中国神经再生研究(英文版) ›› 2023, Vol. 18 ›› Issue (5): 1040-1045.doi: 10.4103/1673-5374.355821

• 原著:脑损伤修复保护与再生 • 上一篇    下一篇

琥珀酸积累诱导Cdc42琥珀酰化抑制脑缺血再灌注后神经干细胞的增殖

  


  • 出版日期:2023-05-15 发布日期:2022-11-01
  • 基金资助:
    中国国家自然科学基金项目(81671164),江苏省自然科学基金项目(BK20211348);和徐州基础研究计划项目(KC21030)

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).

摘要:

缺血性琥珀酸累积可通过影响线粒体呼吸链产生大量活性氧分子从而导致脑损伤。然而,琥珀酸累积是否可影响脑缺血再灌注后神经干细胞增殖,目前尚不明确。实验以大脑中动脉闭塞建立了脑缺血再灌注损伤大鼠模型,其血清和大脑中的琥珀酸水平明显上调,同时氧糖剥夺复氧也可刺激原代神经干细胞中产生大量的琥珀酸。琥珀酸可在细胞内衍生为琥珀酸二乙酯,外源性琥珀酸二乙酯不仅明显抑制C17.2神经干细胞系细胞的增殖,还能加剧脑缺血再灌注损伤大鼠模型的梗死体积。此外,外源性琥珀酸二乙酯还可增加C17.2细胞中Cdc42琥珀酰化,并抑制Cdc42 GTPase的活性。而以去琥珀酰化酶SIRT5小干扰核糖核酸转染后,可明显增加C17.2细胞中Cdc42琥珀酰化水平,并降低Cdc42 GTPase活性。表明琥珀酸的积累可通过诱导Cdc42的琥珀酰化来降低Cdc42 GTPase活性,从而抑制神经干细胞的增殖,继而加重脑缺血再灌注损伤。

https://orcid.org/0000-0003-0052-750X (Lin-Yan Huang); 

https://orcid.org/0000-0002-6507-2000 (Ju-Yun Ma); 

https://orcid.org/0000-0002-1807-0643 (Jin-Xiu Song); 

https://orcid.org/0000-0001-7745-3188 (Jing-Jing Xu); 

https://orcid.org/0000-0003-2857-9563 (Rui Hong); 

https://orcid.org/0000-0002-9840-0090 (Hai-Di Fan); 

https://orcid.org/0000-0002-0443-8769 (Heng Cai); 

https://orcid.org/0000-0003-0493-6407 (Wan Wang); Wang 

https://orcid.org/0000-0002-9173-504X (Yan-Ling Wang);  

https://orcid.org/0000-0002-2283-5880 (Zhao-Li Hu);

https://orcid.org/0000-0002-4199-8095 (Jian-Gang Shen); 

https://orcid.org/0000-0002-1479-701X (Su-Hua Qi)

关键词: 神经干细胞, 神经发生, 增殖, 琥珀酸, Cdc42, 琥珀酰化, SIRT 5, GPR91, 预后, 脑缺血再灌注

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