Depletion of PINK1 mediates mitochondrial dynamics in chronic MPP+ toxicity

Mitochondrial dysfunction is implicated in sporadic and familial Parkinson disease (PD); however, the regulation of mitochondrial function during PD‐related cellular stress remains unclear. We previously found that low dose chronic MPP+ treatment over 2 weeks caused both fragmentation and enlargement of mitochondria accompanied by suppression of mtDNA encoded protein synthesis. Since the mitochondrial kinase PTEN‐induced kinase 1 (PINK1) may regulate the mitochondrial fission/fusion machinery, we hypothesized that alterations in endogenous PINK1 function contributes to chronic MPP+ induced mitochondrial dysfunction. We found that chronic MPP+ treatment caused a significant decrease in PINK1 expression, which is disproportionately greater than the reduction in other mitochondrial proteins by mitophagy. Both mitochondrial fission and fusion proteins DRP1 and MFN2 were also decreased. Over‐expressing Wt‐PINK restored levels of DRP1, MFN2 and mitochondrial transcription factor A involved in mitochondrial biogenesis. The mechanism underlying PINK1 depletion during chronic MPP+ treatment involved HSP90α phosphorylation through an ERK1/2‐dependent mechanism. Preventing ERK1/2 activation or overexpression of PINK1 ameliorated the mitochondrial fission and fusion protein imbalance in MPP+‐treated cells. In sum, depletion of endogenous PINK1 protein is implicated in chronic MPP+ induced mitochondrial dysfunction. Given that mutations in the PINK1 gene are linked to autosomal recessive parkinsonism, these data support PINK1 loss of function as a possible point of convergence for neurotoxic and genetic causes of PD. Supported in part by NIH grants NS065789 and AG026389.