Document Detail

Inhibition of early apoptotic events by Akt/PKB is dependent on the first committed step of glycolysis and mitochondrial hexokinase.
MedLine Citation:
PMID:  11390360     Owner:  NLM     Status:  MEDLINE    
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.
K Gottlob; N Majewski; S Kennedy; E Kandel; R B Robey; N Hay
Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, Non-P.H.S.; Research Support, U.S. Gov't, P.H.S.    
Journal Detail:
Title:  Genes & development     Volume:  15     ISSN:  0890-9369     ISO Abbreviation:  Genes Dev.     Publication Date:  2001 Jun 
Date Detail:
Created Date:  2001-06-06     Completed Date:  2001-07-05     Revised Date:  2012-06-22    
Medline Journal Info:
Nlm Unique ID:  8711660     Medline TA:  Genes Dev     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1406-18     Citation Subset:  IM    
Department of Molecular Genetics, University of Illinois at Chicago, Chicago, Illinois 60607, USA.
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MeSH Terms
Apoptosis / genetics,  physiology*
Cells, Cultured
Cytochrome c Group / metabolism
Exoribonucleases / metabolism
Glucose / metabolism
Glycolysis / physiology*
Hexokinase / metabolism*
Ion Channels / metabolism
Mitochondria / enzymology,  metabolism*
Porins / metabolism
Protein-Serine-Threonine Kinases / metabolism,  physiology*
Proto-Oncogene Proteins / metabolism,  physiology*
Proto-Oncogene Proteins c-akt
Proto-Oncogene Proteins c-bcl-2 / metabolism
Voltage-Dependent Anion Channels
bcl-X Protein
Grant Support
Reg. No./Substance:
0/Bcl2l1 protein, rat; 0/Cytochrome c Group; 0/Ion Channels; 0/Porins; 0/Proto-Oncogene Proteins; 0/Proto-Oncogene Proteins c-bcl-2; 0/Voltage-Dependent Anion Channels; 0/bcl-X Protein; 50-99-7/Glucose; EC; EC protein, rat; EC Kinases; EC Proteins c-akt; EC 3.1.-/Exoribonucleases

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