title: To involvement the conformation of the adenine nucleotide translocase in opening the Tl(+)-induced permeability transition pore in Ca(2+)-loaded rat liver mitochondria.
abstract: The conformation of adenine nucleotide translocase (ANT) has a profound impact in opening the mitochondrial permeability transition pore (MPTP) in the inner membrane. Fixing the ANT in 'c' conformation by phenylarsine oxide (PAO), tert-butylhydroperoxide (tBHP), and carboxyatractyloside as well as the interaction of 4,4'-diisothiocyanostilbene-2,2'-disulfonate (DIDS) with mitochondrial thiols markedly attenuated the ability of ADP to inhibit the MPTP opening. We earlier found (Korotkov and Saris, 2011) that calcium load of rat liver mitochondria in medium containing TlNO3 and KNO3 stimulated the Tl(+)-induced MPTP opening in the inner mitochondrial membrane. The MPTP opening as well as followed increase in swelling, a drop in membrane potential (ΔΨmito), and a decrease in state 3, state 4, and 2,4-dinitrophenol-uncoupled respiration were visibly enhanced in the presence of PAO, tBHP, DIDS, and carboxyatractyloside. However, these effects were markedly inhibited by ADP and membrane-penetrant hydrophobic thiol reagent, N-ethylmaleimide (NEM) which fix the ANT in 'm' conformation. Cyclosporine A additionally potentiated these effects of ADP and NEM. Our data suggest that conformational changes of the ANT may be directly involved in the opening of the Tl(+)-induced MPTP in the inner membrane of Ca(2+)-loaded rat liver mitochondria. Using the Tl(+)-induced MPTP model is discussed in terms finding new transition pore inhibitors and inducers among different chemical and natural compounds.
authors.affiliation: Sechenov Institute of Evolutionary Physiology and Biochemistry, the Russian Academy of Sciences, Thorez pr. 44, 194223 St. Petersburg, Russian Federation. Electronic address: korotkov@SK1645.spb.edu.
authors.forename: Sergey M
authors.initials: SM
authors.lastname: Korotkov
authors.affiliation: Sechenov Institute of Evolutionary Physiology and Biochemistry, the Russian Academy of Sciences, Thorez pr. 44, 194223 St. Petersburg, Russian Federation.
authors.forename: Svetlana A
authors.initials: SA
authors.lastname: Konovalova
authors.affiliation: Sechenov Institute of Evolutionary Physiology and Biochemistry, the Russian Academy of Sciences, Thorez pr. 44, 194223 St. Petersburg, Russian Federation.
authors.forename: Irina V
authors.initials: IV
authors.lastname: Brailovskaya
authors.affiliation: Department of Food and Environmental Sciences, University of Helsinki, P.O. Box 56, Viikki Biocenter 1, FI-00014 Helsinki, Finland.
authors.forename: Nils-Erik L
authors.initials: NE
authors.lastname: Saris
mesh_terms: D017878:4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid / Q000494:pharmacology; D000818:Animals; D001152:Arsenicals / Q000494:pharmacology; D001278:Atractyloside / Q000031:analogs & derivatives / Q000494:pharmacology; D002118:Calcium / Q000494:pharmacology; D016572:Cyclosporine / Q000494:pharmacology; D005033:Ethylmaleimide / Q000494:pharmacology; D008297:Male; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008930:Mitochondria, Liver / Q000187:drug effects / Q000502:physiology*; D000226:Mitochondrial ADP, ATP Translocases / Q000737:chemistry* / Q000502:physiology*; D033681:Mitochondrial Membrane Transport Proteins / Q000502:physiology*; D051336:Mitochondrial Membranes / Q000187:drug effects / Q000502:physiology; D000083162:Mitochondrial Permeability Transition Pore; D011487:Protein Conformation; D017208:Rats, Wistar; D013438:Sulfhydryl Compounds / Q000494:pharmacology*; D020122:tert-Butylhydroperoxide / Q000494:pharmacology
chemical_list: D001152:Arsenicals; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D013438:Sulfhydryl Compounds; C029341:oxophenylarsine; D001278:Atractyloside; D016572:Cyclosporine; D000226:Mitochondrial ADP, ATP Translocases; D020122:tert-Butylhydroperoxide; D005033:Ethylmaleimide; D017878:4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid; C003853:carboxyatractyloside; D002118:Calcium
keywords: Adenine nucleotide translocase conformation; Ca(2+); Mitochondrial permeability transition; Mitochondrial swelling; Rat liver mitochondria; Tl(+)