title: The estrogen-related receptor α inverse agonist XCT 790 is a nanomolar mitochondrial uncoupler.
abstract: XCT 790 is widely used to inhibit estrogen-related receptor α (ERRα) activity as an inverse agonist. Here, we report that XCT 790 potently activates AMP kinase (AMPK) in a dose-dependent and ERRα-independent manner, with active concentrations more than 25-fold below those typically used to perturb ERRα. AMPK activation is secondary to inhibition of energy production as XCT 790 rapidly depletes the pool of cellular ATP. A concomitant increase in oxygen consumption rates suggests uncoupling of the mitochondrial electron transport chain. Consistent with this, XCT 790 decreased mitochondrial membrane potential without affecting mitochondrial mass. Therefore, XCT 790 is a potent, fast-acting, mitochondrial uncoupler independent of its inhibition of ERRα. The biological activity together with structural features in common with the chemical uncouplers FCCP and CCCP indicates likely mode of action as a proton ionophore.
authors.affiliation: Department of Cell Biology, University of Texas Southwestern Medical Center , Dallas, Texas 75390, United States.
authors.forename: Banu
authors.initials: B
authors.lastname: Eskiocak
authors.forename: Aktar
authors.initials: A
authors.lastname: Ali
authors.forename: Michael A
authors.initials: MA
authors.lastname: White
mesh_terms: D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D054314:Drug Inverse Agonism; D006801:Humans; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D009570:Nitriles / Q000494:pharmacology*; D010084:Oxidation-Reduction; D010101:Oxygen Consumption; D010766:Phosphorylation; D061209:Proton Ionophores / Q000494:pharmacology*; D011960:Receptors, Estrogen / Q000037:antagonists & inhibitors / Q000378:metabolism*; D013844:Thiazoles / Q000494:pharmacology*; D000097983:ERRalpha Estrogen-Related Receptor
chemical_list: D009570:Nitriles; D061209:Proton Ionophores; D011960:Receptors, Estrogen; D013844:Thiazoles; D000097983:ERRalpha Estrogen-Related Receptor; C488234:XCT790