HIF-1α/STOML2/PGAM5信号通路调控线粒体自噬在神经元低氧响应中的作用及机制研究

低氧响应可辅助神经元抵抗低氧诱导的细胞损伤，有效的线粒体质控是低氧响应的重要环节。线粒体自噬是细胞内主要的线粒体质控机制，在抵抗神经元损伤中有重要作用，但线粒体自噬在神经元低氧响应中的作用及调控机制尚不清楚。我们前期发现低氧可激活PINK1依赖性线粒体自噬，同时伴随HIF-1α的活化及其下游线粒体蛋白STOML2水平的上调，并协同上调了参与PINK1稳定于线粒体膜上的蛋白PGAM5水平。因此，我们推测HIF-1α、STOML2和PGAM5可能构成了一条新的低氧信号通路，参与了神经元低氧响应中PINK1依赖性线粒体自噬的启动。本项目拟在前期研究基础上，利用低氧动物及细胞模型，深入阐明HIF-1α/STOML2/PGAM5信号通路在神经元低氧响应中激活PINK1依赖性线粒体自噬及抵抗低氧诱导的神经元损伤中的作用及新机制，为低氧相关神经系统疾病的干预提供新的治疗靶点。

Hypoxic response could help neurons to resist hypoxia-induced injury, in which effective mitochondrial quality control is an important link. Mitophagy is a critical cellular mitochondrial quality control mechanism and plays an important role in the resistance to neuronal injury, while the role and regulatory mechanisms of mitophagy in neuronal hypoxia response are still unclear. We previously found that hypoxia could activate PINK1-dependent mitophagy, and induce HIF-1α activation and its downstream protein STOML2 up-regulation, as well as the increase of PGAM5, a protein involved in the stabilization of PINK1 on mitochondrial membrane. We speculate that HIF-1α, STOML2 and PGAM5 may constitute a new hypoxic signaling pathway, which participates in the activation of PINK1-dependent mitophagy in neuronal hypoxia response. Based on previous studies, this project intends to explore the role and mechanism of HIF-1α-STOML2-PGAM5 axis in activating PINK1-dependent mitophagy and preventing hypoxia-induced nerve injury in hypoxic animal and cell models. This study will provide a new idea to reveal the hypoxic response mechanism of neurons, provide potential therapeutic targets for the intervention of hypoxia-related neurological diseases.