Hexokinase-mitochondria interaction mediated by Akt is required to inhibit apoptosis in the presence or absence of Bax and Bak.
The serine/threonine kinase Akt inhibits mitochondrial cytochrome c release and apoptosis induced by a variety of proapoptotic stimuli. The antiapoptotic activity of Akt is coupled, at least in part, to its effects on cellular metabolism. Here, we provide genetic evidence that Akt is required to maintain hexokinase association with mitochondria. Targeted disruption of this association impairs the ability of growth factors and Akt to inhibit cytochrome c release and apoptosis. Targeted disruption of mitochondria-hexokinase (HK) interaction or exposure to proapoptotic stimuli that promote rapid dissociation of hexokinase from mitochondria potently induce cytochrome c release and apoptosis, even in the absence of Bax and Bak. These effects are inhibited by activated Akt, but not by Bcl-2, implying that changes in outer mitochondrial membrane (OMM) permeability leading to apoptosis can occur in the absence of Bax and Bak and that Akt inhibits these changes through maintenance of hexokinase association with mitochondria.
Majewski
Nathan
N
Department of Biochemistry and Molecular Genetics, University of Illinois at Chicago, Chicago, Illinois 60607, USA.
Nogueira
Veronique
V
Bhaskar
Prashanth
P
Coy
Platina E
PE
Skeen
Jennifer E
JE
Gottlob
Kathrin
K
Chandel
Navdeep S
NS
Thompson
Craig B
CB
Robey
R Brooks
RB
Hay
Nissim
N
D000818:Animals; D017209:Apoptosis; D001667:Binding, Competitive; D002460:Cell Line; D049109:Cell Proliferation; D002478:Cells, Cultured; D003022:Clotrimazole / Q000494:pharmacology; D045304:Cytochromes c / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005347:Fibroblasts / Q000378:metabolism; D018014:Gene Transfer Techniques; D006131:Growth Inhibitors / Q000494:pharmacology; D006133:Growth Substances / Q000378:metabolism; D006593:Hexokinase / Q000737:chemistry*; D015151:Immunoblotting; D020287:In Situ Nick-End Labeling; D007425:Intracellular Membranes / Q000378:metabolism; D008564:Membrane Potentials; D051379:Mice; D008856:Microscopy, Fluorescence; D008928:Mitochondria / Q000378:metabolism*; D010725:Phosphocreatine / Q000378:metabolism; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D051381:Rats; D019284:Thapsigargin / Q000494:pharmacology; D013997:Time Factors; D014466:Ultraviolet Rays
D006131:Growth Inhibitors; D006133:Growth Substances; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D010725:Phosphocreatine; D019284:Thapsigargin; D045304:Cytochromes c; D006593:Hexokinase; C494920:Akt1 protein, rat; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D003022:Clotrimazole