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) cause early-onset, autosomal-recessive Parkinsons disease (PD). While previous studies showed age-related declines in dopamine release and ATP levels in Pink1-/- mice, the mechanisms remain unclear. Using a novel TH-Mito-Dendra2 transgenic mouse model to label dopaminergic neuron mitochondria, it is found that PINK1 loss leads to age-dependent deficits in mitochondrial axonal trafficking, characterized by reduced anterograde movement and increased static mitochondria in acute brain slices, which more closely mimic in vivo conditions. Pharmacological induction of reactive oxygen species (ROS) and calcium release impaired mitochondrial mobility. Pink1 knockout mice exhibited elevated mitochondrial calcium, ROS levels, and p38 MAPK hyperactivation. Treatment with p38 inhibitor SB202190 restored mitochondrial motility and increased anterograde transport. Our findings suggest that PINK1 loss disrupts mitochondrial trafficking by disturbing calcium homeostasis and ROS production via the p38 pathway, contributing to PD pathogenesis. Table of Contents O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=181 SRC="FIGDIR/small/602426v3_ufig1.gif" ALT="Figure 1"> View larger version (68K): org.highwire.dtl.DTLVardef@1352742org.highwire.dtl.DTLVardef@a48086org.highwire.dtl.DTLVardef@1f209daorg.highwire.dtl.DTLVardef@164ed23_HPS_FORMAT_FIGEXP M_FIG C_FIG Using a novel mouse model with labeled dopaminergic neuron mitochondria, Zhao J. et al. discovered age dependent disruptions in mitochondrial transport. Their research showed progressive deterioration of mitochondrial movement, characterized by reduced anterograde movement and increased static mitochondria. These changes were associated with higher oxidative stress and hyperactivation of p38 MAPK in Parkinsons disease.