The redox state of endogenous pyridine nucleotides can determine both the degree of mitochondrial oxidative stress and the solute selectivity of the permeability transition pore

Acetoacetate, an NADH oxidant, stimulated the ruthenium red-insensitive rat liver mitochondrial Ca2+ efflux without significant release of stated respiration, disruption of membrane potential (Delta psi) or mitochondrial swelling. This process is compatible with the opening of the currently designated loll conductance state of the permeability transition pore (PTP) and, under our experimental conditions, was associated with a partial oxidation of the mitochondrial pyridine nucleotides, In contrast, diamide, a thiol oxidant, induced a fast mitochondrial Ca2+ efflux associated with a release of state-4 respiration, a disruption of Delta psi and a large amplitude mitochondrial swelling. This is compatible with the opening of the high conductance state of the PTP and was associated with extensive oxidation of pyridine nucleotides, Interestingly, the addition of carbonyl cyanide p-(trifluoromethoxy)phenylhydrazone to the acetoacetate experiment promoted a fast shift from the low to the high conductance state of the PTP, Both acetoacetate and diamide-induced mitochondrial permeabilization were inhibited by exogenous catalase, We propose that the shift from a low to a high conductance state of the PTP can be promoted by the oxidation of NADPH. This impairs the antioxidant function of the glutathione reductase/peroxidase system, strongly strengthening the state of mitochondrial oxidative stress. (C) 2000 Federation of European Biochemical Societies, Published by Elsevier Science B.V. All rights reserved.