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Mitochondria damage and ferroptosis involved in Ni-induced hepatotoxicity in mice
Ling Wei1, Zhicai Zuo1, Zhuangzhi Yang2
1College of Veterinary Medicine, Sichuan Agricultural University, Wenjiang, Chengdu, 611130, China.
Abstract:
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 (NiCl2)-treatment could induce mice hepatotoxicity including hepatic histopathological alterations and up-regulation of serum AST and ALT. According to the results, NiCl2 increased malondialdehyde (MDA) production while reducing total antioxidant capacity (T-AOC) activity and glutathione (GSH) content. Additionally, NiCl2 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 NiCl2-treated mice. Meanwhile, NiCl2 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 NiCl2 treatment may induce hepatic damage through mitochondrial damage and ferroptosis.
Insights
Nickel chloride (NiCl2) exposure causes liver damage in mice by inducing mitochondrial dysfunction and ferroptosis. This study clarifies nickel
Area of Science:
- Environmental toxicology
- Hepatology
- Mitochondrial biology
- Cellular pathology
Background:
- Nickel (Ni) is a known environmental toxicant with confirmed hepatotoxicity.
- The precise mechanisms underlying Ni-induced liver damage remain incompletely understood.
- Investigating these mechanisms is crucial for understanding and mitigating Ni toxicity.
Purpose of the Study:
- To elucidate the molecular mechanisms by which nickel chloride (NiCl2) induces hepatotoxicity in mice.
- To investigate the roles of mitochondrial damage and ferroptosis in NiCl2-induced liver injury.
- To identify key molecular markers associated with NiCl2-induced hepatic damage.
Main Methods:
- Mice were treated with nickel chloride (NiCl2) to induce hepatotoxicity.
- Hepatic histopathology, serum enzyme levels (AST, ALT), oxidative stress markers (MDA, T-AOC, GSH), and mitochondrial function (mt-ROS, MMP, respiratory complexes, ATP) were assessed.
- Ferroptosis-related markers, including iron content, COX-2, GPX4, FTH1, and NCOA4 expression, were analyzed.
Main Results:
- NiCl2 treatment led to significant hepatic histopathological alterations and elevated serum AST and ALT levels.
- NiCl2 exposure increased lipid peroxidation (MDA) and decreased antioxidant capacity (T-AOC) and glutathione (GSH) levels.
- Mitochondrial damage, characterized by increased mt-ROS and MMP depolarization, alongside decreased respiratory chain complex activity and ATP production, was observed.
- NiCl2 induced hepatic ferroptosis, evidenced by increased liver iron content and altered expression of key regulatory proteins (COX-2, GPX4, FTH1, NCOA4).
Conclusions:
- Nickel chloride (NiCl2) induces significant hepatotoxicity in mice.
- Mitochondrial damage and ferroptosis are key mechanisms contributing to NiCl2-induced liver injury.
- The findings provide insights into the molecular pathways of nickel toxicity and potential therapeutic targets.
