Manganese induces S-nitrosylation of PINK1 leading to nerve cell damage by repressing PINK1/Parkin-mediated mitophagy

Chronic exposure to excess manganese (Mn) causes neurotoxicity, which is characterized by Parkinson-like symptoms and referred to as manganism. In the last few decades, mitochondrial damage and subsequent energy failure have been reported to be important mechanisms of Mn toxicity, yet how Mn causes mitochondrial damage remains largely unknown. Here, we demonstrated that Mn induced S-nitrosation of phosphatase and tensin homolog (PTEN)-induced putative kinase 1 (PINK1), a master regulator in the mitophagy pathway, results in dysregulation of mitophagy and nerve cell injury in the rat striatum. We cultured primary neurons and used 1400 W, a potent and selective inducible nitric oxide synthase (iNOS) inhibitor, as an intervention to verify the precise mechanism of Mn-induced dysregulation of mitophagy. We demonstrated that Mn-induced S-nitrosylation of PINK1 decreased the phosphorylated level of parkin RBR E3 ubiquitin-protein ligase (Parkin), as well as the translocation of Parkin to damaged mitochondria, which led to the accumulation of damaged mitochondria and mitochondrial-mediated apoptosis. Our findings indicated the unusual connection between nitrative stress and mitochondrial dysfunction in Mn-induced neurotoxicity. These data highlight the role of S-nitrosation of PINK1 in Mn-induced dysregulation of mitophagy and provide a reliable target for the development of specific drugs and the early treatment of manganism, which has important theoretical and practical significance.