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Accumulating evidence has revealed pivotal roles of glycogen synthase kinase-3[beta] (GSK3[beta]) inactivation on cardiac protection. Because the precise mechanisms of cardiac protection against ischemia/reperfusion (I/R) injury by GSK3[beta]-inactivation remain elusive, we investigated the relationship between GSK3[beta]-mediated mitochondrial hexokinase II (mitoHK-II; a downstream target of GSK3[beta]) dissociation and mitochondrial permeability transition pore (mPTP) opening. In Langendorff-perfused hearts, GSK3[beta] inactivation by SB216763 improved the left ventricular-developed pressure and retained mitoHK-II binding after I/R. In permeabilized myocytes, GSK3[beta] depolarized mitochondrial membrane potential with accelerated mitochondrial calcein release (suggesting GSK3[beta]-mediated mPTP opening) and decreased mitoHK-II bindings. GSK3[beta]-mediated mPTP opening depended on mitoHK-II binding, i.e., it was accelerated by dissociation of mitoHK-II (dicyclohexylcarbodiimide) and attenuated by enhancement of mitoHK-II binding (dextran). However, inactivation of mitoHK-II by glucose-depletion or glucose-6-phosphate inhibited the GSK3[beta]-mediated mPTP opening. We conclude that GSK3[beta]-mediated mPTP opening may be involved in I/R injury and regulated by mitoHK-II binding and activity. Keywords: Glycogen synthase kinase-3[beta], Mitochondrial permeability transition pore, Mitochondrial hexokinase II, Ischemia-reperfusion, Author(s): Takamitsu Tanaka[sup.1], Masao Saotome[sup.1], Hideki Katoh[sup.1], Terumori Satoh[sup.1], Prottoy Hasan[sup.1], Hayato Ohtani[sup.1], Hiroshi Satoh[sup.1], Hideharu Hayashi[sup.1] and Yuichiro Maekawa[sup.1] Introduction Mitochondria play pivotal roles not only manipulating cellular function [...]