title: KB-R7943, a plasma membrane Na(+)/Ca(2+) exchanger inhibitor, blocks opening of the mitochondrial permeability transition pore.
abstract: The isothiourea derivative, KB-R7943, inhibits the reverse-mode of the plasma membrane sodium/calcium exchanger and protects against ischemia/reperfusion injury. The mechanism through which KB-R7943 confers protection, however, remains controversial. Recently, KB-R7943 has been shown to inhibit mitochondrial calcium uptake and matrix overload, which may contribute to its protective effects. While using KB-R7943 for this purpose, we find here no evidence that KB-R7943 directly blocks mitochondrial calcium uptake. Rather, we find that KB-R7943 inhibits opening of the mitochondrial permeability transition pore in permeabilized cells and isolated liver mitochondria. Furthermore, we find that this observation correlates with protection against calcium ionophore-induced mitochondrial membrane potential depolarization and cell death, without detrimental effects to basal mitochondrial membrane potential or complex I-dependent mitochondrial respiration. Our data reveal another mechanism through which KB-R7943 may protect against calcium-induced injury, as well as a novel means to inhibit the mitochondrial permeability transition pore.
authors.affiliation: Department of Anesthesiology and Pain Medicine, Mitochondria and Metabolism Center, University of Washington, Seattle, WA, United States.
authors.forename: Brian M
authors.initials: BM
authors.lastname: Wiczer
authors.affiliation: Department of Anesthesiology and Pain Medicine, Mitochondria and Metabolism Center, University of Washington, Seattle, WA, United States.
authors.forename: Raluca
authors.initials: R
authors.lastname: Marcu
authors.affiliation: Department of Anesthesiology and Pain Medicine, Mitochondria and Metabolism Center, University of Washington, Seattle, WA, United States. Electronic address: bhawkins@uw.edu.
authors.forename: Brian J
authors.initials: BJ
authors.lastname: Hawkins
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism; D015220:Calcium Channels / Q000187:drug effects; D016923:Cell Death / Q000187:drug effects; D002460:Cell Line; D006367:HeLa Cells; D006801:Humans; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D051379:Mice; D008930:Mitochondria, Liver / Q000187:drug effects / Q000378:metabolism; D033681:Mitochondrial Membrane Transport Proteins / Q000187:drug effects* / Q000378:metabolism; D000083162:Mitochondrial Permeability Transition Pore; D010101:Oxygen Consumption / Q000187:drug effects; D019831:Sodium-Calcium Exchanger / Q000037:antagonists & inhibitors*; D013890:Thiourea / Q000031:analogs & derivatives* / Q000494:pharmacology
chemical_list: C101670:2-(2-(4-(4-nitrobenzyloxy)phenyl)ethyl)isothiourea methanesulfonate; D015220:Calcium Channels; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D019831:Sodium-Calcium Exchanger; C034703:mitochondrial calcium uniporter; D013890:Thiourea; D002118:Calcium
keywords: Calcium retention capacity; KB-R7943; Mitochondria; Permeability transition