Mechanism of dihydrolipoate stimulation of the mitochondrial permeability transition: Effect of different respiratory substrates

The stimulation of the mitochondrial permeability transition (MPT) by dihyd rolipoate (DHLA) was studied in rat liver mitochondria in the presence of d ifferent respiratory substrates, The Ca2+ threshold for the induction of MP T was lowest for pyruvate, followed by 2-hydroxybutyrate, 2-oxoglutarate, g lutamate plus malate, and succinate plus rotenone, both in the presence and absence of DHLA. DHLA was not able to induce MPT in the absence of Ca2+, i n the presence of cyclosporin A, or rotenone with pyridine nucleotide-depen dent substrates. The difference in sensitivity of MPT to I)HLA with various substrates was correlated with the redox state of pyridine nucleotides but not the redox state of glutathione, These findings demonstrate that DHLA i nduced MPT pore opening through the P-site thiol, The similarities between the effect of DHLA and that of production of reactive oxygen species found in model experiments suggest that DHLA stimulates MPT by production of reac tive oxygen species that exhaust the antioxidant defence.