PERMEABILIZATION OF THE MITOCHONDRIAL INNER MEMBRANE BY SHORT CECROPIN-A-MELITTIN HYBRID PEPTIDES

A number of cecropin-A(-)melittin hybrid peptides have previously been shown to be potent antibacterial agents [Andreu, D., Ubach, J., Boman , A., Wahlin, B., Wade, D., Merrifield, R. B. and Boman, Il. G. (1992) FEBS Lett. 296, 190-194]. In the present report we analyze their acti on on biological systems using rat liver mitochondria as a test system . We demonstrate that the longest peptide, cecropin-A-(1 - 8) -melitti n(1 - 18) permeabilizes the mitochondrial inner membrane allowing the movement of both charged and non-charged solutes. Concentrations used have already been shown to be bactericidal. This effect is also demons trated under respiring conditions where succinate oxidation is uncoupl ed. Shorter analogs also permeabilize mitochondria although at ten-fol d higher concentrations. Heparin potentiates the peptide effects at lo w concentrations, while at high concentration it becomes inhibitory. W e propose that the cecropin-melittin analogs disrupt the mitochondrial membrane in a detergent-like mode rather than by creating selective c hannels as had been previously suggested.