Abstract：
The pathogenesis of Parkinson\'s disease (PD) has been associated with mitochondrial dysfunction. Given that the PINK1/Parkin pathway governs mitochondrial quality control by inducing mitophagy to remove damaged mitochondria, therapeutic approaches to activate PINK1/Parkin-mediated mitophagy have the potential in the treatment of PD. Here, we have identified a new small molecule, BL-918, as an inducer of mitophagy via activating the PINK1/Parkin pathway. BL-918 triggers PINK1 accumulation and Parkin mitochondrial translocation to initiate PINK1/Parkin-mediated mitophagy. We found that mitochondrial membrane potential and mitochondrial permeability transition pore were involved in BL-918-induced PINK1/Parkin pathway activation. Moreover, we showed that BL-918 mitigated PD progression in MPTP-induced PD mice in a PINK1-dependent manner. Our results unravel a new activator of the PINK1/Parkin signaling pathway and provide a potential strategy for the treatment of PD and other diseases with dysfunctional mitochondria.
摘要：
帕金森病(PD)的发病机制与线粒体功能障碍有关。鉴于PINK1/Parkin通路通过诱导线粒体自噬去除受损线粒体来控制线粒体质量控制，激活PINK1/Parkin介导的线粒体自噬的治疗方法具有治疗PD的潜力。这里,我们发现了一个新的小分子,BL-918，通过激活PINK1/Parkin通路作为线粒体自噬的诱导剂。BL-918触发PINK1积累和Parkin线粒体易位以启动PINK1/Parkin介导的线粒体自噬。我们发现线粒体膜电位和线粒体通透性转换（mPT）孔参与BL-918诱导的PINK1/Parkin通路激活。此外，我们发现BL-918以PINK1依赖性方式减轻MPTP诱导的PD小鼠的PD进展.我们的结果揭示了PINK1/Parkin信号通路的新激活剂，并为PD和其他线粒体功能失调的疾病的治疗提供了潜在的策略。
