Proton permeability and the regulation of potassium permeability in mitochondria by uncoupling agents

Abstract

The addition of agents that uncouple electron transfer from energy conservation (uncouplers) to state 4 mitochondria causes the following ion movements: K⁺ is extruded from the mitochondria in association with phosphate and possibly other anions, but not H⁺. Endogenous Ca⁺⁺ is extruded from the mitochondria, and H⁺ moves in to counter-balance the Ca⁺⁺ movement; some phosphate movement may be associated with Ca⁺⁺ extrusion. The rate and extent of K⁺ extrusion induced by uncoupler is dependent on the concentrations of external phosphate and divalent ions. Phosphate induces K⁺ extrusion, while Mg⁺⁺ and Mn⁺⁺ inhibit it. TheV _max of K⁺ transport is 300 μmoles K⁺/g protein per min. The K _m for FCCP-induced potassium extrusion is 0.25 μM at pH 7.4. The inhibitory effect of Mg⁺⁺ is noncompetitive with respect to uncoupler concentration but competitive with respect to phosphate concentration. The experimental evidence does not support the existence of high H⁺ permeability in the presence of uncoupler. A correlation is observed between the rate of K⁺ extrusion and the energy reserves supplied from the high energy intermediate. The action of uncoupler in inducing K⁺ permeability is considered to arise through its action in depleting the energy reserves of mitochondria rather than through a specific activating effect of permeability by the uncoupler itself. The relationship of membrane potential to regulation of K⁺ permeability is discussed.