DLP1‐Dependent Mitochondrial Fragmentation Mediates 1‐methyl‐4‐phenylpyridinium (MPP + ) Toxicity in Neurons

Selective degeneration of nigrostriatal dopaminergic neurons in Parkinson disease (PD) could be modeled by the administration of MPP + . Mitochondrial dysfunction represents a critical event in the pathogenesis of PD, and abnormal mitochondrial dynamics is increasingly implicated in PD. In this study, we investigated the effect of MPP + on mitochondrial dynamics and its temporal/causal relationship with other toxic effects induced by MPP + by fluorescence time‐lapse microscopy. In SH‐SY5Y cells, MPP + causes a rapid and biphasic increase in mitochondrial fragmentation which could be completely blocked by genetic inactivation of DLP1. While blockage of mitochondrial fragmentation partially rescued ATP decline and increased [Ca 2+ ] i , it almost completely prevented MPP + ‐induced increased ROS production, loss of mitochondrial membrane potential, enhanced autophagy, and cell death. Thiol antioxidant NAC, or glutamate receptor antagonist D‐AP5, could also partially alleviate MPP + ‐induced mitochondrial fragmentation. We further demonstrated that MPP + also elicits rapid mitochondrial fragmentation in primary cortical neurons. Overall, our data suggest that DLP1‐dependent mitochondrial fragmentation plays a crucial role in mediating MPP + ‐induced mitochondria abnormalities and cellular dysfunction. Supported by NIH R21NS071184 and American Parkinson Disease Association.