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Multi-parameter Measurement of the Permeability Transition Pore Opening in Isolated Mouse Heart Mitochondria
Published on: September 7, 2012
Induction of the mitochondrial permeability transition in vitro by short-chain carboxylic acids
C M Palmeira1, M I Rana, C B Frederick
1Department of Biochemistry and Molecular Biology, University of Minnesota School of Medicine, Duluth 55812, USA.
Abstract:
We recently reported that acrylic acid (AA) induces the MPT in vitro, which we suggested might be a critical event in the acute inflammatory and hyperplastic response of the olfactory epithelium. The purpose of the present investigation was to determine if induction of the MPT is a general response to short-chain carboxylic acids or if there are critical physical chemical parameters for this response. Freshly isolated rat liver mitochondria were incubated in the presence of varying concentrations of selected carboxylic acids. All of the acids that we tested caused a concentration-dependent induction of the MPT, which was blocked by cyclosporine A. Although the C4 carboxylic acids were slightly more potent than the C5 acids, there was no correlation with the degree of saturation, the octanol/water coefficient (log P), or the dissociation constant (pK(a)) of the acids that we tested. We conclude that induction of the MPT in vitro is a general response to short-chain carboxylic acids having a pK(a) of 4 to 5.
Insights
Short-chain carboxylic acids, including acrylic acid, generally induce the mitochondrial permeability transition (MPT) in vitro. This effect is observed for acids with a pKa of 4 to 5 and is blocked by cyclosporine A.
Area of Science:
- Biochemistry
- Toxicology
- Cell Biology
Background:
- Acrylic acid (AA) was previously shown to induce mitochondrial permeability transition (MPT) in vitro.
- This MPT induction was hypothesized to be crucial for acute inflammatory and hyperplastic responses in the olfactory epithelium.
Purpose of the Study:
- To investigate whether MPT induction is a general response to short-chain carboxylic acids.
- To identify critical physicochemical parameters governing MPT induction by these acids.
Main Methods:
- Incubation of freshly isolated rat liver mitochondria with varying concentrations of selected carboxylic acids.
- Assessment of MPT induction and its inhibition by cyclosporine A.
Main Results:
- All tested carboxylic acids induced MPT in a concentration-dependent manner.
- Cyclosporine A effectively blocked the MPT induction.
- No significant correlation was found between MPT induction potency and saturation, octanol/water coefficient (log P), or dissociation constant (pKa), except for the general pKa range.
Conclusions:
- MPT induction in vitro is a general response to short-chain carboxylic acids.
- The critical factor for MPT induction appears to be the pKa of the carboxylic acid, specifically within the range of 4 to 5.
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