title: The translocator protein (peripheral benzodiazepine receptor) mediates rat-selective activation of the mitochondrial permeability transition by norbormide.
abstract: We have investigated the mechanism of rat-selective induction of the mitochondrial permeability transition (PT) by norbormide (NRB). We show that the inducing effect of NRB on the PT (i) is inhibited by the selective ligands of the 18kDa outer membrane (OMM) translocator protein (TSPO, formerly peripheral benzodiazepine receptor) protoporphyrin IX, N,N-dihexyl-2-(4-fluorophenyl)indole-3-acetamide and 7-chloro-5-(4-chlorophenyl)-1,3-dihydro-1-methyl-2H-1,4-benzodiazepin-2-one; and (ii) is lost in digitonin mitoplasts, which lack an intact OMM. In mitoplasts the PT can still be induced by the NRB cationic derivative OL14, which contrary to NRB is also effective in intact mitochondria from mouse and guinea pig. We conclude that selective NRB transport into rat mitochondria occurs via TSPO in the OMM, which allows its translocation to PT-regulating sites in the inner membrane. Thus, species-specificity of NRB toward the rat PT depends on subtle differences in the structure of TSPO or of TSPO-associated proteins affecting its substrate specificity.
authors: C.N.R. Institute of Neurosciences at the Department of Biomedical Sciences, University of Padova, Italy.
authors: Alessandra
authors: A
authors: Zulian
authors: Justina
authors: J
authors: Sileikytė
authors: Valeria
authors: V
authors: Petronilli
authors: Sergio
authors: S
authors: Bova
authors: Federica
authors: F
authors: Dabbeni-Sala
authors: Gabriella
authors: G
authors: Cargnelli
authors: David
authors: D
authors: Rennison
authors: Margaret A
authors: MA
authors: Brimble
authors: Brian
authors: B
authors: Hopkins
authors: Paolo
authors: P
authors: Bernardi
authors: Fernanda
authors: F
authors: Ricchelli
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D002352:Carrier Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D006168:Guinea Pigs; D051379:Mice; D008930:Mitochondria, Liver / Q000187:drug effects* / Q000378:metabolism / Q000648:ultrastructure; D033681:Mitochondrial Membrane Transport Proteins / Q000187:drug effects* / Q000502:physiology; D000083162:Mitochondrial Permeability Transition Pore; D008969:Molecular Sequence Data; D015394:Molecular Structure; D009636:Norbornanes / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D011963:Receptors, GABA-A / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D012378:Rodenticides / Q000494:pharmacology; D016415:Sequence Alignment; D013379:Substrate Specificity
chemical_list: D002352:Carrier Proteins; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D009636:Norbornanes; D011963:Receptors, GABA-A; D012378:Rodenticides; C069997:Tspo protein, rat; C005321:norbormide