The voltage sensor of the mitochondrial permeability transition pore is tuned by the oxidation-reduction state of vicinal thiols. Increase of the gating potential by oxidants and its reversal by reducing agents - PubMed (original) (raw)

. 1994 Jun 17;269(24):16638-42.

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The voltage sensor of the mitochondrial permeability transition pore is tuned by the oxidation-reduction state of vicinal thiols. Increase of the gating potential by oxidants and its reversal by reducing agents

V Petronilli et al. J Biol Chem. 1994.

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Abstract

Reaction of isolated mitochondria with a variety of agents that lead to oxidation or cross-linking of sulfhydryl groups leads to an increased "open" probability of the permeability transition pore, a cyclosporin A-sensitive channel. We have investigated the mechanism by which the pore is induced by menadione, diamide, arsenite, and tert-butylhydroperoxide. We find that these inducers increase the probability of pore opening by shifting its gating potential to higher values. Furthermore, the induced shift was prevented by treatment with N-ethylmaleimide or dithiothreitol. At moderate levels of depolarization an apparent I50 for N-ethylmaleimide of bout 5 microM can be defined, while the N-ethylmaleimide or dithiothreitol effects are overcome by maximal depolarization. We conclude that the oxidation-reduction state of vicinal thiols in cysteinyl residues plays a critical role in tuning the voltage sensor of the transition pore, with an increase of gating potential (i.e. an increase in the probability of pore opening despite a high transmembrane potential difference) as the couple is poised to a more oxidized state. These findings may have implications for the mechanism of cell damage under oxidative stress.

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