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