuzhou Medical University, Xuzhou, Jiangsu Province, China;  3Research Center for Biochemistry and Molecular Biology and Jiangsu Key Laboratory of Brain Disease Bioinformation, Xuzhou Medical University, Xuzhou, Jiangsu Province, China;  4School of Chinese Medicine, The University of Hong Kong, Hong Kong Special Administrative Region, China
  • Online:2023-05-15 Published:2022-11-01
  • Contact: Su-Hua Qi, PhD, suhuaqi@xzhmu.edu.cn.
  • Supported by:
    This work was 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), and Xuzhou Basic Research Program, No. KC21030 (to LYH).

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Abstract: 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. 

Key words: Cdc42, cerebral ischemia/reperfusion injury, GPR91, neural stem cells, neurogenesis, proliferation, SIRT5, succinate, succinylation