Glycogen synthase kinase-3β opens mitochondrial permeability transition pore through mitochondrial hexokinase II dissociation

The journal of physiological sciences: JPS

Takamitsu Tanaka¹ 

[1] Hamamatsu University School of Medicine

关键词: Glycogen synthase kinase-3β;    Mitochondrial permeability transition pore;    Mitochondrial hexokinase II;    Ischemia–reperfusion;   

DOI  :  10.1007/s12576-018-0611-y

学科分类：生理学

来源: Springer

【 摘 要 】

Accumulating evidence has revealed pivotal roles of glycogen synthase kinase-3β (GSK3β) inactivation on cardiac protection. Because the precise mechanisms of cardiac protection against ischemia/reperfusion (I/R) injury by GSK3β-inactivation remain elusive, we investigated the relationship between GSK3β-mediated mitochondrial hexokinase II (mitoHK-II; a downstream target of GSK3β) dissociation and mitochondrial permeability transition pore (mPTP) opening. In Langendorff-perfused hearts, GSK3β inactivation by SB216763 improved the left ventricular-developed pressure and retained mitoHK-II binding after I/R. In permeabilized myocytes, GSK3β depolarized mitochondrial membrane potential with accelerated mitochondrial calcein release (suggesting GSK3β-mediated mPTP opening) and decreased mitoHK-II bindings. GSK3β-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 GSK3β-mediated mPTP opening. We conclude that GSK3β-mediated mPTP opening may be involved in I/R injury and regulated by mitoHK-II binding and activity.

【 授权许可】

CC BY