The antibiotic X-537A, already characterized as an ionophore for mono-, di-and trivalent cations across lipid membranes, inhibits ATP hydrolysis and glutamate oxidation stimulated in mitochondria by ion translocators such as monazomycin and beauvericin with the selectivity pattern: Cs + > Rb + > K + > Na + > Li+. The ionophoremediated inhibition of both ATPase and respiration is fully reversed by concentration gradients of K + and H + imposed between intra-extra mitochondrial compartments. It is not reversed by modifying the concentrations of divalent or trivalent cations in the medium. These data as well as the substrate dependance of the respiratory inhibition indicate that X-537A inhibits energy transduction primarily by mediating the translocation of protons in exchange for K + rather than by complexing divalent cations. Because of its ability to catalyze net proton transfer, concentrations of X-537A above 5 x 10 -6 M uncouple the respiratory control of intact mitochondria. At concentrations below 10-6 M, the antibiotic releases the oligomycin-induced respiratory control of submitochondrial sonic particles with an alkali ion and proton-dependent selectivity as that shown to transport ions across lipid bilayers. It also stimulates a lanthanide-sensitive, ruthenium red-insensitive uptake of Ca 2+ in submitochondrial sonic particles apparently occurring through an antiport type of electroneutral exchange diffusion of Ca 2+ out/2H + in.The antibiotic X-537A is an ion-transporting membrane carrier of the widest ionic selectivity properties known. Not only is it able to transport alkali metal, divalent and trivalent cations through natural and model membranes but protons as well (Lardy,
Carboxylic ionophores such as nigericin, dianemycin, the monensins and compounds Lilly A217 or X-537 A, stimulate an electron-transport dependent accumulation of Ca 2 § and phosphate into mitochondria. Ion accumulation is stimulated under conditions of limited Ca 2 § loading imposed by phosphate in the presence of/3-hydxoxybutyrate. Carboxylic ionophores do not affect divalent ion uptake when ~-hydroxybutyratr is 9 2+ 9 replaced for by succmate. They block Ca and phosphate accumulation when energy is provided from the hydrolysis of ATP, or from the oxidation of glutamate, c~-ketoglutarate, pyruvate or glutamate + malate. Nigericin-like antibiotics also transform the indefinite prolongation of state 3 respiration induced by Ca 2+ and phosphate on ~-hydroxybutyrate oxidation, into tightly coupled state 3 to 4 transitions. Evidence suggests 9 24 9 9 § that electrophoretlc Ca transport occurs m parallel wath proton or K carriers. The anion movements associated to Ca 2. uptake are most probably driven by the existent ApH across the mitochondrial membrane.
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