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<p>Mutations in <i>PTEN-induced putative kinase 1</i> (<i>PINK1</i>) cause early-onset, autosomal-recessive Parkinson’s disease (PD). While previous studies have shown age-related declines in dopamine release and ATP levels in <i>Pink1</i><sup><i>−/−</i></sup> mice, the mechanisms remain unclear. Using a novel TH-Mito-Dendra2 transgenic mouse model to label dopaminergic neuron mitochondria, we show that PINK1 loss leads to age-dependent defects in axonal mitochondrial trafficking in acute brain slices. These deficits are characterized by reduced anterograde transport and increased mitochondrial stalling. Pharmacological induction of reactive oxygen species (ROS) and calcium release impaired mitochondrial mobility. Consistent with this, <i>Pink1</i> knockout mice exhibited elevated mitochondrial calcium, oxidation levels, and p38 MAPK hyperactivation. Treatment with a calcium channel blocker and p38 inhibitor SB202190 restored mitochondrial motility and increased anterograde transport. Together, our findings suggest that PINK1 loss disrupts mitochondrial trafficking by disturbing calcium and redox homeostasis via the p38 pathway, contributing to PD pathogenesis.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年6月24日

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  • Jingyu Zhao,
  • Yuanxin Chen,
  • Lianteng Zhi,
  • Qing Xu,
  • Juan Subiry,
  • Zebang Chen,
  • Shiquan Cui,
  • Hui Zhang,
  • Chenjian Li

摘要

Mutations in PTEN-induced putative kinase 1 (PINK1) cause early-onset, autosomal-recessive Parkinson’s disease (PD). While previous studies have shown 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, we show that PINK1 loss leads to age-dependent defects in axonal mitochondrial trafficking in acute brain slices. These deficits are characterized by reduced anterograde transport and increased mitochondrial stalling. Pharmacological induction of reactive oxygen species (ROS) and calcium release impaired mitochondrial mobility. Consistent with this, Pink1 knockout mice exhibited elevated mitochondrial calcium, oxidation levels, and p38 MAPK hyperactivation. Treatment with a calcium channel blocker and p38 inhibitor SB202190 restored mitochondrial motility and increased anterograde transport. Together, our findings suggest that PINK1 loss disrupts mitochondrial trafficking by disturbing calcium and redox homeostasis via the p38 pathway, contributing to PD pathogenesis.