title: Mitochondria and GSK-3beta in cardioprotection against ischemia/reperfusion injury.
abstract: The mitochondrion is a powerhouse of the cell, a platform of cell signaling and decision-maker of cell death, including death by ischemia/reperfusion. Ischemia shuts off ATP production by mitochondria, and cell viability is compromised by energy deficiency and build-up of cytotoxic metabolites during ischemia. Furthermore, the mitochondrial permeability transition pore (mPTP) is primed by ischemia to open upon reperfusion, leading to reperfusion-induced cell necrosis. mPTP opening can be suppressed by ischemic preconditioning (IPC) and other interventions that induce phosphorylation of GSK-3beta. Activation of the mitochondrial ATP-sensitive K(+) channel (mK(ATP) channel) is an important signaling step in a trigger phase of IPC, which ultimately enhances GSK-3beta phosphorylation upon reperfusion, and this channel functions as a mediator of cytoprotection as well. The mitochondrial Ca(2+)-activated K(+) channel appears to play roles similar to those of the mK(ATP) channel, though regulatory mechanisms of the channels are different. Phosphorylated GSK-3beta inhibits mPTP opening presumably by multiple mechanisms, including preservation of hexokinase II in mPTP complex, prevention of interaction of cyclophilin-D with adenine nucleotide translocase, inhibition of p53 activation and attenuation of ATP hydrolysis during ischemia. However, cytoprotective signaling pathways to GSK-3beta phosphorylation and other mPTP regulatory factors are modified by co-morbidities, including type 2 diabetes, and such modification makes the myocardium refractory to IPC and other cardioprotective agents. Regulatory mechanisms of mPTP, and their alterations by morbidities frequently associated with ischemic heart disease need to be further characterized for translation of mitochondrial and mPTP biology to the clinical arena.
authors.affiliation: Division of Cardiology, Second Department of Internal Medicine, Sapporo Medical University School of Medicine, South-1 West-16, Chuo-ku, Sapporo, 060-8543, Japan. miura@sapmed.ac.jp
authors.forename: Tetsuji
authors.initials: T
authors.lastname: Miura
authors.forename: Masaya
authors.initials: M
authors.lastname: Tanno
mesh_terms: D000818:Animals; D002316:Cardiotonic Agents / Q000494:pharmacology; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D019157:Ischemic Preconditioning, Myocardial / Q000379:methods; D008929:Mitochondria, Heart / Q000378:metabolism*; D033681:Mitochondrial Membrane Transport Proteins / Q000378:metabolism; D000083162:Mitochondrial Permeability Transition Pore; D009203:Myocardial Infarction / Q000209:etiology / Q000517:prevention & control; D015428:Myocardial Reperfusion Injury / Q000150:complications / Q000503:physiopathology*; D010766:Phosphorylation; D015398:Signal Transduction
chemical_list: D002316:Cardiotonic Agents; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; D038362:Glycogen Synthase Kinase 3