Effect of the mitochondrial transition pore inhibitor, S-15176, on rat liver mitochondria: ATP synthase modulation and mitochondrial uncoupling induction.
S-15176 is a new inhibitor of the permeability transition pore (PTP) which has been shown to display anti-ischemic properties. We show here that S-15176 prevented PTP, cytochrome c release and maintained mitochondrial membrane potential when low concentrations of S-15176 were used (not exceeding 50 nmol/mg protein). For higher concentrations S-15176 is able to collapse mitochondrial potential. This effect was reversed by the recoupling agent 6-ketocholestanol (6-KCh) suggesting that S-15176 has uncoupling properties. In addition, S-15176 is able to inhibit ATP synthase activity and to stimulate the hydrolytic activity of the enzyme but none of these effects appears to be related to its PTP inhibiting property. These data demonstrate that S-15176 interacts with several targets in mitochondria and these pharmacological properties should be considered in the examination of its health benefits as well as its potential cytotoxicity.
Morin
Didier
D
INSERM, U660, Créteil F-94010, France; Université Paris XII, Créteil F-94010, France. didier.morin@creteil.inserm.fr
Zini
Roland
R
Berdeaux
Alain
A
Tillement
Jean-Paul
JP
D025181:ATP Synthetase Complexes / Q000378:metabolism*; D000244:Adenosine Diphosphate / Q000494:pharmacology; D000818:Animals; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006863:Hydrogen-Ion Concentration; D007473:Ion Channels / Q000378:metabolism*; D007653:Ketocholesterols / Q000494:pharmacology; D008564:Membrane Potentials / Q000187:drug effects; D008930:Mitochondria, Liver / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D033681:Mitochondrial Membrane Transport Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051336:Mitochondrial Membranes / Q000187:drug effects / Q000502:physiology; D000083162:Mitochondrial Permeability Transition Pore; D024101:Mitochondrial Proteins / Q000378:metabolism*; D025261:Mitochondrial Proton-Translocating ATPases / Q000378:metabolism; D009570:Nitriles / Q000494:pharmacology; D009840:Oligomycins / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology*; D017494:Proton Pumps / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D013997:Time Factors; D000071256:Uncoupling Protein 1
D004791:Enzyme Inhibitors; D007473:Ion Channels; D007653:Ketocholesterols; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D024101:Mitochondrial Proteins; D009570:Nitriles; D009840:Oligomycins; D010879:Piperazines; D017494:Proton Pumps; C416838:S 15176; D000071256:Uncoupling Protein 1; C100076:mesoxalonitrile; C063833:6-ketocholestanol; D000244:Adenosine Diphosphate; D025181:ATP Synthetase Complexes; D025261:Mitochondrial Proton-Translocating ATPases