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 growt h factor-mediated cell survival. Activated Akt, like Bcl-2 and Bcl-xL, prev ents closure of a PT pore component, the voltage-dependent anion channel (V DAC); intracellular acidification; mitochondrial hyperpolarization and the decline in oxidative phosphorylation that precedes cytochrome c release. Ho wever, unlike Bcl-2 and Bcl-xL, the ability of activated Akt to preserve mi tochondrial integrity, and thereby inhibit apoptosis, requires glucose avai lability and is coupled to its metabolism. Hexokinases are known to bind to VDAC and directly couple intramitochondrial ATP synthesis to glucose metab olism, We provide evidence that such coupling serves as a downstream effect or function for Akt. First, Akt increases mitochondria-associated hexokinas e activity. Second, the antiapoptotic activity of Akt requires only the fir st committed step of glucose metabolism catalyzed by hexokinase. Finally, e ctopic hexokinase expression mimics the ability of Akt to inhibit cytochrom e c release and apoptosis. We therefore propose that Akt increases coupling of glucose metabolism to oxidative phosphorylation and regulates PT pore o pening via the promotion of hexokinase-VDAC interaction at the outer mitoch ondrial membrane.