Perfluorooctane sulfonate induces ferroptosis-dependent non-alcoholic steatohepatitis via autophagy-MCU-caused mitochondrial calcium overload and MCU-ACSL4 interaction

• Published in: Ecotoxicology and environmental safety 2024-07, Vol.280, p.116553, Article 116553
• Main Authors: Ren, Siyu, Wang, Jianyu, Dong, Zhanchen, Li, Jixun, Ma, Yu, Yang, Ying, Zhou, Tian, Qiu, Tianming, Jiang, Liping, Li, Qiujuan, Sun, Xiance, Yao, Xiaofeng
• Format: Article
• Language: English
• Subjects: Alkanesulfonic Acids - toxicity; Animals; Autophagy; Autophagy - drug effects; Calcium - metabolism; Calcium Channels - metabolism; Cell Line; Coenzyme A Ligases - metabolism; Ferroptosis; Ferroptosis - drug effects; Fluorocarbons - toxicity; Hepatocytes - drug effects; Humans; Male; Mice; Mice, Inbred C57BL; Mitochondria - drug effects; Mitochondria - metabolism; Mitochondrial calcium uniporter; Non-alcoholic Fatty Liver Disease - chemically induced; Non-alcoholic Fatty Liver Disease - pathology; Nonalcoholic steatohepatitis; Perfluorooctane sulfonate
• ISSN: 0147-6513; 1090-2414; 1090-2414
• DOI: 10.1016/j.ecoenv.2024.116553

The incidence of nonalcoholic steatohepatitis (NASH) is related with perfluorooctane sulfonate (PFOS), yet the mechanism remains ill-defined. Mounting evidence suggests that ferroptosis plays a crucial role in the initiation of NASH. In this study, we used mice and human hepatocytes L-02 to investigate the role of ferroptosis in PFOS-induced NASH and the effect and molecular mechanism of PFOS on liver ferroptosis. We found here that PFOS caused NASH in mice, and lipid accumulation and inflammatory response in the L-02 cells. PFOS induced hepatic ferroptosis in vivo and in vitro, as evidenced by the decrease in glutathione peroxidase 4 (GPX4), and the increases in cytosolic iron, acyl-CoA synthetase long-chain family member 4 (ACSL4) and lipid peroxidation. In the PFOS-treated cells, the increases in the inflammatory factors and lipid contents were reversed by ferroptosis inhibitor. PFOS-induced ferroptosis was relieved by autophagy inhibitor. The expression of mitochondrial calcium uniporter (MCU) was accelerated by PFOS, leading to subsequent mitochondrial calcium accumulation, and inhibiting autophagy reversed the increase in MCU. Inhibiting mitochondrial calcium reversed the variations in GPX4 and cytosolic iron, without influencing the change in ACSL4, induced by PFOS. MCU interacted with ACSL4 and the siRNA against MCU reversed the changes in ACSL4，GPX4 and cytosolic iron systemically. This study put forward the involvement of hepatic ferroptosis in PFOS-induced NASH and identified MCU as the mediator of the autophagy-dependent ferroptosis. [Display omitted] •PFOS induces hepatic ferroptosis in vivo and in vitro.•PFOS-related NASH is mediated by autophagy-dependent ferroptosis.•The increase in MCU is induced by autophagy, causing mitochondrial Ca2+ overload.•ACSL4 interacts with MCU, and PFOS accelerates ACSL4-MCU interaction.•MCU mediates autophagy-dependent ferroptosis under PFOS exposure.