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Dihydrolipoic acid (DHLA) has been found to stimulate the Ca2+-induced mitochondrial permeability transition (MPT) in rat liver mitochondria (RLM) [Biochem. Mol. Biol. Int. 44 (1998) 127] which could be due to its prooxidant properties. We therefore investigated whether DHLA stimulated superoxide anion (O2•-) generation in RLM and in bovine heart submitochondrial particles (SMP). In RLM DHLA caused a concentration-dependent O2•- generation assayed by lucigenin chemiluminiscence. The stimulation was seen with the lowest concentrations of DHLA (5 μM) with pyruvate as the respiratory substrate, with 2-oxoglutarate or especially succinate the stimulation was less pronounced. Stimulation of O2•- production by DHLA was also observed in bovine heart SMP using an electron spin-trapping technique. Radical scavengers (butylhydroxytoluene and TEMPO) decreased O2•- generation induced by DHLA and inhibited MPT. Slight reduction of the mitochondrial membrane potential by a small amount of a protonophorous uncoupling agent also delayed the DHLA-induced MPT. These data indicate that the stimulation of MPT by DHLA is due to DHLA-derived prooxidants, i.e. stimulated production of O2•- and possibly other free radicals.