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Abstract
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.