GPX4 degradation via chaperone-mediated autophagy contributes to antimony-triggered neuronal ferroptosis

• Published in: Ecotoxicology and environmental safety Vol. 234; p. 113413
• Main Authors: Yu, Shali, Li, Zhijie, Zhang, Qin, Wang, Rui, Zhao, Zixuan, Ding, Wenjie, Wang, Fengxu, Sun, Chuan, Tang, Juan, Wang, Xiaoke, Zhang, Hongbing, Huang, Rongrong, Wu, Qiyun, Jiang, Junkang, Zhao, Xinyuan
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier Inc 01.04.2022; Elsevier
• Subjects: Antimony; Chaperone-mediated autophagy; Ferroptosis; GPX4 degradation; Neurotoxicity; Antimony; Ferroptosis; Neurotoxicity; GPX4 degradation; Chaperone-mediated autophagy
• ISSN: 0147-6513; 1090-2414; 1090-2414
• DOI: 10.1016/j.ecoenv.2022.113413

Exposure to antimony (Sb), recently identified as a nerve pollutant, can result in neuron damage; but, associated-neurotoxicological mechanisms were still not clear. Herein, we assessed the role of ferroptosis in Sb-mediated neurotoxicity and clarified the underlying mechanism. Following Sb exposure, ferroptosis was significantly promoted in vivo and in vitro. Moreover, following use of ferrostatin-1 (fer-1) to inhibit ferroptosis, Sb-induced ferroptosis in PC12 cells was effectively attenuated. Sb accelerated lysosomal transport and subsequent degradation of glutathione peroxidase 4 (GPX4), resulting in ferroptosis. Furthermore, chaperone-mediated autophagy (CMA) was activated following treatment with Sb, while inhibition of CMA by lysosomal associated protein 2 A (LAMP2A) knockdown attenuated Sb-induced GPX4 degradation. Sb treatment also increased expression of the chaperones heat shock cognate protein 70 (HSC70) and heat shock protein 90 (HSP90) and the lysosome receptor LAMP2A, and increased binding of HSP90, HSC70, and LAMP2A with GPX4 was observed, indicating increased formation of the chaperone-GPX4 complex. Finally, GPX4 overexpression significantly protected PC12 cells from activation of Sb-stimulated ferroptosis and subsequent cytotoxicity. Collectively, our results provide a original mechanism by which Sb triggers neurotoxicity, to concluded that Sb stimulates neuronal ferroptosis through CMA-mediated GPX4 degradation. [Display omitted]