Hexokinases and cardioprotection

Abstract

As mediators of the first enzymatic step in glucose metabolism, hexokinases (HKs) orchestrate a variety of catabolic and anabolic uses of glucose, regulate antioxidant power by generating NADPH for glutathione reduction, and modulate cell death processes by directly interacting with the voltage-dependent anion channel (VDAC), a regulatory component of the mitochondrial permeability transition pore (mPTP). Here we summarize the current state-of-knowledge about HKs and their role in protecting the heart from ischemia/reperfusion (I/R) injury, reviewing: 1) the properties of different HK isoforms and how their function is regulated by their subcellular localization; 2) how HKs modulate glucose metabolism and energy production during I/R; 3) the molecular mechanisms by which HKs influence mPTP opening and cellular injury during I/R; 4) how different metabolic and HK profiles correlate with susceptibility to I/R injury and cardioprotective efficacy in cancer cells, neonatal hearts, and normal, hypertrophied and failing adult hearts, and how these difference may guide novel therapeutic strategies to limit I/R injury in the heart.

Real-Time Fluorescence Measurements of ROS and [Ca2+] in Ischemic / Reperfused Rat Hearts: Detectable Increases Occur only after Mitochondrial Pore Opening and Are Attenuated by Ischemic Preconditioning

“…One such established mechanism involves hexokinase 2 (HK2) whose binding to mitochondria is associated with resistance to mPTP opening [22,56,57] and also with stabilisation of contact sites between the inner and outer membrane whose breakage may enhance cytochrome c release [56,58]. HK2 is known to dissociate from heart mitochondria during reperfusion and this is prevented by IP [21,22,56,57]. Indeed, there is a very strong inverse correlation between the amount of HK2 remaining bound to mitochondria at the end of ischemia and the infarct size after 120 min of reperfusion [21].…”

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. 21 Mitochondrial hexokinase 2 stabilizes contact sites between the inner and outer mitochondrial membranes and thereby attenuates loss of cytochrome C from the intermembrane space to the cytosol during myocardial ischemia/ reperfusion.…”

A1 adenosine receptor-induced phosphorylation and modulation of transglutaminase 2 activity in H9c2 cells: A role in cell survival

“…For example, hexokinase 1 (HK1) and acidic leucine-rich nuclear phosphoprotein 32 family member A (ANP32A) both exhibited in excess of 5-fold increases compared to the control. The former is a recognised as a mediator of cardioprotection via its interaction with mitochondrial voltage-dependent anion-selective channel protein 1 (VDAC1), which increased by over 2-fold in stimulated cells [62,63]. Interestingly, VDAC1 was previously identified as a TG2 substrate in PMA-stimulated H9c2 cells [27].…”