BAX constitutively translocates to and from the mitochondria independently of BH3 proteins.

  • Major finding: BAX constitutively translocates to and from the mitochondria independently of BH3 proteins.

  • Clinical relevance: The rate of BAX dissociation from the mitochondria contributes to apoptotic priming.

  • Impact: BAX “translocation” in response to apoptotic stimuli may in fact be a shift in its equilibrium.

BAX is a proapoptotic BCL-2 family member that commits cells to apoptosis by initiating mitochondrial outer membrane permeabilization. BAX is predominantly cytosolic and is thought to be activated and targeted to the mitochondria by proapoptotic BH3 proteins. However, this model is largely based on data from experimental systems that do not allow real-time analysis of changes in protein localization or signal transduction. Using live-cell spinning-disk confocal imaging, Schellenberg and colleagues evaluated the dynamics of GFP-tagged BAX localization in healthy, nonapoptotic cells. Contrary to existing models of BAX function, BAX constitutively targeted to the mitochondria and inserted into the outer mitochondrial membrane in the absence of apoptotic stimuli and was constantly extracted back to the cytosol to maintain a dynamic equilibrium between these subcellular compartments. In addition, BAX targeting to the outer mitochondrial membrane was unaffected in cells lacking proapoptotic BH3 proteins and did not require prior conversion to its active conformation. In the presence of an apoptotic stimulus, such as detachment from the extracellular matrix, BAX rapidly accumulated on mitochondria, but survival signaling induced by focal adhesion kinase and AKT promoted BAX dissociation from mitochondria. Apoptosis following cell detachment was significantly higher in cells expressing a BAX mutant that dissociates more slowly from the mitochondria, and cells expressing mutant BAX were more sensitive to apoptosis induced by an inhibitor of the antiapoptotic proteins BCL-2 and BCL-XL, suggesting that alterations in the rate of BAX mitochondrial dissociation contribute to apoptotic priming. Collectively, these results suggest that BAX “translocation” to the mitochondria in response to apoptotic stimuli is actually a shift in the equilibrium between the cytosolic and mitochondrial outer membrane fractions that occurs independently of cytosolic BH3 proteins, which raises the possibility that current apoptotic models may need to be updated.

Schellenberg B, Wang P, Keeble JA, Rodriguez-Enriquez R, Walker S, Owens TW, et al. Bax exists in a dynamic equilibrium between the cytosol and mitochondria to control apoptotic priming. Mol Cell 2013 Jan 31 [Epub ahead of print].

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