TY - JOUR
T1 - Targeting Hexokinase II to mitochondria to modulate energy metabolism and reduce ischemia-reperfusion injury in heart
AU - Nederlof, Rianne
AU - Eerbeek, Otto
AU - Hollmann, Markus
AU - Southworth, Richard
AU - Zuurbier, Coert J
PY - 2014/4
Y1 - 2014/4
N2 - 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 IR injury in skeletal muscle and heart, attenuates cardiac hypertrophy and remodelling, and is one of the major end-effectors through which ischemic preconditioning protects against myocardial ischemia-reperfusion injury. Mechanisms of mtHKII cardioprotection against reperfusion injury entail the maintenance of regulated OMM permeability during ischemia and reperfusion resulting in stabilisation of mitochondrial membrane potential, the prevention of OMM breakage and cytochrome C release, and reduced ROS 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 ischemic 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 is now to harness mtHKII in the treatment of infarction, stroke, elective surgery and transplantation. Remote ischemic preconditioning, metformin administration and miR-155/miR-144 manipulations are potential means of doing just that.
AB - 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 IR injury in skeletal muscle and heart, attenuates cardiac hypertrophy and remodelling, and is one of the major end-effectors through which ischemic preconditioning protects against myocardial ischemia-reperfusion injury. Mechanisms of mtHKII cardioprotection against reperfusion injury entail the maintenance of regulated OMM permeability during ischemia and reperfusion resulting in stabilisation of mitochondrial membrane potential, the prevention of OMM breakage and cytochrome C release, and reduced ROS 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 ischemic 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 is now to harness mtHKII in the treatment of infarction, stroke, elective surgery and transplantation. Remote ischemic preconditioning, metformin administration and miR-155/miR-144 manipulations are potential means of doing just that.
U2 - 10.1111/bph.12363
DO - 10.1111/bph.12363
M3 - Article
SN - 0007-1188
VL - 171
SP - 2067
EP - 2079
JO - British Journal of Pharmacology
JF - British Journal of Pharmacology
IS - 8
ER -
