Mechanism of uncoupling in mitochondria: uncouplers as ionophores for cycling cations and protons.

Classical uncouplers such as 2,4-dinitrophenol have been shown to be ionophores with the capability for transporting monovalent or divalent cations with equal efficiency. The conditions appropriate for the maximal expression of this ionophoric capability have been explored. Two critical factors are the polarity of the organic phase and the pH of the aqueous phase that is equilibrated with the organic phase. The demonstrated cationic ionophoric capability of uncouplers, taken in conjunction with the known ability of uncouplers to cycle protons across a membrane phase, provides the experimental basis for the thesis that uncoupling of electron flow from ATP synthesis via classical uncouplers involves the substitution of one coupled process by another. Uncoupling thus reduces to the replacement of one driven reaction (ATP synthesis) by the driven reaction (cyclical transport) mediated by the uncoupler.