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. Linked Articles This article is part of a themed issue on Mitochondrial Pharmacology: Energy, Injury & Beyond. To view the other articles in this issue visit http://dx.doi.org/10.1111/bph.2014.171.issue-8

The Immune-Metabolic Basis of Effector Memory CD4+ T Cell Function under Hypoxic Conditions

“…Other examples of DCm stabilizing mechanisms include the calcium-binding mitochondrial carrier protein SCaMC-1 (SLC25A24), which buffers intramitochondrial calcium to prevent membrane depolarization (27), and recruitment of hexokinase II to the outer mitochondrial membrane. Mitochondrial localization of hexokinase II is proposed to stabilize DCm via physical interaction with mitochondrial membrane proteins, or by maintaining local ADP levels or increasing glucose-mediated OXPHOS (28).…”

Molecular Basis of Cardioprotection

“…[375][376][377][378] Hexokinase 2 is the predominant isoform in the heart, and it plays a major role in cellular glucose metabolism; its mitochondrial localization favors glycolysis. 377 Hexokinase 2 localization to the mitochondria is facilitated by RISK activation, 377,379 but also by decreased cytosolic glucose-6-phosphate concentration, 380 and reduced glucose-6-phosphate concentration, in turn, is one consequence of IPC.…”

Hexokinases and cardioprotection

“…HKI and HK2 are the most abundant, with HKI (“the brain HK”) ubiquitous in most tissues, especially brain and red blood cells [23, 24] where glycolysis plays a critical role in energy production. In contrast, HK2 (“the muscle HK”) is found primarily in insulin-sensitive tissues such as adipocytes, adult skeletal and cardiac muscle [25, 26]. Few data are available for human heart, but a recent report indicates that in non-dilated human atrial tissue, HKI is the most abundant isoform [27].…”

“…3 and see [26] for review). The first mechanism is a direct (nonmetabolic) action and the remaining four are indirect (metabolic) actions.…”