RT Journal Article
SR Electronic
T1 Src inhibition rescues FUNDC1-mediated neuronal mitophagy in ischaemic stroke
JF Stroke and Vascular Neurology
JO Stroke Vasc Neurol
FD BMJ Publishing Group Ltd
SP 367
OP 379
DO 10.1136/svn-2023-002606
VO 9
IS 4
A1 Tang, Tianchi
A1 Hu, Li-bin
A1 Ding, Chao
A1 Zhang, Zhihua
A1 Wang, Ning
A1 Wang, Tingting
A1 Zhou, Hang
A1 Xia, Siqi
A1 Fan, Linfeng
A1 Fu, Xiong-jie
A1 Yan, Feng
A1 Zhang, Xiangnan
A1 Chen, Gao
A1 Li, Jianru
YR 2024
UL http://svn.bmj.com/content/9/4/367.abstract
AB Background Ischaemic stroke triggers neuronal mitophagy, while the involvement of mitophagy receptors in ischaemia/reperfusion (I/R) injury-induced neuronal mitophagy remain not fully elucidated. Here, we aimed to investigate the involvement of mitophagy receptor FUN14 domain-containing 1 (FUNDC1) and its modulation in neuronal mitophagy induced by I/R injury.Methods 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 vitro. Stroke outcomes of mice with two genotypes were assessed. Neuronal mitophagy was analysed both in vivo and in vitro. Activities of FUNDC1 and its regulator Src were evaluated. The impact of Src on FUNDC1-mediated mitophagy was assessed through administration of Src antagonist PP1.Results To our surprise, FUNDC1 knockout mice subjected to tMCAO showed stroke outcomes comparable to those of their wild-type littermates. Although neuronal mitophagy could be activated by I/R injury, FUNDC1 deletion did not disrupt neuronal mitophagy. Transient activation of FUNDC1, represented by dephosphorylation of Tyr18, was detected in the early stages (within 3 hours) of neuronal I/R injury; however, phosphorylated Tyr18 reappeared and even surpassed baseline levels in later stages (after 6 hours), accompanied by a decrease in FUNDC1-light chain 3 interactions. Spontaneous 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 injury. Finally, FUNDC1-mediated mitophagy in neurons under I/R conditions can be rescued by pharmacological inhibition of Src.Conclusions FUNDC1 is inactivated by Src during the later stage (after 6 hours) of neuronal I/R injury, and rescue of FUNDC1-mediated mitophagy may serve as a potential therapeutic strategy for treating ischaemic stroke.Data are available upon reasonable request.