Fatty Acids Induce Chloride Permeation in Rat Liver Mitochondria by Activation of the Inner Membrane Anion Channel (IMAC)

Abstract

The inner membrane of freshly isolated mammalian mitochondria is poorly permeable to Cl⁻. Low, nonlytic concentrations (≤30 μM) of long-chain fatty acids or their branched-chain derivatives increase permeation of Cl⁻ as indicated from rapid large-scale swelling of mitochondria suspended in slightly alkaline KCl medium (supplemented with valinomycin). Myristic, palmitic, or 5-doxylstearic acid are powerful inducers of Cl⁻ permeation, whereas lauric, phytanic, stearic, or 16-doxylstearic acid stimulate Cl⁻ permeation in a lesser extent. Fatty acid-induced Cl⁻ permeation across the inner membrane correlates well with the property of nonesterified fatty acids to release endogenous Mg²⁺ from mitochondria. Myristic acid stimulates anion permeation in a selective manner, similar as was described for A23187, an activator of the inner membrane anion channel (IMAC). Myristic acid-induced Cl⁻ permeation is blocked by low concentrations of tributyltin chloride (IC₅₀≈1.5 nmol/mg protein). Moreover, myristic acid activates a transmembrane ion current in patch-clamped mitoplasts (mitochondria with the outer membrane removed) exposed to alkaline KCl medium. This current is best ascribed to the opening of an ion channel with a single-channel conductance of 108 pS. We propose that long-chain fatty acids can activate IMAC by withdrawal of Mg²⁺ from intrinsic binding sites.