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琥珀酸脱氢酶亚基A（SDHA）介导的小胶质细胞胞外陷阱形成参与脑缺血再灌注损伤

Succinate Dehydrogenase Subunit A (SDHA) Mediated Microglia Extracellular Traps Formation Participating in Cerebral Ischemic Reperfusion Injury.

作者信息

Zhao Lili, Li Tao, Dang Meijuan, Li Ye, Lu Jialiang, Lu Ziwei, Chen Zhiyang, Huang Qiao, Chen Yujie, Yang Yang, Feng Yuxuan, Wang Xiaoya, Jian Yating, Wang Heying, Guo Yingying, Zhang Lei, Jiang Yu, Fan Songhua, Wu Shengxi, Fan Hong, Kuang Fang, Zhang Guilian

机构信息

Department of Neurology, the Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, 710004, China.

Department of Neurobiology, School of Basic Medicine, Fourth Military Medical University, Xi'an, Shaanxi, 710032, China.

出版信息

Adv Sci (Weinh). 2025 Sep;12(35):e11873. doi: 10.1002/advs.202411873. Epub 2025 Aug 20.

DOI:10.1002/advs.202411873
PMID:40832885
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC12463099/
Abstract

Ischemia reperfusion (I/R) injury associated with recanalization therapy in acute ischemic stroke (AIS) exacerbates the initial brain damage. However, it remains a clinical challenge due to limited understanding of the underlying mechanisms of I/R injury. This study aims to investigate the mechanism of succinate dehydrogenase (SDH)-mediated succinate oxidation in microglia extracellular traps (MiETs) formation and neuronal injury after cerebra I/R injury. The results show that microglia are the main cell type producing extracellular traps (ETs) at 24 h at cerebral parenchyma after cerebral I/R. Additionally, oxygen glucose deprivation/re-oxygenation (OGD/R) could induce MiETs formation and increased level of mitochondrial reactive oxygen species (mtROS). Microglia switches toward glycolysis with enhanced SDH activity and upregulated expression of SDH subunit A (SDHA) during MiETosis. Dimethyl malonate (DMM), a competitive SDH inhibitor, could reduce MiETosis by inhibiting succinate oxidation and mtROS production during reperfusion. Furthermore, DMM is found to alleviate neuronal injury after OGD/R exposure and neurological behavior disorders after cerebral I/R, and the effect is similar to MiETosis inhibitor BB-Cl amidine. These findings reveal a novel functional state of microglia and the role of succinate oxidation in MiETosis after cerebral I/R and provide a novel potential target for the treatment of AIS.

摘要

急性缺血性卒中（AIS）再通治疗相关的缺血再灌注（I/R）损伤会加重初始脑损伤。然而，由于对I/R损伤潜在机制的了解有限，它仍然是一个临床挑战。本研究旨在探讨琥珀酸脱氢酶（SDH）介导的琥珀酸氧化在脑I/R损伤后小胶质细胞胞外陷阱（MiETs）形成和神经元损伤中的机制。结果表明，小胶质细胞是脑I/R后24小时脑实质中产生胞外陷阱（ETs）的主要细胞类型。此外，氧糖剥夺/复氧（OGD/R）可诱导MiETs形成并增加线粒体活性氧（mtROS）水平。在MiETosis过程中，小胶质细胞向糖酵解转变，SDH活性增强，SDH亚基A（SDHA）表达上调。竞争性SDH抑制剂丙二酸二甲酯（DMM）可通过抑制再灌注期间的琥珀酸氧化和mtROS产生来减少MiETosis。此外，发现DMM可减轻OGD/R暴露后的神经元损伤和脑I/R后的神经行为障碍，其效果与MiETosis抑制剂BB-Cl脒类似。这些发现揭示了小胶质细胞的一种新功能状态以及琥珀酸氧化在脑I/R后MiETosis中的作用，并为AIS的治疗提供了一个新的潜在靶点。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/40a5/12463099/c658a0b4f323/ADVS-12-e11873-g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/40a5/12463099/f040ae06f416/ADVS-12-e11873-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/40a5/12463099/8cdac99b3a15/ADVS-12-e11873-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/40a5/12463099/f54a183c5fb7/ADVS-12-e11873-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/40a5/12463099/d170d165c88f/ADVS-12-e11873-g009.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/40a5/12463099/dbf80eb9f0d4/ADVS-12-e11873-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/40a5/12463099/c70d13b62b50/ADVS-12-e11873-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/40a5/12463099/dbaec4e57c83/ADVS-12-e11873-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/40a5/12463099/c658a0b4f323/ADVS-12-e11873-g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/40a5/12463099/f040ae06f416/ADVS-12-e11873-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/40a5/12463099/8cdac99b3a15/ADVS-12-e11873-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/40a5/12463099/f54a183c5fb7/ADVS-12-e11873-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/40a5/12463099/d170d165c88f/ADVS-12-e11873-g009.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/40a5/12463099/dbf80eb9f0d4/ADVS-12-e11873-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/40a5/12463099/c70d13b62b50/ADVS-12-e11873-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/40a5/12463099/dbaec4e57c83/ADVS-12-e11873-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/40a5/12463099/c658a0b4f323/ADVS-12-e11873-g008.jpg

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