Loss of PINK1 causes age-dependent mitochondrial trafficking deficits in nigrostriatal dopaminergic neurons through aberrant activation of p38 MAPK

Mutations in PTEN-induced putative kinase 1 ( PINK1 ) gene cause early-onset, autosomal-recessive familial inherited Parkinson’s disease (PD). Previous studies have shown age-related declines in dopamine release and ATP levels in the striatum of Pink1 ^-/- mice, but the underlying mechanisms remain unclear. While the role of PINK1 in mitochondrial transport has been studied in cell culture and Drosophila , its impacts on axonal transport in dopaminergic neurons and the consequent synaptic and axonal degeneration in vivo remain critical questions that warrant further investigation. In this study, we developed a TH-mito-Dendra2 transgenic mouse model to label mitochondria in dopaminergic neurons with Dendra2 protein. Using this model, we found that loss of PINK1 causes age-dependent deficits in mitochondrial axonal trafficking, with reduced anterograde movement and increased static mitochondria in acute brain slices. Inducing ROS and calcium release pharmacologically impaired mitochondrial motility, and Pink1 ^-/- mice exhibited elevated mitochondrial calcium and ROS levels. Furthermore, Pink1 ^-/- mice showed p38 MAPK hyperactivation and reduced Miro1 expression. Treatment with the p38 inhibitor SB202190 restored mitochondrial motility and increased anterograde transport. Taken together, our findings suggest that loss of PINK1 disrupts mitochondrial trafficking by disturbing calcium homeostasis and ROS production via the p38 pathway for PD pathogenesis.