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.

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.

PASSAMONTI, SABINA;
1994-01-01

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.
1994
http://www.jbc.org/search?author1=&fulltext=&pubdate_year=1994&volume=269&firstpage=16638&submit=yes
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11368/2633889
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