Mitochondria damage and ferroptosis involved in Ni-induced hepatotoxicity in mice.

[Display omitted] • High doses of NiCl 2 induces liver damage in mice. • NiCl 2 induces mitochondrial damage in the liver of mice. • NiCl2 induce ferroptosis by inducing mitochondrial damage and down-regulating ferritin. Nickel (Ni) is an environmental toxicant that can cause toxic damage to humans and animals. Although the hepatotoxicity of Ni has been confirmed, its precise mechanism is still unclear. In this study, the results showed that nickel chloride (NiCl 2)-treatment could induce mice hepatotoxicity including hepatic histopathological alterations and up-regulation of serum AST and ALT. According to the results, NiCl 2 increased malondialdehyde (MDA) production while reducing total antioxidant capacity (T-AOC) activity and glutathione (GSH) content. Additionally, NiCl 2 induced mitochondrial damage which was featured by increase in mitochondrial ROS (mt-ROS) and mitochondrial membrane potential (MMP) depolarization. The mitochondrial respiratory chain complexes I-IV and ATP content were decreased in the liver of NiCl 2 -treated mice. Meanwhile, NiCl 2 caused hepatic ferroptosis accompanied by increased iron content in the liver and up-regulation of cyclooxygenase 2 (COX-2) protein and mRNA expression levels, down-regulation of glutathione eroxidase 4 (GPX4), ferritin heavy chain 1 (FTH1) and nuclear receptor coactivator 4 (NCOA4) protein and mRNA expression levels. Altogether, the above mentioned results indicate that NiCl 2 treatment may induce hepatic damage through mitochondrial damage and ferroptosis. [ABSTRACT FROM AUTHOR]