Studies on the ionophorous antibiotics. XVI. The ionophore-mediated calcium transport and concomitant osmotic swelling of mitochondria.

Abstract

The effects of various carboxylic ionophores on divalent metal cation translocation in mitochondria have been investigated. High levels of divalent cation ionophores lysocellin and lasalocid A (10-50,uM) produced mitochondrial osmotic swelling in Ca2+ or Mg22+ medium, which was associated with an increase of cation influx. The extent of swelling was a function of both the ionophore and cation concentrations in the medium. This effect was larger in mitochondria de-energized by treatment with antimycin A and oligomycin than in respiring mitochondria. On the other hand, the monovalent cation ionophores carriomycin and etheromycin at concentrations of 50-100 am also induced mitochondrial swelling in Ca2+ medium but were ineffective in Mg2+ medium. Addition of ruthenium red reversed divalent cation ionophore-induced swelling and released Ca2+ from preloaded mitochondria.In contrast, ruthenium red increased monovalent cation ionophore-induced swelling. In a divalent cation-free medium, lysocellin and lasalocid A caused depletion of membrane-bound Ca2+ and released endogenous Ca2+ and Mg2+ from mitochondria, while carriomycin and etheromycin exerted only a limited effect. These results indicate that the divalent cation ionophores affect divalent cation distribution in mitochondria by increasing both influx and efflux of the cations through the inner membrane.Carboxylic ionophores catalyze an electroneutral exchange of cations for H+ across biological membranes and thereby selectively alter membrane permeability to cations.2,3) These compounds have served as useful tools for studying the molecular mechanism of both cation transport systems and cation-dependent biological processes.4-6) In mitochondria, these antibiotics cause depletion of intramitochondrial alkali and alkaline earth metal cations and induce a secondary release of anions, thereby inhibiting mitochondrial energy transducing reactions.'-9) These compounds, therefore, are considered to mimic naturally occurring cation/H+ antiport in the mitochondrial inner membrane and cause a net extrusion of cations.2,10) On the other hand, it is known that the neutral ionophores such as valinomycin and synthetic ligands, which form positively-charged complexes with cations, promote the electrophoretic influx of cations by mitochondria in response to electrical potential gradient on the inner membrane.11,12)We have previously reported13) that a monovalent cation ionophore etheromycin (CP-38295 or T-40517) and the calcium ionophores lasalocid A and lysocellin mobilized the intracellular calcium of blood platelets, thus inducing the secretion reaction and aggregation. Since etheromycin is thought to exert this activity through increasing alkali metal cation movement, these findings led us to consider a probable regulatory role of monovalent cations on calcium metabolism as proposed by LOWE et at.14)In the present study, by the use of ionophores with various cation selectivity profiles, we show * To whom inquiries should be directed .

Selective toxicity of antibacterial agents—still a valid concept or do we miss chances and ignore risks?

“…energy conversion and regulation of membrane potential. Mammalian mitochondrial functions represent targets for antibiotics as documented already > 50 years ago [53][54][55][56][57][58][59][60][61][62][63][64][65][66][67][68][69]. Antibiotics interact not only with prokaryotic-and mitochondrial ribosomes but with eukaryotic 80S-ribosomes as well, so that human mitochondria and 80S-ribosomes represent a cancer target for antibiotics, too [70][71][72][73][74].…”