Src inhibition rescues FUNDC1-mediated neuronal mitophagy in ischaemic stroke

作     者：Tianchi Tang Li-bin Hu Chao Ding Zhihua Zhang Ning Wang Tingting Wang Hang Zhou Siqi Xia Linfeng Fan Xiong-jie Fu Feng Yan Xiangnan Zhang Gao Chen Jianru Li 

作者机构：Department of NeurosurgeryZhejiang University School of Medicine Second Affiliated HospitalHangzhouZhejiangChina 2NeurosurgeryZhejiang University School of Medicine Second Affiliated HospitalHangzhouZhejiangChina 3Zhejiang University School of MedicineHangzhouZhejiangChina 4Zhejiang University Department of PharmacologyHangzhouZhejiangChina 

出 版 物：《Stroke & Vascular Neurology》 (卒中与血管神经病学（英文）)

年 卷 期：2024年第9卷第4期

页      面：367-379,I0022-I0031页

核心收录：

学科分类：1002[医学-临床医学] 100204[医学-神经病学] 10[医学] 

基　　金：supported by the National Natural Science Foundation of China(Nos.81971099,82171273,82171275 and 82202407) Natural Science Foundation of Zhejiang Province(LQ20H090015) Innovative Talent Program of Zhejiang Health Department(2020RC012) Key R&D Program of Zhejiang(2022C03133)and Key Program of Zhejiang(WKJ-ZJ-2004) sponsored by Zheng Shu Medical Elite Scholarship Fund 

主　　题：FUNDC1 involvement injury 

摘      要：Background Ischaemic stroke triggers neuronal mitophagy,while the involvement of mitophagy receptors in ischaemia/reperfusion(I/R)injury-induced neuronal mitophagy remain not fully ***,we aimed to investigate the involvement of mitophagy receptor FUN14 domain-containing 1(FUNDC1)and its modulation in neuronal mitophagy induced by I/R *** Wild-type and FUNDC1 knockout mice were generated to establish models of neuronal I/R injury,including transient middle cerebral artery occlusion(tMCAO)in vivo and oxygen glucose deprivation/reperfusion in *** outcomes of mice with two genotypes were *** mitophagy was analysed both in vivo and in *** of FUNDC1 and its regulator Src were *** impact of Src on FUNDC1-mediated mitophagy was assessed through administration of Src antagonist *** To our surprise,FUNDC1 knockout mice subjected to tMCAO showed stroke outcomes comparable to those of their wild-type *** neuronal mitophagy could be activated by I/R injury,FUNDC1 deletion did not disrupt neuronal *** activation of FUNDC1,represented by dephosphorylation of Tyr18,was detected in the early stages(within 3hours)of neuronal I/R injury;however,phosphorylated Tyr18 reappeared and even surpassed baseline levels in later stages(after 6hours),accompanied by a decrease in FUNDC1-light chain 3 *** inactivation of FUNDC1 was associated with Src activation,represented by phosphorylation of Tyr416,which changed in parallel with the level of phosphorylated FUNDC1(Tyr18)during neuronal I/R ***,FUNDC1-mediated mitophagy in neurons under I/R conditions can be rescued by pharmacological inhibition of *** FUNDC1 is inactivated by Src during the later stage(after 6hours)of neuronal I/R injury,and rescue of FUNDC1-mediated mitophagy may serve as a potential therapeutic strategy for treating ischaemic stroke.