Manganese-induced alpha-synuclein overexpression aggravates mitochondrial damage by repressing PINK1/Parkin-mediated mitophagy
| Autor: | Zhuo-Fan Liu, Meng-Yu Lei, Kuan Liu, Wei Liu, Yu Deng, Jing Li, Lin Cong, Zhi-Qi Liu, Zhuo Ma, Bin Xu |
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| Rok vydání: | 2021 |
| Předmět: |
Male
animal diseases Ubiquitin-Protein Ligases PINK1 Apoptosis Mitochondrion Toxicology environment and public health Parkin 03 medical and health sciences chemistry.chemical_compound 0404 agricultural biotechnology Downregulation and upregulation Cell Line Tumor Mitophagy medicine Animals Humans heterocyclic compounds Phosphorylation Rats Wistar Gait 030304 developmental biology Alpha-synuclein Neurons 0303 health sciences Gene knockdown Manganese Chemistry Neurotoxicity 04 agricultural and veterinary sciences General Medicine medicine.disease 040401 food science nervous system diseases Cell biology Mitochondria nervous system alpha-Synuclein Female Open Field Test Protein Kinases Food Science |
| Zdroj: | Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association. 152 |
| ISSN: | 1873-6351 |
| Popis: | 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 (α-Syn) overexpression, the role of α-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 α-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 α-Syn protein levels and increased the interaction between α-Syn and mitochondria. We then used a lentivirus vector containing α-Syn shRNA to examine the effect of Mn-induced α-Syn protein on PINK1/Parkin-mediated mitophagy in SH-SY5Y cells. Our data demonstrated that the knockdown of α-Syn decreased the interaction between α-Syn and PINK1. The enhanced level of phosphorylated Parkin (p-Parkin) was due to the decrease of the interaction between α-Syn and PINK1. Moreover, the knockdown of α-Syn increased recruitment of p-Parkin to mitochondria. Collectively, these observations revealed that Mn-induced α-Syn overexpression repressed PINK1/Parkin-mediated mitophagy and exacerbated mitochondrial damage. |
| Databáze: | OpenAIRE |
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