Abu-Hamad S, Zaid H, Israelson A, Nahon E, Shoshan-Barmatz V.. Hexokinase-I protection against apoptotic cell death is mediated via interaction with the voltage-dependent anion channel-1: mapping the site of binding. J Biol Chem 283: 13482-13490

Department of Life Sciences, Ben-Gurion University of the Negev, Beer-Sheva 84105, Israel.
Journal of Biological Chemistry (Impact Factor: 4.57). 06/2008; 283(19):13482-90. DOI: 10.1074/jbc.M708216200
Source: PubMed


In brain and tumor cells, the hexokinase isoforms HK-I and HK-II bind to the voltage-dependent anion channel (VDAC) in the outer mitochondrial membrane. We have previously shown that HK-I decreases murine VDAC1 (mVDAC1) channel conductance, inhibits cytochrome c release, and protects against apoptotic cell death. Now, we define mVDAC1 residues, found in two cytoplasmic domains, involved in the interaction with HK-I. Protection against cell death by HK-I, as induced by overexpression of native or mutated mVDAC1, served to identify the mVDAC1 amino acids required for interaction with HK-I. HK-I binding to mVDAC1 either in isolated mitochondria or reconstituted in a bilayer was inhibited upon mutation of specific VDAC1 residues. HK-I anti-apoptotic activity was also diminished upon mutation of these amino acids. HK-I-mediated inhibition of cytochrome c release induced by staurosporine was also diminished in cells expressing VDAC1 mutants. Our results thus offer new insights into the mechanism by which HK-I promotes tumor cell survival via inhibition of cytochrome c release through HK-I binding to VDAC1. These results, moreover, point to VDAC1 as a key player in mitochondrially mediated apoptosis and implicate an HK-I-VDAC1 interaction in the regulation of apoptosis. Finally, these findings suggest that interference with the binding of HK-I to mitochondria by VDAC1-derived peptides may offer a novel strategy by which to potentiate the efficacy of conventional chemotherapeutic agents.

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    • "The hydrophobic region is essential for the insertion into the mitochondria but not for the direct binding to VDAC. Mutational experiments on VDAC- 1, identified critical residues in the cytosolic portion of VDAC [37] required for interaction with HKII. Interestingly, HKII detachment does not trigger cell death per se in all cellular systems, whereas it markedly increases the cytotoxicity of many cytocidal treatments [33] [38]. "
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    ABSTRACT: Cancer cells depend on an altered energy metabolism characterized by increased rates of both glycolysis and glutaminolysis. Accordingly, corresponding key metabolic enzymes are overexpressed or hyperactivated. As a result, this newly acquired metabolic profile determines most other cancer hallmarks including resistance to cell death. Recent findings highlighted metabolic enzymes as direct modulators of cell death pathways. Conversely, key mediators of cell death mechanisms are emerging as new binding partners of glycolytic actors; moreover, there is evidence that metabolic regulators re-localize to specific subcellular compartments or organelles to modulate various types of cell demise. The final outcome is the resistance against cell death programs. Current findings give a new meaning to metabolic pathways and allow understanding how they affect cancer-specific pathological alterations. Furthermore, they shed light on potentially targetable functions of metabolic actors to restore susceptibility of cancer cells to death. Here, we discuss an emerging interplay between cell metabolism and cell death, focusing on interactions that may offer new options of targeted therapies in cancer treatment involving more specifically hexokinases and glyceraldehyde-3-phosphate dehydrogenase.
    Biochemical Pharmacology 11/2014; 92(1). DOI:10.1016/j.bcp.2014.07.005 · 5.01 Impact Factor
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    • "Our VHC model allows the explanation of the Warburg effect as a result of the OMP-dependent electrical suppression of the outer membrane permeability [23] [24]. Dissociation of HK from the VDAC-HK complex by 3-bromopyruvate [32] or by peptides derived from HK [12] [55] [56] or VDAC [8] [57], especially in combination with the MOM permeabilizing factors [56], should cause the OMP collapse. Under such treatments, the drugs increasing cytoplasmic concentration of calcium ions [39] might favor cell death. "
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    ABSTRACT: The simplest mechanism of the generation of the mitochondrial outer membrane potential (OMP) by the VDAC (voltage-dependent anion channel)-hexokinase complex (VHC), suggested earlier, and by the VDAC-glucokinase complex (VGC), was computationally analyzed. Even at less than 4 % of VDACs bound to hexokinase, the calculated OMP is high enough to trigger the electrical closure of VDACs beyond the complexes at threshold concentrations of glucose. These results confirmed our previous hypothesis that the Warburg effect is caused by the electrical closure of VDACs, leading to global restriction of the outer membrane permeability coupled to aerobic glycolysis. The model showed that the inhibition of the conductance and/or an increase in the voltage sensitivity of a relatively small fraction of VDACs by factors like tubulin potentiate the electrical closure of the remaining free VDACs. The extrusion of calcium ions from the mitochondrial intermembrane space by the generated OMP, positive inside, might increase cancer cell resistance to death. Within the VGC model, the known effect of induction of ATP release from mitochondria by accumulated glucose-6-phosphate in pancreatic beta cells might result not only of the known effect of GK dissociation from the VDAC-GK complex, but also of a decrease in the free energy of glucokinase reaction, leading to the OMP decrease and VDAC opening. We suggest that the VDAC-mediated electrical control of the mitochondrial outer membrane permeability, dependent on metabolic conditions, is a fundamental physiological mechanism of global regulation of mitochondrial functions and of cell death.
    Biochimica et Biophysica Acta 01/2014; 1838(5). DOI:10.1016/j.bbamem.2014.01.001 · 4.66 Impact Factor
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    • "The binding of hexokinase with VDAC allows the direct access of hexokinase to mitochondrial ATP in the glycolytic pathway. Recent studies also revealed that hexokinase inhibits apoptosis by binding to VDAC and preventing the release of cytochrome c [84] [122] [125]. "
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    ABSTRACT: Glycogen synthase kinase 3 (GSK3) is a serine/threonine protein kinase that is involved in the multiple signaling processes of a cell. Increasing evidence suggests that GSK3β plays a key role in multiple cellular processes in the progression of diabetes, obesity, Alzheimer's disease (AD), Parkinson's disease (PD), inflammatory diseases, schizophrenia, bipolar and several mood disorders, and mitochondrial diseases. Recent research has found that increased GSK3β activity is linked to the pathogenesis of AD through amyloid beta (Aβ), phosphorylated tau and mitochondrial dysfunction. Recent research has also revealed that GSK3β is elevated in AD-affected tissues and is critically involved in dissociating the voltage-dependent anion channel 1 (VDAC1) protein from hexokinases, and causing disrupted glucose metabolism, mitochondrial dysfunction and activating apoptotic cell death. The purpose of this article is to review recent research that is elucidating the role of GSK3β in AD pathogenesis. We discuss the involvement of GSK3β in the phosphorylation of VDAC1 and dissociation of VADC1 with hexokinases in AD neurons.
    Biochimica et Biophysica Acta 06/2013; 1832(12). DOI:10.1016/j.bbadis.2013.06.012 · 4.66 Impact Factor
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