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Molecular and Cellular Biology, January 2004, p. 730-740, Vol. 24, No. 2
0270-7306/04/$08.00+0     DOI: 10.1128/MCB.24.2.730-740.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Akt Inhibits Apoptosis Downstream of BID Cleavage via a Glucose-Dependent Mechanism Involving Mitochondrial Hexokinases

Nathan Majewski,1 Veronique Nogueira,1 R. Brooks Robey,2,3 and Nissim Hay1*

Departments of Biochemistry and Molecular Genetics,1 Medicine, University of Illinois at Chicago, Chicago, Illinois 60607,2 Veterans Administration Chicago Healthcare System, Chicago, Illinois 606123

Received 7 July 2003/ Returned for modification 18 August 2003/ Accepted 27 October 2003

The serine/threonine kinase Akt/protein kinase B inhibits apoptosis induced by a variety of stimuli, including overexpression or activation of proapoptotic Bcl-2 family members. The precise mechanisms by which Akt prevents apoptosis are not completely understood, but Akt may function to maintain mitochondrial integrity, thereby preventing cytochrome c release following an apoptotic insult. This effect may be mediated, in part, via promotion of physical and functional interactions between mitochondria and hexokinases. Here we show that growth factor deprivation induced proteolytic cleavage of the proapoptotic Bcl-2 family member BID to yield its active truncated form, tBID. Activated Akt inhibited mitochondrial cytochrome c release and apoptosis following BID cleavage. Akt also antagonized tBID-mediated BAX activation and mitochondrial BAK oligomerization, two downstream events thought to be critical for tBID-induced apoptosis. Glucose deprivation, which impaired the ability of Akt to maintain mitochondrion-hexokinase association, prevented Akt from inhibiting BID-mediated apoptosis. Interestingly, tBID independently elicited dissociation of hexokinases from mitochondria, an effect that was antagonized by activated Akt. Ectopic expression of the amino-terminal half of hexokinase II, which is catalytically active and contains the mitochondrion-binding domain, consistently antagonized tBID-induced apoptosis. These results suggest that Akt inhibits BID-mediated apoptosis downstream of BID cleavage via promotion of mitochondrial hexokinase association and antagonism of tBID-mediated BAX and BAK activation at the mitochondria.

* Corresponding author. Mailing address: University of Illinois at Chicago, Department of Biochemistry and Molecular Genetics (M/C 669), College of Medicine, 900 S. Ashland Ave., Chicago, IL 60607. Phone: (312) 355-1684. Fax: (312) 355-2032. E-mail: nhay{at}uic.edu.

Molecular and Cellular Biology, January 2004, p. 730-740, Vol. 24, No. 2
0022-538X/04/$08.00+0     DOI: 10.1128/MCB.24.2.730-740.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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