Nataly Shulga

Activation of Glycogen Synthase Kinase 3β Disrupts the Binding of Hexokinase II to Mitochondria by Phosphorylating Voltage-Dependent Anion Channel and Potentiates Chemotherapy-Induced Cytotoxicity

Transformed cells are highly glycolytic and overexpress hexokinase II (HXK II). HXK II is capable of binding to the mitochondria through an interaction with the voltage-dependent anion channel (VDAC), an abundant outer mitochondrial membrane protein. The binding of HXK II to mitochondria has been shown to protect against loss of cell viability. Akt activation inhibits apoptosis partly by promoting the binding of HXK II to the mitochondria, but the mechanism through which Akt accomplishes this has not been characterized. The present report shows that Akt mediates the binding of HXK II to the mitochondria by negatively regulating the activity of glycogen synthase kinase 3beta (GSK3beta). On inhibition of Akt, GSK3beta is activated and phosphorylates VDAC. HXK II is unable to bind VDAC phosphorylated by GSK3beta and dissociates from the mitochondria. Inhibition of Akt potentiates chemotherapy-induced cytotoxicity, an effect that is dependent on GSK3beta activation and its attendant ability to disrupt the binding of HXK II to the mitochondria. Moreover, agents that can force the detachment of HXK II from mitochondria in the absence of Akt inhibition or GSK3beta activation promoted a synergistic increase in cell killing when used in conjunction with chemotherapeutic drugs. Such findings indicate that interference with the binding of HXK II to mitochondria may be a practicable modality by which to potentiate the efficacy of conventional chemotherapeutic agents.

Sirtuin-3 deacetylation of cyclophilin D induces dissociation of hexokinase II from the mitochondria.

We demonstrate that the transition from a reliance on glycolysis to oxidative phosphorylation in a transformed cell line is dependent on an increase in the levels and activity of sirtuin-3. Sirtuin-3 deacetylates cyclophilin D, diminishing its peptidyl-prolyl cis-trans isomerase activity and inducing its dissociation from the adenine nucleotide translocator. Moreover, the sirtuin-3-induced inactivation of cyclophilin D causes a detachment of hexokinase II from the mitochondria that is necessary for stimulation of oxidative phosphorylation. These results might have important implications for the role of sirtuin-3 in the metabolism of some cancer cells and their susceptibility to mitochondrial injury and cytotoxicity.

Hexokinase II detachment from the mitochondria potentiates cisplatin induced cytotoxicity through a caspase-2 dependent mechanism.

Cancer cells are frequently glycolytic and over-express hexokinase II (HXK II). In cancer cells, the majority of hexokinase II is localized to the mitochondria through interaction with the voltage dependent anion channel (VDAC). Disruption in the binding of hexokinase II to the mitochondria has been shown to promote mitochondrial injury provoked by pro-apoptotic proteins. The present study demonstrates that cisplatin induces the PIDD (P53 induced protein with a death domain) dependent activation of caspase-2. In turn, caspase-2 cleaves and activates Bid, resulting in the oligomerization of Bak and the release of cytochrome c. Notably, the detachment of hexokinase II from the mitochondria markedly potentiates the onset of caspase-2 induced mitochondrial damage, thus resulting in a synergistic induction of cisplatin induced cytotoxicity.

Acyl Coenzyme A-binding Protein Augments Bid-induced Mitochondrial Damage and Cell Death by Activating μ-Calpain

Activation of calpain has been shown to occur in some contexts of cell injury and to be essential for loss of cell viability. Part of this may be mediated at the mitochondrial level. It has been demonstrated that calpain activity is necessary for the complete discharge of apoptosis-inducing factor from the mitochondrial intermembrane space and can cause the cleavage of full-length Bid to a more potent truncated form (Polster, B. M., Basanez, G., Etxebarria, A., Hardwick, J. M., and Nicholls, D. G. (2005) J. Biol. Chem. 280, 6447-6454). In this study, we identify acyl-CoA-binding protein (ACBP) as playing a critical role in the activation of calpain upon exposure of mitochondria to both full-length Bid and truncated Bid (t-Bid). Suppression of ACBP levels by small interfering RNA inhibited the t-Bid-induced activation of mitochondrial μ-calpain and release of apoptosis-inducing factor from the mitochondrial intermembrane space and the cleavage of full-length Bid to t-Bid. Moreover, ACBP required the presence of the peripheral benzodiazepine receptor (for which ACBP is a ligand) to be retained at the mitochondria, to activate μ-calpain, and to amplify Bid-induced mitochondrial damage.

Tumor Necrosis Factor-α Can Provoke Cleavage and Activation of Sterol Regulatory Element-binding Protein in Ethanol-exposed Cells via a Caspase-dependent Pathway That Is Cholesterol Insensitive

Ethanol induces the development of hepatic steatosis, increasingly recognized as causing vulnerability to subsequent liver injury. Ethanol has been shown to activate SREBP-1 (sterol regulatory element-binding protein) processing through the conventional cholesterol-sensitive pathway (1). The present study demonstrates that ethanol can also bring about SREBP-1 cleavage and activation through a novel pathway dependent on the endoplasmic reticulum-localized caspases-4 and -12. Evidence is presented that tumor necrosis factor can stimulate caspase-4 and -12 activation in ethanol-exposed cells, which cleaves SREBP-1 to a transcriptionally active form to induce the synthesis of lipogenic enzymes and triglycerides. Moreover, the caspase-4 and -12-dependent activation of SREBP-1 is insensitive to the normal negative feedback exerted by cholesterol and is mediated by the translocation of the scaffolding protein, TRAF-2, to the endoplasmic reticulum.

Retraction: GRIM-19-mediated translocation of STAT3 to mitochondria is necessary for TNF-induced necroptosis

Retraction of: J. Cell Sci. 125 , [2995-3003][1] This article has been retracted at the request of the corresponding author, John G. Pastorino. This notice updates and replaces a recent [Expression of Concern][2], published on 15 February 2016. Journal of Cell Science was alerted to potential

Retraction: Sirtuin-3 modulates Bak- and Bax-dependent apoptosis

Retraction of: J. Cell Sci. (2013) 126 , [274-288][1] This article has been retracted at the request of the corresponding author, John G. Pastorino. This notice updates and replaces a recent [Expression of Concern][2], published on 15 February 2016. Journal of Cell Science was alerted to