Manganese-induced alpha-synuclein overexpression aggravates mitochondrial damage by repressing PINK1/Parkin-mediated mitophagy

Chronic manganese (Mn) exposure is related to elevated risks of neurodegenerative diseases, and mitochondrial dysfunction is considered a critical pathophysiological feature of Mn neurotoxicity. Although previous research has demonstrated Mn-induced alpha-synuclein (alpha-Syn) overexpression, the role of alpha-Syn in mitochondrial dysfunction remains unclear. Here, we used Wistar rats and human neuroblastoma cells (SH-SY5Y cells) to elucidate the molecular mechanisms underlying how alpha-Syn overexpression induced by different doses of Mn (15, 30, and 60 mg/kg) results in mitochondrial dysfunction. We found that Mn-induced neural cell injury was associated with mitochondrial damage. Furthermore, Mn upregulated alpha-Syn protein levels and increased the interaction between alpha-Syn and mitochondria. We then used a lentivirus vector containing alpha-Syn shRNA to examine the effect of Mn-induced alpha-Syn protein on PINK1/Parkin-mediated mitophagy in SH-SY5Y cells. Our data demonstrated that the knockdown of alpha-Syn decreased the interaction between alpha-Syn and PINK1. The enhanced level of phosphorylated Parkin (p-Parkin) was due to the decrease of the interaction between alpha-Syn and PINK1. Moreover, the knockdown of alpha-Syn increased recruitment of p-Parkin to mitochondria. Collectively, these observations revealed that Mn-induced alpha-Syn overexpression repressed PINK1/Parkin-mediated mitophagy and exacerbated mitochondrial damage.