Ischemic accumulation of succinate induces Cdc42 succinylation and inhibits neural stem cell proliferation after cerebral ischemia/reperfusion
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 oc...
| Main Authors: | , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Wolters Kluwer Medknow Publications
2023-01-01
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| Series: | Neural Regeneration Research |
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| Online Access: | http://www.nrronline.org/article.asp?issn=1673-5374;year=2023;volume=18;issue=5;spage=1040;epage=1045;aulast=Huang |
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| author | 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 |
| author_facet | 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 |
| author_sort | Lin-Yan Huang |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-11T06:46:03Z |
| format | Article |
| id | doaj.art-9ce18f7cfdfd4f94a2cd6714e11893a7 |
| institution | Directory Open Access Journal |
| issn | 1673-5374 |
| language | English |
| last_indexed | 2024-04-11T06:46:03Z |
| publishDate | 2023-01-01 |
| publisher | Wolters Kluwer Medknow Publications |
| record_format | Article |
| series | Neural Regeneration Research |
| spelling | doaj.art-9ce18f7cfdfd4f94a2cd6714e11893a72022-12-22T04:39:20ZengWolters Kluwer Medknow PublicationsNeural Regeneration Research1673-53742023-01-011851040104510.4103/1673-5374.355821Ischemic accumulation of succinate induces Cdc42 succinylation and inhibits neural stem cell proliferation after cerebral ischemia/reperfusionLin-Yan HuangJu-Yun MaJin-Xiu SongJing-Jing XuRui HongHai-Di FanHeng CaiWan WangYan-Ling WangZhao-Li HuJian-Gang ShenSu-Hua QiIschemic 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.http://www.nrronline.org/article.asp?issn=1673-5374;year=2023;volume=18;issue=5;spage=1040;epage=1045;aulast=Huangcdc42; cerebral ischemia/reperfusion injury; gpr91; neural stem cells; neurogenesis; proliferation; sirt5; succinate; succinylation |
| spellingShingle | 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 Ischemic accumulation of succinate induces Cdc42 succinylation and inhibits neural stem cell proliferation after cerebral ischemia/reperfusion Neural Regeneration Research cdc42; cerebral ischemia/reperfusion injury; gpr91; neural stem cells; neurogenesis; proliferation; sirt5; succinate; succinylation |
| title | Ischemic accumulation of succinate induces Cdc42 succinylation and inhibits neural stem cell proliferation after cerebral ischemia/reperfusion |
| title_full | Ischemic accumulation of succinate induces Cdc42 succinylation and inhibits neural stem cell proliferation after cerebral ischemia/reperfusion |
| title_fullStr | Ischemic accumulation of succinate induces Cdc42 succinylation and inhibits neural stem cell proliferation after cerebral ischemia/reperfusion |
| title_full_unstemmed | Ischemic accumulation of succinate induces Cdc42 succinylation and inhibits neural stem cell proliferation after cerebral ischemia/reperfusion |
| title_short | Ischemic accumulation of succinate induces Cdc42 succinylation and inhibits neural stem cell proliferation after cerebral ischemia/reperfusion |
| title_sort | ischemic accumulation of succinate induces cdc42 succinylation and inhibits neural stem cell proliferation after cerebral ischemia reperfusion |
| topic | cdc42; cerebral ischemia/reperfusion injury; gpr91; neural stem cells; neurogenesis; proliferation; sirt5; succinate; succinylation |
| url | http://www.nrronline.org/article.asp?issn=1673-5374;year=2023;volume=18;issue=5;spage=1040;epage=1045;aulast=Huang |
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