Akting Up with Hexokinase at the Mitochondria

Abstract

Akt, a serine-threonine protein kinase, promotes cell survival by inhibiting the release of mitochondrial cytochrome c that occurs in response to proapoptotic stimuli. This antiapoptotic effect depends on glucose and is related to Akt's role in regulating cell metabolism. Majewski et al. investigated the relationship between the association of the glycolytic enzyme hexokinase (HK) with the outer mitochondrial membrane and the antiapoptotic effect of Akt. Both basal and insulin-stimulated mitochondrial HK activity was reduced in mouse embryo fibroblast cell lines lacking Akt compared with that in wild-type cells. The ability of clotrimazole (which disrupts the association of HK with mitochondria) to stimulate apoptosis was enhanced in cells lacking Akt, whereas clotrimazole enhanced the sensitivity to apoptosis of Rat1a fibroblasts expressing activated Akt. Similarly, a peptide that corresponds to the HKII mitochondrial-binding motif (N-HKII peptide) decreased mitochondrial HK activity and impaired the ability of Akt and growth factors to prevent mitochondrial release of cytochrome c and apoptosis. Both clotrimazole and the N-HKII peptide stimulated cytochrome c release and apoptosis in cells lacking the proapoptotic proteins Bax and Bak, as did ultraviolet irradiation combined with growth factor withdrawal (a treatment the authors previously showed to lead to dissociation of HK from mitochondria). Activated Akt inhibited apoptosis in cells lacking Bax and Bak, whereas Bcl-2 did not, but did not inhibit calcium-dependent apoptosis. Thus, the authors conclude that HK association with mitochondria plays a critical role in the antiapoptotic effect of Akt and that HK dissociation from mitochondria can promote apoptosis through a mechanism that is at least partly independent of Bax and Bak. N. Majewski, V. Nogueira, P. Bhaskar, P. E. Coy, J. E. Skeen, K. Gottlob, N. S. Chandel, C. B. Thompson, R. B. Robey, N. Hay, Hexokinase-mitochondria interaction mediated by Akt is required to inhibit apoptosis in the presence or absence of Bax or Bak. Mol. Cell 16 , 819-830 (2004). [Online Journal]