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Mechanism of chronic dietary iron overload-induced liver damage in mice
1State Key Laboratory of Food Science and Technology, Nanchang University, Nanchang 330047, P.R. China.
Abstract:
Chronic iron overload may result in hepatic fibrosis and even neoplastic transformation due to a burst of reactive oxygen species (ROS). Mitochondria have been proposed to be important in the production of ROS. The purpose of this study was to investigate the role of the mitochondrial permeability transition pore (mPTP) in the burst of ROS, and to clarify the mechanism whereby ROS induced by iron overload results in hepatic damage. It has been demonstrated that when ferrocene-induced iron-overloaded mice were fed the cyclosporin A (CsA), a specific inhibitor of the mPTP, diet (10 mg/kg/day) for 50 days, liver-to-body weight ratio, serum levels of alanine transaminase (ALT) and aspartate transaminase (AST), ROS production, mitochondrial swelling, loss of mitochondrial membrane potential (Δψ) and hepatocyte apoptosis decreased. However, the total antioxidant status, including superoxide dismutase (SOD), glutathione peroxidase (GSH-Px) and catalase activities, increased. The protective effect of CsA on the liver of iron-overloaded mice may be due to inhibition of the ROS burst and a successive antioxidant effect. To the best of our knowledge, these data provide the first support for the theory that ROS-induced ROS release (RIRR) may be involved in the burst of ROS in the liver and greatly contribute to the hepatic damage initiated by iron overload.
Insights
Chronic iron overload causes liver damage via reactive oxygen species (ROS). Inhibiting the mitochondrial permeability transition pore (mPTP) with cyclosporin A protected the liver by reducing ROS, suggesting mPTP
Area of Science:
- Hepatology
- Mitochondrial Biology
- Oxidative Stress Research
Background:
- Chronic iron overload is linked to liver damage, including fibrosis and cancer, primarily through reactive oxygen species (ROS) generation.
- Mitochondria are implicated as key sites for ROS production in cellular damage.
- The mitochondrial permeability transition pore (mPTP) is a potential regulator of mitochondrial function and ROS release.
Purpose of the Study:
- To investigate the role of the mitochondrial permeability transition pore (mPTP) in the burst of ROS during iron overload.
- To elucidate the mechanism by which ROS, induced by iron overload, contribute to hepatic damage.
- To assess the therapeutic potential of mPTP inhibition in mitigating iron overload-induced liver injury.
Main Methods:
- Ferrocene-induced iron overload model in mice.
- Administration of cyclosporin A (CsA), a specific mPTP inhibitor, for 50 days.
- Assessment of liver-to-body weight ratio, serum liver enzymes (ALT, AST), ROS production, mitochondrial function (swelling, membrane potential), hepatocyte apoptosis, and antioxidant status (SOD, GSH-Px, catalase).
Main Results:
- CsA treatment significantly reduced liver-to-body weight ratio, ALT, AST levels, ROS production, mitochondrial swelling, and hepatocyte apoptosis in iron-overloaded mice.
- CsA administration increased total antioxidant status, including superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), and catalase activities.
- These findings suggest CsA's protective effect is mediated by inhibiting ROS burst and enhancing antioxidant capacity.
Conclusions:
- The mitochondrial permeability transition pore (mPTP) plays a critical role in the ROS burst associated with iron overload-induced liver damage.
- Inhibition of mPTP by CsA confers significant hepatoprotection against iron overload by mitigating oxidative stress.
- ROS-induced ROS release (RIRR) is proposed as a key mechanism contributing to hepatic damage in chronic iron overload.
