Akt protein kinase B inhibits cell death by preventing the release of cytochrome c from mitochondria

Growth factors signaling through the phosphoinositide 3-kinase/Akt pathway promote cell survival. The mechanism by which the serine/threonine kinase A kt prevents cell death remains unclear. We have previously shown that Akt i nhibits the activity of DEVD-targeted caspases without changing the steady; state levels of Bcl-2 and Bcl-x(L). Here we show that Akt inhibits apoptosi s and, the processing of procaspases to their active. forms by delaying mit ochondrial changes in a caspase-independent manner. Akt activation is suffi cient to inhibit the release of cytochrome c from mitochondria and the alte rations in the inner mitochondrial membrane potential. However, Akt cannot inhibit apoptosis induced by microinjection of cytochrome c. We also demons trated that Akt inhibits apoptosis and cytochrome c release induced by seve ral proapoptotic Bcl-2 family members. Taken together, our results show tha t AM promotes cell survival by intervening in the apoptosis cascade before cytochrome c release and caspase activation via a mechanism that is distinc t from Bad phosphorylation.