Nitration of Drp1 provokes mitophagy activation mediating neuronal injury in experimental autoimmune encephalomyelitis.

Active autophagy/mitophagy could mediate neurodegeneration and motor disabilities in multiple sclerosis (MS). Mitochondrial recruitment of dynamin-related protein 1 (Drp1) is a crucial step to initiate mitophagy. Peroxynitrite (ONOO) could be a player in MS pathology but the mechanisms remain unknown. We used animal model of experimental autoimmune encephalomyelitis (EAE) and tested whether ONOO mediates Drp1 assembly in mitochondria for mitophagy and aggravates MS pathology. We found that autophagy/mitophagy activation was coincidently increased with axonal damage, apoptosis and disease progression in active EAE mice, which were remarkably attenuated by mitochondrial division/mitophagy inhibitor Mdivi-1. Importantly, increased ONOO production was companied with Drp1 mitochondrial recruitment, PINK1/Parkin-mediated mitophagy, axonal degeneration and neuronal cell death, which were reversed by peroxynitrite decomposition catalyst (PDC). Furthermore, ONOO production induced Drp1 nitration, promoted Drp1 assembly and mitochondrial recruitment for mitophagy activation, contributing to the EAE pathology. Together, we conclude that ONOO serves as a key mediator in Drp1 nitration modification and assembly for facilitating mitophagy activation. Targeting ONOO-mediated Drp1 assembly and mitochondrial recruitment could be an important therapeutic strategy for multiple sclerosis treatment.