Manganese-induced PINK1 S-nitrosylation exacerbates nerve cell damage by promoting ZNF746 repression of mitochondrial biogenesis

Occupational exposure and non-occupational exposure to excessive levels of manganese (Mn) result in neuronal cell dam-age through mitochondrial dysfunction. The functional integrity of mitochondria is maintained by mitophagy and mito-chondrial biogenesis. Although Mn-induced S-nitrosylation of PTEN-induced putative kinase 1 (PINK1) can interfere with mitophagy, its effect on mitochondrial biogenesis remains unclear. In this study, we established a rat model of Mn poison-ing or manganism to examine the relationship between PINK1 S-nitrosylation and impairment of mitochondrial biogen-esis, and found that treatment with 60 mg/kg Mn induced marked neurobehavioral abnormalities in rats and significantly increased the S-nitrosylation level of PINK1. We also found that the nuclear-encoded peroxisome proliferator-activated re-ceptor gamma coactivator 1 alpha (PPARGC1A)-mediated mitochondrial biogenesis was significantly upregulated in rats treated with 15 and 30 mg/kg Mn, and downregulated in rats treated with 60 mg/kg Mn. We further investigated the role of S-nitrosylated PINK1 and its molecular mechanism in the high-dose Mn-mediated impairment of mitochondrial biogen-esis in primary cultured neurons treated with the nitric oxide synthase 2 (NOS2) inhibitor 1400 W. Our results revealed that the PPARGC1A-mediated mitochondrial biogenesis was upregulated in neurons treated with 100 mu M, but downreg-ulated in neurons treated with 200 mu M Mn, which was similar to the in vivo results. However, treatment with 1400W could effectively prevent the 200 mu M Mn-mediated impairment of mitochondrial biogenesis by suppressing nitric oxide (NO)-mediated PINK1 S-nitrosylation and rescuing Parkin-interacting substrate (PARIS, ZNF746) degradation, thereby upreg-ulating mitochondrial biogenesis via PPARGC1A. These findings demonstrated that S-nitrosylation of PINK1 and subse-quent prevention of ZNF746 degradation were crucial signaling processes involved in the Mn-mediated impairment of mitochondrial biogenesis, which might serve as an underlying mechanism of Mn-induced neurotoxicity. Furthermore, this study provided a reliable target for the prevention and treatment of manganism.

Automated summary

This study found that manganese poisoning can cause impairment of mitochondrial biogenesis. Further investigation revealed that S-nitrosylation of PINK1 and subsequent ZNF746 protein degradation are crucial signaling processes involved in the impairment of mitochondrial biogenesis caused by manganese poisoning.