The Estrogen-Related Receptor α Inverse Agonist XCT 790 Is a Nanomolar Mitochondrial Uncoupler

XCT 790 is widely used to inhibit estrogen-related receptor alpha (ERR alpha) activity as an inverse agonist. Here, we report that XCT 790 potently activates AMP kinase (AMPK) in a dose-dependent and ERR alpha-independent manner, with active concentrations more than 25-fold below those typically used to perturb ERR alpha. 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 mitodiondrial 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 ERR alpha. 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.