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Quantitative Correlation between the Proton-carrying and Respiratory-stimulating Properties of Uncoupling Agents using Rat Liver Mitochondria

Abstract

THE observation that dinitrophenol stimulates respiration and decreases work performance1 by uncoupling oxidative phosphorylation2 has stimulated great interest in the mechanism of action of uncoupling agents. The “chemical theory” of oxidative phosphorylation proposes that uncouplers catalyse the hydrolysis of a high energy intermediate of oxidative phosphorylation (xe)3,4, although the existence of such an intermediate remains speculative. Alternatively, Mitchell's “chemiosmotic hypothesis”5 proposes that uncoupling agents facilitate proton translocation across the mitochondrial inner membrane; thus disrupting a pH gradient and membrane potential, which he has proposed to be the “proton motive force” supporting ATP synthesis. The demonstration that uncouplers accelerate the decay of pH gradients following the addition of HCl to mitochondrial suspensions, provided initial support for this mechanism of action6. Subsequent reports have demonstrated a close relationship between alteration of proton conductivity of artificial bilayer membranes and uncoupler potency7,8, although this conclusion has been disputed9,10. Nevertheless, effects on artificial membranes may not be expected to correlate absolutely with an action on mitochondria. For this reason, we have compared the proton-transporting and respiratory-releasing properties of uncoupling agents, using intact mitochondria.

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CUNARRO, J., WEINER, M. Quantitative Correlation between the Proton-carrying and Respiratory-stimulating Properties of Uncoupling Agents using Rat Liver Mitochondria. Nature 245, 36–37 (1973). https://doi.org/10.1038/245036a0

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