Gradual changes in permeability of inner mitochondrial membrane precede the mitochondrial permeability transition.
Some compounds are known to induce solute-nonselective permeability of the inner mitochondrial membrane (IMM) in Ca2+-loaded mitochondria. Existing data suggest that this process, following the opening of a mitochondrial permeability transition pore, is preceded by different solute-selective permeable states of IMM. At pH 7, for instance, the K0.5 for Ca2+-induced pore opening is 16 microM, a value 80-fold above a therapeutically relevant shift of intracellular Ca2+ during ischemia in vivo. The present work shows that in the absence of Ca2+, phenylarsine oxide and tetraalkyl thiuram disulfides (TDs) are able to induce a complex sequence of IMM permeability changes. At first, these agents activated an electrogenic K+ influx into the mitochondria. This K+-specific pathway had K0.5 = 35 mM for K+ and was inhibited by bromsulfalein with Ki = 2.5 microM. The inhibitors of mitochondrial KATP channel, ATP and glibenclamide, did not inhibit K+ transport via this pathway. Moreover, 50 microM glibenclamide induced by itself K+ influx into the mitochondria. After the increase in K+ permeability of IMM, mitochondria become increasingly permeable to protons. Mechanisms of H+ leak and nonselective permeability increase could also be different depending on the type of mitochondrial permeability transition (MPT) inducer. Thus, permeabilization of mitochondria induced by phenylarsine oxide was fully prevented by ADP and/or cyclosporin A, whereas TD-induced membrane alterations were insensitive toward these inhibitors. It is suggested that MPT in vivo leading to irreversible apoptosis is irrelevant in reversible ischemia/reperfusion injury.
Biophysical Group, Novosibirsk Institute of Chemical Kinetics & Combustion, Novosibirsk, Institutskaya 3, 630090, Russian Federation.
M Y
MY
Balakirev
G
G
Zimmer
D000143:Acids / Q000378:metabolism; D000468:Alkalies / Q000378:metabolism; D000818:Animals; D001152:Arsenicals / Q000494:pharmacology; D016227:Benzoquinones / Q000494:pharmacology; D006863:Hydrogen-Ion Concentration; D007425:Intracellular Membranes / Q000187:drug effects / Q000502:physiology*; D008930:Mitochondria, Liver / Q000187:drug effects / Q000378:metabolism* / Q000502:physiology; D010539:Permeability; D010545:Peroxides / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D013438:Sulfhydryl Compounds / Q000378:metabolism; D020122:tert-Butylhydroperoxide
D000143:Acids; D000468:Alkalies; D001152:Arsenicals; D016227:Benzoquinones; D010545:Peroxides; D013438:Sulfhydryl Compounds; C029341:oxophenylarsine; D020122:tert-Butylhydroperoxide; C034257:duroquinone