Akt and Bcl-x(L) promote growth factor-independent survival through distinct effects on mitochondrial physiology

A comparison of Akt- and Bcl-x(L)-dependent cell survival was undertaken us ing interleukin-3-dependent FL5.12 cells. Expression of constitutively acti ve Akt allows cells to survive for prolonged periods following growth facto r withdrawal, This survival correlates with the expression level of activat ed Akt and is comparable in magnitude to the protection provided by the ant i apoptotic gene Bcl-x(L). Although both genes prevent cell death, Akt-prot ected cells can be distinguished from Bclx(L)-protected cells on the basis of increased glucose transporter expression, glycolytic activity, mitochond rial potential, and cell size. In addition, Akt-expressing cells require hi gh levels of extracellular nutrients to support cell survival. In contrast, Bcl-x(L)-expressing cells deprived of interleukin-3 survive in a more vege tative state, in which the cells are smaller, have lower mitochondrial pote ntial, reduced glycolytic activity, and are less dependent on extracellular nutrients. Thus, Akt and Bcl-x(L) suppress mitochondrion-initiated apoptos is by distinct mechanisms. Akt-mediated survival is dependent on promoting glycolysis and maintaining a physiologic mitochondrial potential. In contra st, Bcl-x(L) maintains mitochondrial integrity in the face of a reduced mit ochondrial membrane potential, which develops as a result of the low glycol ytic rate in growth factor-deprived cells.