Studies on the ionophorous antibiotics. XII. Effects of ionophore lysocellin on cation distribution and respiration in mitochondria

Abstract

The effects of the ionophore lysocellin on the movements of Ca2+, Mg2+ and alkali metal cations and its effect on energy utilization by rat liver mitochondria have been investigated. At a concentration of 0.05 micrometer, lysocellin induced dissociation of membrane-bound calcium, and an apparent steady state was established across the inner membrane between energy-linked calcium accumulation and the ionophore-induced depletion of calcium. No detectable efflux of intramitochondrial Ca2+ and Mg2+ was induced by 0.05 micrometer lysocellin, but the uptake of exogenously added calcium was significantly inhibited. The ionophore augmented Mg2+ release from mitochondria induced by Ca2+ addition and also caused rapid release of K+ from mitochondria preloaded with K+ by valinomycin or monazomycin. High levels (0.5 approximately 10 micrometer of lysocellin caused massive depletion of endogenous Ca2+, Mg2+ and K+ from mitochondria, resulting in disruption of mitochondrial functions including release of state 4 respiration, stimulation of ATPase and inhibition of ADP- or DNP-stimulated respiration. Structure-activity studies with chemically modified compounds of lysocellin indicated the important role of terminal carboxylic acid and C21 hydroxyl function in the activity of the ionophore, and there is a good correlation between the effect of lysocellin on mitochondrial cation movements and its ability to complex with cations determined in an organic solvent-water two-phase partition system.