Akt and Bcl-xL Are Independent Regulators of the Mitochondrial Cell Death Pathways
In vivo, hematopoietic cells require continuous signals from their microenvironment to prevent activation of the endogenous programmed cell death machinery. Cell survival is therefore limited by the availability of ligands for the receptors that can influence cell survival. Following loss of receptor engagement, IL-3-dependent hematopoietic cells undergo a rapid decline in cellular metabolism, characterized by reductions in surface expression of the glucose transporter GLUT-1, mitochondrial potential, and cellular ATP. Two distinct classes of oncogenes can prevent cell death in response to declines in glucose uptake and metabolism following growth factor withdrawal: pro-survival Bc1-2 proteins, such as Bcl-xL, or an activated form of Akt. However, Bcl-xL and Akt appear to promote survival by distinct mechanisms. Expression of activated Akt leads to maintenance of glucose transporter expression, glycolytic activity, mitochondrial potential, and cell size, while Bcl-xL-expressing cells deprived of growth factor survive in a more vegetative state characterized by small cells with reduced mitochondrial potential and glycolytic activity. Akt-mediated survival is dependent on promoting glycolysis and maintaining a physiologic mitochondrial potential. In contrast, Bcl-xL maintains mitochondrial integrity in the face of a reduced mitochondrial membrane potential in growth factor-deprived cells. Thus, Akt and Bcl-xL suppress mitochondrial-initiated apoptosis by distinct mechanisms.
KeywordsGlucose Uptake Mitochondrial Membrane Potential Outer Mitochondrial Membrane Glycolytic Activity Mitochondrial Integrity
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