INHIBITION OF PROTEIN IMPORT INTO MITOCHONDRIA BY AMPHIPHILIC CATIONS- POTENTIAL TARGETS AND MECHANISM OF ACTION

In this paper we describe for the first time the inhibitory effect of three amphiphilic cations, trifluoperazine, propranolol and dibucaine on mitochondrial protein import. The amphiphilic cations did not affec t binding of mitochondrial precursor proteins to mitochondria Import i nto mitoplasts was affected in a similar manner to intact mitochondria , indicating that the protein import machinery of the inner membrane o f mitochondria was responsible for the observed effect. At concentrati ons which completely inhibited protein import, the amphiphilic cations did not affect the membrane potential (Delta Psi) across the inner me mbrane. The inhibitory potency of amphiphilic cations reflects their l ipid/water partition coefficient and relatively high concentrations of the drugs were required for complete inhibition, hence we propose tha t the mechanism of protein import inhibition by amphiphilic cations is due to membrane perturbing effects. We discuss the implications of ou r findings in view of the possible connection between various inner mi tochondrial membrane channels and the protein import pore. (C) 1998 Ac ademic Press.