Ferroptosis contributes to methylmercury-induced cytotoxicity in rat primary astrocytes and Buffalo rat liver cells

Lihua Dong, Bobo Yang, Yu Zhang, Suhua Wang, Fang Li, Guangwei Xing, Marcelo Farina, Yubin Zhang, Kwaku Appiah-Kubi, Alexey A. Tinkov, Michael Aschner, Haifeng Shi, Tingting Liu, Rongzhu Lu

Research output: Contribution to journalArticlepeer-review

Abstract

Objective: Ferroptosis is an iron-dependent nonapoptotic form of cell death, characterized by iron accumulation and lipid peroxidation. However, the role of ferroptosis in methylmercury (MeHg)-induced cytotoxicity has yet to be fully characterized. The purpose of this study was to investigate the role of ferroptosis in MeHg-induced cytotoxicity in both brain and liver cells. Methods: The effects of MeHg on cell viability, cytotoxicity, intracellular iron content, reduced glutathione (GSH) content, ferroptosis-related proteins, cytosolic and lipid reactive oxygen species (ROS) generation were determined in rat primary astrocytes (AST) and Buffalo Rat Liver (BRL) cells in the absence or presence of the ferroptosis inhibitors deferoxamine (DFO) or ferrostatin-1 (Fer-1). Results: MeHg treatment decreased cell viability and increased cytotoxicity in AST and BRL cells. MeHg induced ferroptosis in AST and BRL cells was reflected by increased cytosolic ROS, lipid ROS and intracellular iron content, all of which were inhibited by the ferroptosis inhibitors DFO and/or Fer-1. MeHg inhibited the expression of ferritin heavy chain 1 (FTH1). Furthermore, MeHg treatment decreased the expression of glutathione peroxidase 4 (GPx4) without altering solute carrier family 7 member 11 (SLC7A11). DFO and Fer-1 significantly increased the expression of GPx4, yet had no effect on SLC7A11 upon MeHg treatment. Conclusions: Our novel results are consistent with ferroptosis as a key event mediating MeHg-induced toxicity, inhibiting GPx4 in AST and BRL cells. Ferroptosis may offer a new target for attenuating MeHg-induced toxic injury.

Original languageEnglish (US)
Pages (from-to)228-236
Number of pages9
JournalNeurotoxicology
Volume90
DOIs
StatePublished - May 2022

Keywords

  • Ferritin heavy chain 1
  • Ferroptosis
  • Glutathione peroxidase 4
  • Methylmercury

ASJC Scopus subject areas

  • Neuroscience(all)
  • Toxicology

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