OGS-MA114 ameliorates FUS mutant-associated ALS pathology by activating PINK1-dependent mitophagy

Mitochondrial dysfunction and impaired mitophagy are increasingly recognized as central contributors to pathogenesis of amyotrophic lateral sclerosis (ALS). In this study, we identified OGS-MA114 (C₂₃H₁₉ClN₄O₃S), as a compound that activates mitophagy through a bioactive chemical library screen in SH-SY5Y cells. OGS-MA114 significantly enhanced autophagic and mitophagic flux, increased Ser65-phosphorylated ubiquitin levels, and promoted Parkin recruitment to damaged mitochondria, indicating activation of the PINK1/Parkin pathway. In SH-SY5Y cells expressing the ALS-associated FUSP525L mutant, OGS-MA114 restored mitochondrial membrane potential, reduced cleaved caspase-3 levels, and improved cell viability under mitochondrial stress conditions. Furthermore, in a transgenic zebrafish model expressing mutant FUSR521C, OGS-MA114 significantly improved locomotor activity and survival while reducing cell death in the spinal cord. These findings suggest that OGS-MA114 ameliorates ALS-associated pathological phenotypes by enhancing PINK1-dependent mitophagy. Thus, pharmacological modulation of mitophagy may provide a useful basis for further investigation of ALS and -related neurodegenerative disorders.