Parkin-mediated mitophagy protects against aluminum trichloride-induced hippocampal apoptosis in mice via the mtROS-NLRP3 pathway

• Published in: Ecotoxicology and environmental safety Vol. 264; p. 115459
• Main Authors: Huo, Siming, Zhang, Xuliang, Xu, Jinyu, Zhang, Jian, Du, Jiayu, Li, Bo, Song, Miao, Shao, Bing, Li, Yanfei, Xu, Feibo
• Format: Journal Article
• Language: English
• Published: Elsevier Inc 01-10-2023; Elsevier
• Subjects: Aluminum; Mitochondrial reactive oxygen species; Mitophagy; Neurodegenerative diseases; NLRP3-inflammasome; Parkin; Bcl-2; TdT; CytC; Aluminum; Al; Mitophagy; TUNEL; AlCl3; NLRP3; Mitochondrial reactive oxygen species; mtROS; LC3; H.E; MWM; AD; Neurodegenerative diseases; SOD2; IL-1β; p62; Parkin-; MMP; PINK1; PD; IL-18; Bax; Caspase1; NLRP3-inflammasome; Caspase3; NDs; ATP; Parkin
• ISSN: 0147-6513; 1090-2414
• DOI: 10.1016/j.ecoenv.2023.115459

Aluminum is a neurotoxic food contaminant. Aluminum trichloride (AlCl3) causes hippocampal mitochondrial damage, leading to hippocampal injury. Damaged mitochondria can release mitochondrial reactive oxygen species (mtROS) and activate nucleotide-binding oligomerization domain-like receptor-containing 3 (NLRP3) inflammasomes and apoptosis. E3 ubiquitin ligase PARK2 (Parkin)-mediated mitophagy can attenuate mitochondrial damage. However, the role of mitophagy in AlCl3-induced mice hippocampal damage and its regulatory mechanism remain elusive. First, C57BL/6 N mice were treated with 0, 44.825, 89.65, and 179.3 mg/kg body weight AlCl3 drinking water for 90 d. Apoptosis, NLRP3-inflammasome activation and mitochondrial damage were increased in AlCl3-induced hippocampal damage. In addition, Parkin-mediated mitophagy peaked in the middle-dose group and was slightly attenuated in the high-dose group. Subsequently, we used wild-type and Parkin knockout (Parkin-/-) mice to investigate the AlCl3-induced hippocampal damage. The results showed that Parkin-/- inhibited mitophagy, and aggravated AlCl3-induced mitochondrial damage, NLRP3-inflammasome activation, apoptosis and hippocampal damage. Finally, we administered MitoQ (mtROS inhibitor) and MCC950 (NLRP3 inhibitor) to AlCl3-treated Parkin-/- mice to investigate the mechanism of Parkin-mediated mitophagy. The results showed that inhibition of mtROS and NLRP3 attenuated hippocampal NLRP3-inflammasome activation, apoptosis, and damage in AlCl3-treated Parkin-/- mice. These findings indicate that Parkin-mediated mitophagy protects against AlCl3-induced hippocampal apoptosis in mice via the mtROS-NLRP3 pathway.
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•Aluminum trichloride (AlCl3) activated Parkin-mediated mitophagy in the hippocampus.•Parkin-mediated mitophagy protected against AlCl3-induced hippocampal damage.•Parkin-mediated mitophagy played protective role via the mtROS-NLRP3-apoptosis axis.