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

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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 were investigated. At a concentration of 0.05 .mu.M, lysocellin induced dissociation of membrane-bound Ca, and an apparent steady state was established across the inner membrane between energy-linked Ca accumulation and the ionophore-induced depletion of Ca. No detectable efflux of intramitochondrial Ca2+ and Mg2+ was induced by 0.05 .mu.M lysocellin, but the uptake of exogenously added Ca was significantly inhibited. The ionophore augmented Mg2+ release from mitocondria induced by Ca2+ addition and also caused rapid release of K+ from mitochondria preloaded with K+ by valinomycin or monazomycin. High levels (0.5 .apprx. 10 .mu.M) 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 DPN-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 was 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 2-phase partition system.