Mitochondrial hexokinase and cardioprotection of the intact heart

Zuurbier, Coert J.; Smeele, Kirsten M.; Eerbeek, Otto

doi:10.1007/s10863-009-9209-7

Cited by 39 publications

(25 citation statements)

References 41 publications

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“…Indeed, it has been proposed that HK2 detachment may be directly or indirectly responsible for the recruitment or activation of pro-apoptotic proteins responsible for OMM permeabilization that leads to the loss of cytochrome c and other apoptogenic factors [17]. Our results confirm those of others [50] that ischaemia decreases HK2 binding to mitochondria (Figure 8) suggesting a possible role for this protein in the observed cytochrome c release. What causes this dissociation during ischaemia is not known, but it could reflect the increased glucose-6-phosphate concentrations that occur during ischaemia [51].…”

Section: Discussionsupporting

confidence: 89%

The role of oxidized cytochrome c in regulating mitochondrial reactive oxygen species production and its perturbation in ischaemia

Pasdois

Parker

Griffiths

et al. 2011

Biochemical Journal

113

107

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Oxidized cytochrome c is a powerful superoxide scavenger within the mitochondrial IMS (intermembrane space), but the importance of this role in situ has not been well explored. In the present study, we investigated this with particular emphasis on whether loss of cytochrome c from mitochondria during heart ischaemia may mediate the increased production of ROS (reactive oxygen species) during subsequent reperfusion that induces mPTP (mitochondrial permeability transition pore) opening. Mitochondrial cytochrome c depletion was induced in vitro with digitonin or by 30 min ischaemia of the perfused rat heart. Control and cytochrome c-deficient mitochondria were incubated with mixed respiratory substrates and an ADP-regenerating system (State 3.5) to mimic physiological conditions. This contrasts with most published studies performed with a single substrate and without significant ATP turnover. Cytochrome c-deficient mitochondria produced more H2O2 than control mitochondria, and exogenous cytochrome c addition reversed this increase. In the presence of increasing [KCN] rates of H2O2 production by both pre-ischaemic and end-ischaemic mitochondria correlated with the oxidized cytochrome c content, but not with rates of respiration or NAD(P)H autofluorescence. Cytochrome c loss during ischaemia was not mediated by mPTP opening (cyclosporine-A insensitive), neither was it associated with changes in mitochondrial Bax, Bad, Bak or Bid. However, bound HK2 (hexokinase 2) and Bcl-xL were decreased in end-ischaemic mitochondria. We conclude that cytochrome c loss during ischaemia, caused by outer membrane permeabilization, is a major determinant of H2O2 production by mitochondria under pathophysiological conditions. We further suggest that in hypoxia, production of H2O2 to activate signalling pathways may be also mediated by decreased oxidized cytochrome c and less superoxide scavenging.

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Section: Discussionsupporting

confidence: 89%

The role of oxidized cytochrome c in regulating mitochondrial reactive oxygen species production and its perturbation in ischaemia

Pasdois

Parker

Griffiths

et al. 2011

Biochemical Journal

113

107

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“…However, one cannot eliminate whether the better ischemic tolerance of the RV is due to its lower workload and energy demands. Interestingly, several reports showed that an increased expression of HK is associated with an improved resistance of cells, including cardiomyocytes, against ischemic injury [61] and apoptosis [15,22,25,28,29,30]. HK is a crucial glycolytic enzyme playing an important role in survival pathways.…”

Section: Discussionmentioning

confidence: 99%

Right-To-Left Ventricular Differences in the Expression of Mitochondrial Hexokinase and Phosphorylation of Akt

Waskova-Arnostova

Elsnicová²,

Kasparova³

et al. 2013

Cell Physiol Biochem

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Background/Aims: Hexokinase (HK) is a key glycolytic enzyme which promotes the maintenance of glucose homeostasis in cardiomyocytes. HK1 isoform is predominantly bound to the outer mitochondrial membrane and highly supports oxidative phosphorylation by increasing the availability of ADP for complex V of the respiratory chain. HK2 isoform is under physiological conditions predominantly localized in the cytosol and upon stimulation of PI3K/ Akt pathway associates with mitochondria and thus can prevent apoptosis. The purpose of this study was to investigate expression and subcellular localization of both HK isoforms in left (LV) and right (RV) heart ventricles of adult male Wistar rats. Methods: Real-Time RT-PCR, Western blotting, and quantitative immunofluorescence microscopy were used. Results: Our results showed a significantly higher expression of both HK1 and HK2 at mRNA and protein levels in the RV compared to the LV. These findings were corroborated by immunofluorescence staining which revealed substantially higher fluorescence signals of both HKs in the RV than in the LV. The ratios of phospho-Ser473-Akt/non-phospho-Akt and phospho-Thr308-Akt/non-phospho-Akt were also markedly higher in the RV than in the LV. Conclusion: These results suggest that the RV has a higher activity of aerobic glycolytic metabolism and may be able to respond faster and more powerfully to stressful stimuli than the LV.

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“…[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.…”

Section: Hexokinasementioning

confidence: 99%

Molecular Basis of Cardioprotection

Heusch

2015

Circulation Research

713

409

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Abstract:Reperfusion is mandatory to salvage ischemic myocardium from infarction, but reperfusion per se contributes to injury and ultimate infarct size. Therefore, cardioprotection beyond that by timely reperfusion is needed to reduce infarct size and improve the prognosis of patients with acute myocardial infarction. The conditioning phenomena provide such cardioprotection, insofar as brief episodes of coronary occlusion/ reperfusion preceding (ischemic preconditioning) or following (ischemic postconditioning) sustained myocardial ischemia with reperfusion reduce infarct size. Even ischemia/reperfusion in organs remote from the heart provides cardioprotection (remote ischemic conditioning). The present review characterizes the signal transduction underlying the conditioning phenomena, including their physical and chemical triggers, intracellular signal transduction, and effector mechanisms, notably in the mitochondria. Cardioprotective signal transduction appears as a highly concerted spatiotemporal program. Although the translation of ischemic postconditioning and remote ischemic conditioning protocols to patients with acute myocardial infarction has been fairly successful, the pharmacological recruitment of cardioprotective signaling has been largely disappointing to date.

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Mitochondrial hexokinase and cardioprotection of the intact heart

Cited by 39 publications

References 41 publications

The role of oxidized cytochrome c in regulating mitochondrial reactive oxygen species production and its perturbation in ischaemia

The role of oxidized cytochrome c in regulating mitochondrial reactive oxygen species production and its perturbation in ischaemia

Right-To-Left Ventricular Differences in the Expression of Mitochondrial Hexokinase and Phosphorylation of Akt

Molecular Basis of Cardioprotection

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