BL-918 activates PINK1/Parkin signaling pathway to ameliorate the progression of Parkinson’s disease

Mitochondrial dysfunction is linked to the pathogenesis of Parkinson’s disease (PD). Since the PINK1/Parkin pathway plays a critical role in mitochondrial quality control by promoting mitophagy to eliminate damaged mitochondria, targeting this pathway could offer therapeutic benefits for PD. In this study, we discovered a novel small molecule, BL-918, that induces mitophagy by activating the PINK1/Parkin pathway. BL-918 stimulates PINK1 accumulation and Parkin translocation to mitochondria, initiating PINK1/Parkin-mediated mitophagy. Our findings reveal that mitochondrial membrane potential and mitochondrial permeability transition pore are involved in the activation of the PINK1/Parkin pathway by BL-918. Additionally, BL-918 was shown to alleviate PD progression in MPTP-induced PD mice in a PINK1-dependent manner. These results identify BL-918 as a new activator of the PINK1/Parkin signaling pathway and suggest a promising approach for treating PD and other conditions related to mitochondrial dysfunction.