Inhibition of early apoptotic events by Akt/PKB is dependent on the first committed step of glycolysis and mitochondrial hexokinase.
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.
Gottlob
K
K
Department of Molecular Genetics, University of Illinois at Chicago, Chicago, Illinois 60607, USA.
Majewski
N
N
Kennedy
S
S
Kandel
E
E
Robey
R B
RB
Hay
N
N
D000818:Animals; D017209:Apoptosis / Q000235:genetics / Q000502:physiology*; D002478:Cells, Cultured; D003574:Cytochrome c Group / Q000378:metabolism; D005095:Exoribonucleases / Q000378:metabolism; D005947:Glucose / Q000378:metabolism; D006019:Glycolysis / Q000502:physiology*; D006593:Hexokinase / Q000378:metabolism*; D007473:Ion Channels / Q000378:metabolism; D008928:Mitochondria / Q000201:enzymology / Q000378:metabolism*; D018272:Porins / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism / Q000502:physiology*; D011518:Proto-Oncogene Proteins / Q000378:metabolism / Q000502:physiology*; D051057:Proto-Oncogene Proteins c-akt; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D051381:Rats; D050994:Voltage-Dependent Anion Channels; D051020:bcl-X Protein
C494813:Bcl2l1 protein, rat; D003574:Cytochrome c Group; D007473:Ion Channels; D018272:Porins; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D050994:Voltage-Dependent Anion Channels; D051020:bcl-X Protein; D006593:Hexokinase; C494920:Akt1 protein, rat; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D005095:Exoribonucleases; D005947:Glucose