Mitochondrial transplantation confers protection against the effects of ischemic stroke by repressing microglial pyroptosis and promoting neurogenesis
作者机构：Department of Experimental Surgery The Second Affiliated Hospital of Air Force Medical University Department of Anesthesiology The Second Affiliated Hospital of Air Force Medical University
出 版 物：《Neural Regeneration Research》 (中国神经再生研究(英文版))
年 卷 期：2024年第19卷第6期
页 面：1325-1335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,Nos. 82201621 (to LS), 31930048 (to QY) and 81720108016 (to QY),and 81971225 (to CG) the Key Research and Development Project of Shaanxi Province,No. 2022SF-189 (to XS) the Tangdu Hospital Supporting Foundation,Nos. 2021ZTXM-006 (to LS) and 2021JSZH-006 (to CG)
主 题：ischemic stroke microglia mitochondria transplantation neurogenesis pyroptosis
摘 要：Transferring healthy and functional mitochondria to the lateral ventricles confers neuroprotection in a rat model of ischemia-reperfusion injury. Autologous mitochondrial transplantation is also beneficial in pediatric patients with cardiac ischemia-reperfusion injury. Thus, transplantation of functional exogenous mitochondria may be a promising therapeutic approach for ischemic disease. To explore the neuroprotective effect of mitochondria transplantation and determine the underlying mechanism in ischemic stroke, in this study we established a photo-thrombosis-induced mouse model of focal ischemia and administered freshly isolated mitochondria via the tail vein or to the injury site(in situ). Animal behavior tests, immunofluorescence staining, 2,3,5-triphenyltetrazolium chloride(TTC) staining, mRNA-seq, and western blotting were used to assess mouse anxiety and memory, cortical infarct area, pyroptosis, and neurogenesis, respectively. Using bioinformatics analysis, western blotting, co-immunoprecipitation, and mass spectroscopy, we identified S100 calcium binding protein A9(S100A9) as a potential regulator of mitochondrial function and determined its possible interacting proteins. Interactions between exogenous and endogenous mitochondria, as well as the effect of exogenous mitochondria on recipient microglia, were assessed in vitro. Our data showed that:(1) mitochondrial transplantation markedly reduced mortality and improved emotional and cognitive function, as well as reducing infarct area, inhibiting pyroptosis, and promoting cortical neurogenesis;(2) microglial expression of S100A9 was markedly increased by ischemic injury and regulated mitochondrial function;(3) in vitro, exogenous mitochondria enhanced mitochondrial function, reduced redox stress, and regulated microglial polarization and pyroptosis by fusing with endogenous mitochondria; and(4) S100A9 promoted internalization of exogenous mitochondria by the microglia, thereby amplifying their pro-proliferation and anti-inflammatory effects. Taken together, our findings show that mitochondrial transplantation protects against the deleterious effects of ischemic stroke by suppressing pyroptosis and promoting neurogenesis, and that S100A9 plays a vital role in promoting internalization of exogenous mitochondria.
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