[Effect of membrane permeability transition on hepatocyte apoptosis of the microcystin-LR-induced mice]
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Updated: Jun 3, 2026
An Intestine/Liver Microphysiological System for Drug Pharmacokinetic and Toxicological Assessment
Published on: December 3, 2020
Jing Liu1, Yinna Wei, Pingping Shen
1National Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing 210093, China.
Objective:
From the view of membrane permeability transition (MPT) to study the mechanism of microcystin (MCs) inducing hepatocyte apoptosis in mice, and unclose the function of reactive oxygen species (ROS) in this process.
Methods:
Use the mice as the model animals and randomly divide them into 4 groups. Group A were injected with physiological saline peritoneal in abdomen, while group B were injected with MC-LR 50 microg/kg bw in abdomen, group C were injected with the MPT inhibitor, Cyclosporin A (CsA) 100 mg/kg bw, in abdomen, and group D were injected with CsA 100 mg/kg bw in abdomen, and then after 1 hour, with MC-LR 50 microg/kg bw. Separate the mice serum, measure AST and ALT concentrations. Separate the mice livers and then perform the mice liver DNA segment detection, mitochondrion membrane potential level measurement, ROS level measurement and western blotting measurement at the expression level of Bcl-2.
Results:
In the group treated with 50 microg/kg bw MC-LR, in the serum, the AST and ALT levels rised. In the liver cells, there was significant DNA ladder, the the expression of Bcl-2 at the level of protein increased, mitochondrion membrane potential level of liver tissue decreased, and the ROS level in the tissue increased. In the group treated with 100 mg/kg bw CsA, every index of the mice has no significant change. While with the pre-treatment of 100 mg/kg bw CsA, and then with 50 microg/kg bw MC-LR in abdomen, the DNA ladder in the liver tissue can be removed, and the serum AST and ALT concentrations, the expression of liver Bcl-2 protein, the mitochondrion membrane potential level and ROS level were conversed to the levels of the control group.
Conclusion:
In vivo the inhibition of transition channel of mitochondrion membrane can inhibit the hepatocyte apoptosis induced by MC-LR.
Insights
Microcystin-LR (MC-LR) induces liver cell apoptosis by disrupting mitochondrial function and increasing reactive oxygen species (ROS). Inhibiting mitochondrial permeability transition (MPT) with Cyclosporin A (CsA) prevents MC-LR-induced hepatocyte apoptosis in vivo.
Area of Science:
- Hepatology
- Toxicology
- Mitochondrial Biology
Background:
- Microcystins (MCs) are potent hepatotoxins implicated in liver damage and apoptosis.
- The precise mechanisms by which MCs induce hepatocyte apoptosis, particularly the role of mitochondrial dysfunction, require further elucidation.
- Reactive oxygen species (ROS) are suspected mediators in various toxicological processes, including apoptosis.
Purpose of the Study:
- To investigate the role of mitochondrial permeability transition (MPT) in MC-LR-induced hepatocyte apoptosis in a mouse model.
- To elucidate the involvement of ROS in the apoptotic pathway triggered by MC-LR exposure.
- To assess the potential of MPT inhibition as a therapeutic strategy against MC-LR toxicity.
Main Methods:
- A mouse model was utilized, with animals divided into four groups: saline control, MC-LR exposure, MPT inhibitor Cyclosporin A (CsA) treatment, and CsA pre-treatment followed by MC-LR exposure.
- Biochemical markers of liver injury (AST, ALT), DNA fragmentation, mitochondrial membrane potential, ROS levels, and Bcl-2 protein expression were analyzed.
- Western blotting was employed to quantify Bcl-2 expression levels.
Main Results:
- MC-LR administration led to elevated serum AST and ALT levels, increased DNA laddering, decreased mitochondrial membrane potential, and elevated ROS levels in liver tissue.
- MC-LR exposure also resulted in altered expression of Bcl-2, a key apoptosis regulator.
- Pre-treatment with CsA significantly attenuated MC-LR-induced liver injury, DNA damage, and normalized mitochondrial function and ROS levels, suggesting a protective effect.
Conclusions:
- Inhibition of the mitochondrial membrane transition pore effectively prevents MC-LR-induced hepatocyte apoptosis in vivo.
- This study highlights MPT and ROS as critical components in the pathogenesis of MC-LR hepatotoxicity.
- Targeting MPT represents a promising therapeutic avenue for managing microcystin poisoning.
