A Mitochondrial Target of Akt

Science's STKE  12 Jun 2001:
Vol. 2001, Issue 86, pp. tw4
DOI: 10.1126/stke.2001.86.tw4

Protein kinase B (PKB)/Akt can promote cell survival in part by blocking apoptosis that is initiated when cytochrome c is released from mitochondria. This effect is also true of the antiapoptotic factors Bcl-2 and Bcl-xL. However, Gottlob et al. report that Akt may act through control of the activity of hexokinase, a glycolytic enzyme that localizes to the mitochondria. Hexokinase also associates with voltage-dependent anion channels (VDACs in the mitochondria, whose closure precedes cytochrome c release. Akt activity increased hexokinase activity and inhibited VDAC closure in rat cells. In the absence of glucose, Akt failed to protect cells from apoptosis. Overexpression of either Akt or hexokinase inhibited cytochrome c release. The authors propose that Akt links glucose metabolism and oxidative phosphorylation to VDAC dynamics by affecting hexokinase activity, but it is not yet clear if hexokinase is a direct substrate of Akt.

K. Gottlob, N. Majewski, S. Kennedy, E. Kandel, R. B. Robey, N. Hay, Inhibition of early apoptotic events by Akt/PKB is dependent on the first committed step of glycolysis and mitochondrial hexokinase. Genes Dev. 15, 1406-1418 (2001). [Abstract] [Full Text]