Benzoquinone inhibits the voltage-dependent induction of the mitochondrial permeability transition caused by redox-cycling naphthoquinones

Carlos M. Palmeira, Kendall B Wallace

Research output: Contribution to journalArticlepeer-review

72 Scopus citations

Abstract

The mitochondrial permeability pore is subject to regulation by a thiol-dependent voltage sensor (Petronilli, V., Costantini, P., Scorrano, L., Colonna, R., Passamonti, S., and Bernardi, P., J. Biol. Chem. 269, 16638-16642, 1994); thiol oxidation increases the gating potential, which increases the probability of pore opening. Monofunctional sulfhydryl-alkylating agents, by preventing formation of the disulfide, inhibit oxidant-induced changes in the gating potential. According to this paradigm, redox-cycling and arylating quinones should have distinct and opposing effects on the voltage-dependent permeabilization of mitochondrial membranes. Freshly isolated rat liver mitochondria were susceptible to a calcium-dependent permeability transition characterized by osmotic swelling and membrane depolarization, both of which were inhibited by Cyclosporine A. 1,4-Naphthoquinone, 2-methyl-1,4-naphthoquinone (menadione), and 2,3-dimethoxy-1,4-naphthoquinone elicited an increase in gating potential of the permeability pore that was prevented by Cyclosporine A or N-ethylmaleimide and reversed by dithiothreitol. Benzoquinone, on the other hand, inhibited NADH-ubiquinone oxidoreductase. Accordingly, in mitochondria energized with glutamate plus malate benzoquinone caused a direct, calcium-independent depolarization of membrane potential and mitochondrial swelling that were not inhibited by Cyclosporine A. In contrast, benzoquinone did not interfere with succinate-supported mitochondrial bioenergetics. In fact, adding benzoquinone to succinate-energized mitochondria prevented induction of the mitochondrial permeability transition by all three redox-cycling naphthoquinones, We attribute this to the electrophilic, sulfhydryl-arylating reactivity of benzoquinone. The results suggest that differences in the mechanisms by which quinones of varying chemical reactivity interfere with mitochondrial bioenergetics can be explained in terms of the distinct manner in which they react with the thiol-dependent voltage sensor of the mitochondrial permeability pore.

Original languageEnglish (US)
Pages (from-to)338-347
Number of pages10
JournalToxicology and Applied Pharmacology
Volume143
Issue number2
DOIs
StatePublished - Apr 1997

Fingerprint Dive into the research topics of 'Benzoquinone inhibits the voltage-dependent induction of the mitochondrial permeability transition caused by redox-cycling naphthoquinones'. Together they form a unique fingerprint.

Cite this