title: Targeting hexokinase II to mitochondria to modulate energy metabolism and reduce ischaemia-reperfusion injury in heart.
abstract: Mitochondrially bound hexokinase II (mtHKII) has long been known to confer cancer cells with their resilience against cell death. More recently, mtHKII has emerged as a powerful protector against cardiac cell death. mtHKII protects against ischaemia-reperfusion (IR) injury in skeletal muscle and heart, attenuates cardiac hypertrophy and remodelling, and is one of the major end-effectors through which ischaemic preconditioning protects against myocardial IR injury. Mechanisms of mtHKII cardioprotection against reperfusion injury entail the maintenance of regulated outer mitochondrial membrane (OMM) permeability during ischaemia and reperfusion resulting in stabilization of mitochondrial membrane potential, the prevention of OMM breakage and cytochrome C release, and reduced reactive oxygen species production. Increasing mtHK may also have important metabolic consequences, such as improvement of glucose-induced insulin release, prevention of acidosis through enhanced coupling of glycolysis and glucose oxidation, and inhibition of fatty acid oxidation. Deficiencies in expression and distorted cellular signalling of HKII may contribute to the altered sensitivity of diabetes to cardiac ischaemic diseases. The interaction of HKII with the mitochondrion constitutes a powerful endogenous molecular mechanism to protect against cell death in almost all cell types examined (neurons, tumours, kidney, lung, skeletal muscle, heart). The challenge now is to harness mtHKII in the treatment of infarction, stroke, elective surgery and transplantation. Remote ischaemic preconditioning, metformin administration and miR-155/miR-144 manipulations are potential means of doing just that.
authors.affiliation: Laboratory of Experimental Intensive Care and Anesthesiology, Department of Anesthesiology, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Rianne
authors.initials: R
authors.lastname: Nederlof
authors.forename: Otto
authors.initials: O
authors.lastname: Eerbeek
authors.forename: Markus W
authors.initials: MW
authors.lastname: Hollmann
authors.forename: Richard
authors.initials: R
authors.lastname: Southworth
authors.forename: Coert J
authors.initials: CJ
authors.lastname: Zuurbier
mesh_terms: D002316:Cardiotonic Agents / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D004734:Energy Metabolism / Q000187:drug effects*; D006331:Heart Diseases / Q000188:drug therapy / Q000201:enzymology / Q000503:physiopathology; D006593:Hexokinase / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D006801:Humans; D008928:Mitochondria / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D058990:Molecular Targeted Therapy / Q000379:methods*; D015428:Myocardial Reperfusion Injury / Q000188:drug therapy* / Q000201:enzymology; D009369:Neoplasms / Q000201:enzymology / Q000503:physiopathology
chemical_list: D002316:Cardiotonic Agents; D006593:Hexokinase
keywords: cell death; diabetes; glycolysis; ischaemia-reperfusion injury; mPTP; mitochondria
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