Mitochondrial Binding of Hexokinase II Inhibits Bax-induced Cytochrome c Release and Apoptosis*

By J. G. Pastorino, N. Shulga, Jan B. Hoek. Journal of Biological Chemistry, 2002

736 citations recorded by the source corpus.

Proapoptotic proteins such as Bax, undergo translocation to the mitochondria during apoptosis, where they mediate the release of intermembrane space proteins including cytochromec. Bax binds to the voltage-dependent anion channel (VDAC). VDAC is a β-barrel protein located in the outer mitochondrial membrane. In planar lipid bilayers, Bax and VDAC form a channel through which cytochrome c can pass. Hexokinase II (HXK II) also binds to VDAC. HXK II catalyzes the first step of glycolysis and is highly expressed in transformed cells, where over 70% of it is bound to the mitochondria. The present study demonstrates that HXK II interferes with the ability of Bax to bind to mitochondria and release cytochrome c. Detachment of HXK II from the mitochondria-enriched fraction isolated from HeLa cells promoted the binding of recombinant Bax-Δ19 and subsequent cytochromec release. Similarly, the addition of recombinant HXK II to the mitochondria-enriched fraction isolated from hepatocytes, cells that do not express HXK II endogenously, prevented the ability of recombinant Bax-Δ19 to bind to the mitochondria and promote cytochrome c release. Similar results were found in intact cells, in which the detachment of mitochondrial bound HXK II or its overexpression potentiated and inhibited, respectively, Bax-induced mitochondrial dysfunction and cell death.

Subfields: Cell Biology, Physiology, Surgery

View Paper: https://www.semanticscholar.org/paper/e4331cc3c4d68e9a8bd22cf00415032a846b38c1

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In Physiology

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Citations in the corpus

• Glycolysis inhibition for anticancer treatment (2006, background): “…may regulate apoptosis (Ishitani and Chuang, 1996; Shashidharan et al., 1999; Tajima et al., 1999; Dastoor and Dreyer, 2001; Gottlob et al., 2001; Pastorino et al., 2002; Rathmell et al., 2003; Majewski et al., 2004), and glucose-6-phosphate isomerase can affect cell motility (Liotta et al.,…”
• Characterization of the human heart mitochondrial proteome (2003, background): “Furthermore, it has recently been shown in human HeLa cells and rat hepatocytes that a hexokinase-mitochondrial association inhibits Bax-induced release of cytochrome c and thereby regulates apoptosi”
• Hexokinase 2 is a key mediator of aerobic glycolysis and promotes tumor growth in human glioblastoma multiforme (2011, background): “Furthermore, the growthpromoting effects of HK2 require both glucose phosphorylation and mitochondrial localization, mediated by activation of the PI3K–AKT signaling pathway, which is known to be aberrant in GBMs (Gottlob et al., 2001; Pastorino et al., 2002; Majewski et al., 2004).”
• Differential Roles of Hypoxia-Inducible Factor 1α (HIF-1α) and HIF-2α in Hypoxic Gene Regulation (2003, neutral): “Akt has been shown to be activated by hypoxia (1, 8, 16, 31, 48, 76).”
• Tumor glycolysis as a target for cancer therapy: progress and prospects (2013, positive): “provides survival advantage to cancer cells [43,44].”
• Akt-Directed Glucose Metabolism Can Prevent Bax Conformation Change and Promote Growth Factor-Independent Survival (2003, background): “Phospho-2-DOG may provide only a short-term survival advantage because accumulation of phospho-2-DOG has been shown to cause dissociation of hexokinase proteins from outer mitochondrial membranes (54), which may lead to apoptosis (20, 47).”
• Mitochondria in cancer cells: what is so special about them? (2008, positive): “Another consequence of hexokinase‐VDAC interaction is that hexokinase occupies binding sites for pro-apoptotic proteins on the OMM and thereby prevents induction of apoptosis (Figure 3de) [ 51 ].”
• Hexokinase II: Cancer's double-edged sword acting as both facilitator and gatekeeper of malignancy when bound to mitochondria (2006, background): “In fact, secondary disruption of the HK– VDAC interaction via non-Akt involved pathways, even in the absence of activation of proapoptotic factors such as Bax and Bak, induces apoptosis (Majewski et al., 2004a).”
• Hypoxia-Inducible Factor 1 and Dysregulated c-Myc Cooperatively Induce Vascular Endothelial Growth Factor and Metabolic Switches Hexokinase 2 and Pyruvate Dehydrogenase Kinase 1 (2007, background): “Particularly, in addition to its rate-limiting role in glucose metabolism, HK2 is overexpressed in most human cancers and suppresses proapoptotic molecules including Bad and Bax at the mitochondrial outer membrane, by which HK2 functions as a key coordinator by integrating glucose metabolism with ap”