title: Cerebrocrast promotes the cotransport of H+ and Cl- in rat liver mitochondria.
abstract: Considering that cerebrocrast stimulates oligomycin-inhibited state 3 respiration simultaneously with mitochondrial transmembrane potential (Deltapsi) dissipation, the mechanism underlying the uncoupler activity of cerebrocrast was assessed by its ability to permeabilize the mitochondrial inner membrane to H(+) or to K(+) or to cotransport anions with H(+). The partition coefficient of cerebrocrast in mitochondrial membrane and its ability to act as a membrane-active compound disturbing membrane lipid organization were also investigated. Cerebrocrast induced no permeabilization of mitochondrial inner membrane to H(+) or K(+), but it was able to transport H(+) in association with Cl(-). Cerebrocrast showed a strong incorporation into the mitochondrial membrane, with a partition coefficient (Kp(m/w)) of 2.7(+/-0.1)x10(5). Cerebrocrast also reduced, in a concentration dependent manner, the phase transition temperature, the cooperative unit size, and the enthalpy associated with the phase transition temperature of DMPC membrane bilayers. It was concluded that the uncoupler activity of cerebrocrast is due to its ability to promote the cotransport of H(+) with Cl(-) through the rat liver mitochondrial inner membrane, and that this cerebrocrast mechanism of action may be potentiated by alterations of membrane lipid organization and membrane lateral heterogeneity.
authors.affiliation: Departamento de Zoologia, Universidade de Coimbra, 3004-517 Coimbra, Portugal. mfer@ci.uc.pt
authors.forename: Maria A S
authors.initials: MA
authors.lastname: Fernandes
authors.forename: Amália S
authors.initials: AS
authors.lastname: Jurado
authors.forename: Romeu A
authors.initials: RA
authors.lastname: Videira
authors.forename: Maria S
authors.initials: MS
authors.lastname: Santos
authors.forename: António J M
authors.initials: AJ
authors.lastname: Moreno
authors.forename: Astrida
authors.initials: A
authors.lastname: Velena
authors.forename: Gunars
authors.initials: G
authors.lastname: Duburs
authors.forename: Catarina R
authors.initials: CR
authors.lastname: Oliveira
authors.forename: Joaquim A F
authors.initials: JA
authors.lastname: Vicente
mesh_terms: D000244:Adenosine Diphosphate / Q000737:chemistry; D000704:Analysis of Variance; D000818:Animals; D001692:Biological Transport; D002712:Chlorides / Q000378:metabolism*; D004095:Dihydropyridines / Q000737:chemistry / Q000494:pharmacology*; D004134:Dimyristoylphosphatidylcholine / Q000737:chemistry; D007425:Intracellular Membranes / Q000378:metabolism; D008051:Lipid Bilayers / Q000378:metabolism; D008055:Lipids / Q000737:chemistry; D008297:Male; D008564:Membrane Potentials; D008928:Mitochondria / Q000473:pathology; D008930:Mitochondria, Liver / Q000187:drug effects* / Q000378:metabolism; D008956:Models, Chemical; D011522:Protons; D051381:Rats; D017208:Rats, Wistar; D013050:Spectrometry, Fluorescence; D013696:Temperature; D013816:Thermodynamics
chemical_list: D002712:Chlorides; D004095:Dihydropyridines; D008051:Lipid Bilayers; D008055:Lipids; D011522:Protons; C073838:2,6-dimethyl-3,5-bis(2'-propoxyethoxycarbonyl)-4-(2''-difluoromethoxyphenyl)-1,4-dihydropyridine; D000244:Adenosine Diphosphate; C038806:1,4-dihydropyridine; D004134:Dimyristoylphosphatidylcholine