University of Medicine and Dentistry of New Jersey

Shulga, N., R. Wilson-Smith, and J.G. Pastorino, Hexokinase II detachment from the mitochondria potentiates cisplatin induced cytotoxicity through a caspase-2 dependent mechanism. . .. Cell Cycle, 2009. Vol. 8(20): : p. 3355-64 (2009 ) .

Pastorino, J.G. and Hoek JB Regulation of Hexokinase II Binding to VDAC.. Journal of Bioenergetics and Biomembranes. Vol. : (2008 July ) .

Pastorino, JG and Shulga, Nataly TNF can provoke cleavage and activation of sterol regulatory element binding protein in ethanol exposed cells via a caspase dependent pathway that is cholesterol-insensitive. Journal of Biological Chemistry. Vol. : (2008 July ) .

Pastorino, J.G. and N. Shulga Tumor necrosis factor-alpha can provoke cleavage and activation of sterol regulatory element-binding protein in ethanol-exposed cells via a caspase-dependent pathway that is cholesterol insensitive. . J Biol Chem,. Vol. 283(37):: p. 25638-49 (2008 ) .

Shulga, N. and Pastorino, J. G. Acyl coenzyme a binding protein augments bid induced mitochondrial damage and cell death by activating mu - calpain. J Biol Chem. Vol. : (2006 ) .

Pastorino J.G., Hoek J.B., and Shulga, N. Activation of Glycogen Synthase Kinase 3² Disrupts the Binding of Hexokinase II to Mitochondria by Phosphorylating Voltage-Dependent Anion Channel and Potentiates Chemotherapy-induced Cytotoxicity. . Cancer Research . Vol. 65: (22) : pp 10545-10554 (2005 ) .

Shulga N, Hoek J.B., and Pastorino J.G., Elevated PTEN Levels Account for the Increased Sensitivity of Ethanol-exposed Cells to Tumor Necrosis Factor-induced Cytotoxicity.. J Biol Chem,. Vol. 280: 9416-9424 (2005 ) .

Hoek J.B., and Pastorino J.G., Cellular signaling mechanisms in alcohol-induced liver damage. Seminars in Liver Disease . Vol. 24 (3): pp. 257-27 (20?? ) .

Pastorino JG, Shulga N, Hoek JB TNF{alpha} induced cell killing in ethanol-exposed cells is dependent on p38 MAPK signaling but independent of Bid and caspase-8.. Am J Physiol Gastrointest Liver Physiol. Vol. : (2003 ) .

Hoek, J.B., Cahill, A., Pastorino, J.G., Alcohol and Mitochondria: A Dysfunctional Relationship.. [Review] Gastroenterology. . Vol. 122(7): 2049-63 (2002 Jun ) .

Top of page

Grants and Contracts

Title: Effects of Ethanol on TNF induced Cytotoxicity
Sponsor: National Institutes of Health/NIAAA
Effective Date(s): 2008 - 2013
Role: P.I.

Title: Targeting Hexokinase II in Chemotherapy.
Sponsor: National Institutes of Health/NCI
Effective Date(s): 2007 - 2012
Role: P.I.

Title: Effects of Ethanol on TNF induced Cytotoxicity
Sponsor: National Institutes of Health/NIAAA
Effective Date(s): 2002 - 2008
Role: P.I.

Top of page

Research Areas

The role of mitochondria in cell injury and apoptosis: The work of my laboratory focuses on the role of mitochondria in cell injury and apoptosis. As such we have been able to investigate a wide range of research interests. The mitochondria have emerged as integral to the areas of cell death and survival. Mitochondria are noted as the primary source of energy generation in the cell. However in this capacity the mitochondria can also assimilate and respond to a number of signaling pathways. Our work has uncovered that mitochondria are central to the reaction of a cell to treatment with tumor necrosis factor (TNF). This is especially critical in the context of alcoholic liver disease (ALD) where the hepatocytes display a propensity to induction of cell killing in the form of apoptosis and necrosis when exposed to TNF. This in turn leads to the alterations in liver architecture and function that are characteristic of ALD. Additionally, the mitochondria are central to energy metabolism and as such, the work performed in my laboratory has uncovered how alterations to mitochondrial outer membrane proteins such as VDAC can influence insulin signaling, thereby having implications for diseases such as diabetes and non-alcoholic fatty liver disease, which have their genesis in metabolic abnormalities. Our studies in mitochondria also impact the field of cancer research. As a central mediator of the cell death response, mitochondria have the potential to be exploited as a chemotherapeutic target. This is especially relevant in highly glycolytic tumors such as gliomas . Our studies have uncovered that hexokinase II (HXK II) in cancerous cells, a protein over-expressed in a number of malignancies, is bound to the mitochondria in a controlled fashion. The binding of HXK II to the mitochondria is mediated through an interaction between HXK II and VDAC, an outer mitochondrial membrane protein. In this configuration, HXK II prevents interaction of VDAC with pro-apoptotic proteins such as Bax and Bak . Treatment of cancer cells with exogenous agents that detach hexokinase II from the mitochondria greatly facilitate the ability of conventional chemotherapeutic agents to kill the transformed cells. Since the expression and binding of HXK II is so much greater in cancer than in normal cells, the influence of hexokinase II detachment on the viability of normal cells is nominal. Study in the fields of apoptosis and mitochondria have increased dramatically in the past decade. Our work over the past 18 years has encompassed both of these areas and the interactions that occur between them. This places use in a unique position to study the myriad of diseases where apoptosis and mitochondria converge and have been implicated in the pathogenesis and progression of disease states.

Top of page