Akt/PKB inhibits early apoptotic events by coupling glucose metabolism to mitochondrial function. This study shows that Akt prevents the closure of the voltage-dependent anion channel (VDAC) in mitochondria, which is essential for maintaining mitochondrial integrity and preventing apoptosis. Akt achieves this by increasing the activity of mitochondrial-bound hexokinase (mtHK), which couples glucose metabolism to oxidative phosphorylation. The first committed step of glycolysis, catalyzed by hexokinase, is sufficient for Akt to inhibit apoptosis. Akt's antiapoptotic effect requires glucose availability and metabolism, and it is independent of de novo protein synthesis. Ectopic expression of hexokinase mimics Akt's ability to inhibit cytochrome c release and apoptosis. The study also shows that Akt promotes the association of hexokinase with the outer mitochondrial membrane through its interaction with VDAC. This interaction is crucial for maintaining mitochondrial function and preventing apoptosis. The results suggest that Akt exerts its antiapoptotic effects through the regulation of mitochondrial hexokinase activity, which is essential for coupling glucose metabolism to oxidative phosphorylation and maintaining mitochondrial integrity. The findings highlight the importance of mitochondrial metabolism in cell survival and provide new insights into the mechanisms by which Akt prevents apoptosis.Akt/PKB inhibits early apoptotic events by coupling glucose metabolism to mitochondrial function. This study shows that Akt prevents the closure of the voltage-dependent anion channel (VDAC) in mitochondria, which is essential for maintaining mitochondrial integrity and preventing apoptosis. Akt achieves this by increasing the activity of mitochondrial-bound hexokinase (mtHK), which couples glucose metabolism to oxidative phosphorylation. The first committed step of glycolysis, catalyzed by hexokinase, is sufficient for Akt to inhibit apoptosis. Akt's antiapoptotic effect requires glucose availability and metabolism, and it is independent of de novo protein synthesis. Ectopic expression of hexokinase mimics Akt's ability to inhibit cytochrome c release and apoptosis. The study also shows that Akt promotes the association of hexokinase with the outer mitochondrial membrane through its interaction with VDAC. This interaction is crucial for maintaining mitochondrial function and preventing apoptosis. The results suggest that Akt exerts its antiapoptotic effects through the regulation of mitochondrial hexokinase activity, which is essential for coupling glucose metabolism to oxidative phosphorylation and maintaining mitochondrial integrity. The findings highlight the importance of mitochondrial metabolism in cell survival and provide new insights into the mechanisms by which Akt prevents apoptosis.