Menadione induces a low conductance state of the mitochondrial inner membrane sensitive to bongkrekic acid

When rat liver mitochondria are allowed to cycle Ca2+ and are incubated in the presence of the pro-oxidant menadione, they undergo swelling, membrane potential (ΔΨ) collapse, and ion release. These effects, which are inhibited by cyclosporin A (CsA), are fully consistent with the opening of the so-called permeability transition pore. However, when Ca2+ cycling is abolished by EGTA, the mitochondria remain energized (ΔΨ collapse and swelling are avoided), but Ca2+ efflux, promoted by the chelating agent, is stimulated by menadione. This stimulation goes together with the release of Mg2+, K+, and adenine nucleotides (AdN) and is inhibited by bongkrekic acid (BKA). The effect of menadione is also characterized by biphasic NAD(P)H oxidation which becomes monophasic in the presence of BKA, CsA, or EGTA and by the oxidation of thiol groups not restrained by the above-mentioned inhibitors. These results suggest that BKA acts indirectly by preserving in the matrix a critical amount of AdN without modifying the monophasic oxidation of pyridine nucleotides by menadione. A critical number of thiol groups also seems to be involved in the phenomenon. Their oxidation most probably causes a conformational change on adenine nucleotide translocase with the opening of the “low-conductance state” of the mitochondrial permeability transition, resulting in ion permeability without ΔΨ disruption and mitochondrial swelling.