Menadione induces a low conductance state of the mitochondrial inner membrane sensitive to bongkrekic acid.
When rat liver mitochondria are allowed to cycle Ca(2+) and are incubated in the presence of the pro-oxidant menadione, they undergo swelling, membrane potential (DeltaPsi) 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 Ca(2+) cycling is abolished by EGTA, the mitochondria remain energized (DeltaPsi collapse and swelling are avoided), but Ca(2+) efflux, promoted by the chelating agent, is stimulated by menadione. This stimulation goes together with the release of Mg(2+), 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 DeltaPsi disruption and mitochondrial swelling.
Toninello
Antonio
A
Dipartimento di Chimica Biologica, Università di Padova, Istituto di Neuroscienze del CNR, Unità per lo studio delle Biomembrane, Viale G. Colombo 3, 35121 Padūa, Italy. antonio.toninello@unipd.it
Salvi
Mauro
M
Schweizer
Matthias
M
Richter
Christoph
C
D000818:Animals; D001865:Bongkrekic Acid / Q000494:pharmacology*; D002118:Calcium / Q000037:antagonists & inhibitors / Q000378:metabolism; D002614:Chelating Agents / Q000494:pharmacology; D016572:Cyclosporine / Q000494:pharmacology; D004533:Egtazic Acid / Q000494:pharmacology; D007425:Intracellular Membranes / Q000187:drug effects* / Q000378:metabolism; D008930:Mitochondria, Liver / Q000187:drug effects* / Q000378:metabolism; D008933:Mitochondrial Swelling / Q000187:drug effects; D009711:Nucleotides / Q000378:metabolism; D010084:Oxidation-Reduction / Q000187:drug effects; D051381:Rats; D024483:Vitamin K 3 / Q000494:pharmacology*
D002614:Chelating Agents; D009711:Nucleotides; D001865:Bongkrekic Acid; D004533:Egtazic Acid; D024483:Vitamin K 3; D016572:Cyclosporine; D002118:Calcium