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Genes & Dev. 15 (11): 1406-1418

Copyright © 2001 by Cold Spring Harbor Laboratory Press.

Vol. 15, No. 11, pp. 1406-1418, June 1, 2001

RESEARCH PAPER
Inhibition of early apoptotic events by Akt/PKB is dependent on the first committed step of glycolysis and mitochondrial hexokinase

Kathrin Gottlob,1 Nathan Majewski,1 Scott Kennedy,1,4 Eugene Kandel,1 R. Brooks Robey,2,3 and Nissim Hay1,5

1 Department of Molecular Genetics; 2 Department of Medicine, University of Illinois at Chicago, Chicago, Illinois 60607, USA; 3 Veterans Administration, Chicago Healthcare System, West Side Division, Chicago, Illinois 60607, USA

The serine/threonine kinase Akt/PKB is a major downstream effector of growth factor-mediated cell survival. Activated Akt, like Bcl-2 and Bcl-xL, prevents closure of a PT pore component, the voltage-dependent anion channel (VDAC); intracellular acidification; mitochondrial hyperpolarization; and the decline in oxidative phosphorylation that precedes cytochrome c release. However, unlike Bcl-2 and Bcl-xL, the ability of activated Akt to preserve mitochondrial integrity, and thereby inhibit apoptosis, requires glucose availability and is coupled to its metabolism. Hexokinases are known to bind to VDAC and directly couple intramitochondrial ATP synthesis to glucose metabolism. We provide evidence that such coupling serves as a downstream effector function for Akt. First, Akt increases mitochondria-associated hexokinase activity. Second, the antiapoptotic activity of Akt requires only the first committed step of glucose metabolism catalyzed by hexokinase. Finally, ectopic hexokinase expression mimics the ability of Akt to inhibit cytochrome c release and apoptosis. We therefore propose that Akt increases coupling of glucose metabolism to oxidative phosphorylation and regulates PT pore opening via the promotion of hexokinase-VDAC interaction at the outer mitochondrial membrane.

[Key Words: Mitochondrial potential; cytochrome c; ATP; Bcl-2; Bcl-xL]


4 Present address: Department of Molecular Biology, MGH and Harvard Medical School, Boston, MA 02114, USA.

5 Corresponding author.


GENES & DEVELOPMENT 15:1406-1418 © 2001 by Cold Spring Harbor Laboratory Press  ISSN 0890-9369/01 $5.00

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Glucose utilization and the PI3-K pathway: mechanisms for cell survival in preimplantation embryos..
J. K Riley and K. H Moley (2006)
Reproduction 131, 823-835
   Abstract »    Full Text »    PDF »
Glucose Withdrawal Induces Oxidative Stress followed by Apoptosis in Glioblastoma Cells but not in Normal Human Astrocytes.
N. Jelluma, X. Yang, D. Stokoe, G. I. Evan, T. B. Dansen, and D. A. Haas-Kogan (2006)
Mol. Cancer Res. 4, 319-330
   Abstract »    Full Text »    PDF »
Phosphatidylinositol 3-Kinase Activity Is Critical for Glucose Metabolism and Embryo Survival in Murine Blastocysts.
J. K. Riley, M. O. Carayannopoulos, A. H. Wyman, M. Chi, and K. H. Moley (2006)
J. Biol. Chem. 281, 6010-6019
   Abstract »    Full Text »    PDF »
Protection of HIF-1-deficient primary renal tubular epithelial cells from hypoxia-induced cell death is glucose dependent.
M. P. Biju, Y. Akai, N. Shrimanker, and V. H. Haase (2005)
Am J Physiol Renal Physiol 289, F1217-F1226
   Abstract »    Full Text »    PDF »
Glucose 6-Phosphate Release of Wild-type and Mutant Human Brain Hexokinases from Mitochondria.
D. A. Skaff, C. S. Kim, H. J. Tsai, R. B. Honzatko, and H. J. Fromm (2005)
J. Biol. Chem. 280, 38403-38409
   Abstract »    Full Text »    PDF »
Activation of Glycogen Synthase Kinase 3{beta} Disrupts the Binding of Hexokinase II to Mitochondria by Phosphorylating Voltage-Dependent Anion Channel and Potentiates Chemotherapy-Induced Cytotoxicity.
J. G. Pastorino, J. B. Hoek, and N. Shulga (2005)
Cancer Res. 65, 10545-10554
   Abstract »    Full Text »    PDF »
The matrix protein CCN1 (CYR61) induces apoptosis in fibroblasts.
V. Todorovicc, C.-C. Chen, N. Hay, and L. F. Lau (2005)
J. Cell Biol. 171, 559-568
   Abstract »    Full Text »    PDF »
Mammalian Target of Rapamycin Promotes Vincristine Resistance through Multiple Mechanisms Independent of Maintained Glycolytic Rate.
D. J. VanderWeele and C. M. Rudin (2005)
Mol. Cancer Res. 3, 635-644
   Abstract »    Full Text »    PDF »
Akt Activates the Mammalian Target of Rapamycin by Regulating Cellular ATP Level and AMPK Activity.
A. Hahn-Windgassen, V. Nogueira, C.-C. Chen, J. E. Skeen, N. Sonenberg, and N. Hay (2005)
J. Biol. Chem. 280, 32081-32089
   Abstract »    Full Text »    PDF »
Involvement of Transforming Growth Factor-{beta}1 Signaling in Hypoxia-induced Tolerance to Glucose Starvation.
A. Suzuki, G.-i. Kusakai, Y. Shimojo, J. Chen, T. Ogura, M. Kobayashi, and H. Esumi (2005)
J. Biol. Chem. 280, 31557-31563
   Abstract »    Full Text »    PDF »
K-ras Codon-Specific Mutations Produce Distinctive Metabolic Phenotypes in Human Fibroblasts.
P. Vizan, L. G. Boros, A. Figueras, G. Capella, R. Mangues, S. Bassilian, S. Lim, W.-N. P. Lee, and M. Cascante (2005)
Cancer Res. 65, 5512-5515
   Abstract »    Full Text »    PDF »
Metformin Prevents High-Glucose-Induced Endothelial Cell Death Through a Mitochondrial Permeability Transition-Dependent Process.
D. Detaille, B. Guigas, C. Chauvin, C. Batandier, E. Fontaine, N. Wiernsperger, and X. Leverve (2005)
Diabetes 54, 2179-2187
   Abstract »    Full Text »    PDF »
Localization of the GLUT8 glucose transporter in murine kidney and regulation in vivo in nondiabetic and diabetic conditions.
M. Schiffer, K. Susztak, M. Ranalletta, A. C. Raff, E. P. Bottinger, and M. J. Charron (2005)
Am J Physiol Renal Physiol 289, F186-F193
   Abstract »    Full Text »    PDF »
Ischemic preconditioning, insulin, and morphine all cause hexokinase redistribution.
C. J. Zuurbier, O. Eerbeek, and A. J. Meijer (2005)
Am J Physiol Heart Circ Physiol 289, H496-H499
   Abstract »    Full Text »    PDF »
Mitochondria and Cancer: Warburg Addressed.
D.C. WALLACE (2005)
Cold Spring Harb Symp Quant Biol 70, 363-374
   Abstract »    PDF »
Akt up-regulation increases resistance to microtubule-directed chemotherapeutic agents through mammalian target of rapamycin.
D. J. VanderWeele, R. Zhou, and C. M. Rudin (2004)
Mol. Cancer Ther. 3, 1605-1613
   Abstract »    Full Text »    PDF »
Putting the Rap on Akt.
J. E. Thompson and C. B. Thompson (2004)
J. Clin. Oncol. 22, 4217-4226
   Abstract »    Full Text »    PDF »

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