Targeting hexokinase II to mitochondria to modulate energy metabolism and reduce ischaemia‐reperfusion injury in heart
- 28 March 2014
- journal article
- review article
- Published by Wiley in British Journal of Pharmacology
- Vol. 171 (8), 2067-2079
- https://doi.org/10.1111/bph.12363
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.Keywords
This publication has 129 references indexed in Scilit:
- Oroxylin A induces dissociation of hexokinase II from the mitochondria and inhibits glycolysis by SIRT3-mediated deacetylation of cyclophilin D in breast carcinomaCell Death & Disease, 2013
- Hexokinase II knockdown results in exaggerated cardiac hypertrophy via increased ROS productionEMBO Molecular Medicine, 2012
- Metabolic Reprogramming: A Cancer Hallmark Even Warburg Did Not AnticipateCancer Cell, 2012
- A novel miR-155/miR-143 cascade controls glycolysis by regulatinghexokinase 2in breast cancer cellsThe EMBO Journal, 2012
- MicroRNA therapeutics in cardiovascular medicineEMBO Molecular Medicine, 2011
- Optical imaging of mitochondrial function uncovers actively propagating waves of mitochondrial membrane potential collapse across intact heartJournal of Molecular and Cellular Cardiology, 2010
- Partial hexokinase II knockout results in acute ischemia–reperfusion damage in skeletal muscle of male, but not female, micePflügers Archiv - European Journal of Physiology, 2010
- What is the mitochondrial permeability transition pore?Journal of Molecular and Cellular Cardiology, 2009
- Hexokinase-2 bound to mitochondria: Cancer's stygian link to the “Warburg effect” and a pivotal target for effective therapySeminars in Cancer Biology, 2008
- VDAC regulation: role of cytosolic proteins and mitochondrial lipidsJournal of Bioenergetics and Biomembranes, 2008