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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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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
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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
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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
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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
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Mitochondria and Cancer: Warburg Addressed.
D.C. WALLACE (2005)
Cold Spring Harb Symp Quant Biol 70, 363-374
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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 »
Mitochondrial Bound Hexokinase Activity as a Preventive Antioxidant Defense: STEADY-STATE ADP FORMATION AS A REGULATORY MECHANISM OF MEMBRANE POTENTIAL AND REACTIVE OXYGEN SPECIES GENERATION IN MITOCHONDRIA.
W. S. da-Silva, A. Gomez-Puyou, M. T. de Gomez-Puyou, R. Moreno-Sanchez, F. G. De Felice, L. de Meis, M. F. Oliveira, and A. Galina (2004)
J. Biol. Chem. 279, 39846-39855
   Abstract »    Full Text »    PDF »
Upstream and downstream of mTOR.
N. Hay and N. Sonenberg (2004)
Genes & Dev. 18, 1926-1945
   Abstract »    Full Text »    PDF »
Proinflammatory interleukin-1 cytokines increase mesangial cell hexokinase activity and hexokinase II isoform abundance.
N. Taneja, P. E. Coy, I. Lee, J. M. Bryson, and R. B. Robey (2004)
Am J Physiol Cell Physiol 287, C548-C557
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Evaluation of Myc E-Box Phylogenetic Footprints in Glycolytic Genes by Chromatin Immunoprecipitation Assays.
J.-w. Kim, K. I. Zeller, Y. Wang, A. G. Jegga, B. J. Aronow, K. A. O'Donnell, and C. V. Dang (2004)
Mol. Cell. Biol. 24, 5923-5936
   Abstract »    Full Text »    PDF »
Akt Decreases Lymphocyte Apoptosis and Improves Survival in Sepsis.
U. Bommhardt, K. C. Chang, P. E. Swanson, T. H. Wagner, K. W. Tinsley, I. E. Karl, and R. S. Hotchkiss (2004)
J. Immunol. 172, 7583-7591
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Akt Stimulates Aerobic Glycolysis in Cancer Cells.
R. L. Elstrom, D. E. Bauer, M. Buzzai, R. Karnauskas, M. H. Harris, D. R. Plas, H. Zhuang, R. M. Cinalli, A. Alavi, C. M. Rudin, et al. (2004)
Cancer Res. 64, 3892-3899
   Abstract »    Full Text »    PDF »
Akt and Hypoxia-Inducible Factor-1 Independently Enhance Tumor Growth and Angiogenesis.
A. M. Arsham, D. R. Plas, C. B. Thompson, and M. C. Simon (2004)
Cancer Res. 64, 3500-3507
   Abstract »    Full Text »    PDF »
The Prognostic Significance of Phosphatidylinositol 3-Kinase Pathway Activation in Human Gliomas.
A. Chakravarti, G. Zhai, Y. Suzuki, S. Sarkesh, P. M. Black, A. Muzikansky, and J. S. Loeffler (2004)
J. Clin. Oncol. 22, 1926-1933
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Regulation of T Lymphocyte Metabolism.
K. A. Frauwirth and C. B. Thompson (2004)
J. Immunol. 172, 4661-4665
   Abstract »    Full Text »    PDF »

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