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Updated: Oct 19, 2026
Assessment of Open Probability of the Mitochondrial Permeability Transition Pore in the Setting of Coenzyme Q Excess
Published on: June 1, 2022
Role of mitochondrial membrane permeability transition in p-hydroxybenzoate ester-induced cytotoxicity in rat
1Department of Toxicology, Tokyo Metropolitan Research Laboratory of Public Health, Japan. yoshio@tokyo-eiken.go.jp
Abstract:
The relationship between mitochondrial membrane permeability transition (MPT) and the toxic effects of the alkyl esters of p-hydroxybenzoic acid (parabens) has been studied in mitochondria and hepatocytes isolated from rat liver. MPT has been proposed as a common final pathway in acute cell death through mitochondrial dysfunction. In isolated mitochondria, propyl-paraben (0.1 to 0.5 mM) in the presence of Ca2+ (50 microM) elicited a concentration-dependent induction of mitochondrial swelling dependent on MPT. This was prevented by pretreatment with a specific inhibitor of MPT, cyclosporin A (0.2 microM). For the other parabens tested, the induction of MPT depended on the relative elongation of alkyl side-chains in their molecular structure and was associated with the partition coefficients. In contrast, the induction caused by p-hydroxybenzoic acid was more potent than that of methyl- or ethyl-paraben. The pretreatment of freshly isolated hepatocytes with cyclosporin A (5 microM) and trifluoperazine (10 microM), which inhibit MPT in a synergistic manner, partially but not completely prevented propyl-paraben (1 mM; plus diazinon, 100 microM)-induced cell death, ATP loss, and decreased mitochondrial membrane potential. These results suggest that the onset of paraben-induced cytotoxicity is linked to mitochondrial failure dependent upon induction of MPT accompanied by the mitochondrial depolarization and depletion of cellular ATP through uncoupling of oxidative phosphorylation.
Insights
Parabens induce cell death by disrupting mitochondrial function. This study shows parabens trigger mitochondrial membrane permeability transition (MPT), leading to cell death, ATP loss, and decreased mitochondrial membrane potential.
Area of Science:
- Biochemistry
- Toxicology
- Cell Biology
Background:
- Mitochondrial membrane permeability transition (MPT) is a critical event in cell death pathways.
- Parabens, commonly used preservatives, have demonstrated toxic effects.
- Understanding the mechanism of paraben toxicity is crucial for risk assessment.
Purpose of the Study:
- To investigate the role of MPT in paraben-induced cytotoxicity.
- To elucidate the relationship between paraben structure and MPT induction.
- To examine the effects of MPT inhibition on paraben toxicity in hepatocytes.
Main Methods:
- Isolated rat liver mitochondria and hepatocytes were used.
- MPT induction was assessed by mitochondrial swelling.
- Cell viability, ATP levels, and mitochondrial membrane potential were measured.
- Inhibitors of MPT, cyclosporin A and trifluoperazine, were employed.
Main Results:
- Propyl-paraben induced MPT in isolated mitochondria in a concentration-dependent manner.
- MPT induction correlated with paraben alkyl chain length and partition coefficients.
- p-hydroxybenzoic acid was more potent than methyl- or ethyl-paraben in inducing MPT.
- MPT inhibitors partially protected hepatocytes from propyl-paraben-induced cell death and mitochondrial dysfunction.
Conclusions:
- Paraben-induced cytotoxicity is linked to MPT induction and subsequent mitochondrial dysfunction.
- MPT leads to mitochondrial depolarization and ATP depletion via uncoupling of oxidative phosphorylation.
- These findings highlight MPT as a key mechanism in paraben toxicity.
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