the apoptotic cell death pathway , in its basic tenents , is conserved among metazoans . during development , resistance to apoptosis is a hallmark of cancer , whereas excessive programmed cell death is associated with degenerative diseases . apoptosis is controlled and amplified through a variety of mechanisms , many of which converge on release of proapoptotic factors from mitochondria ( danial and korsmeyer , 2004 ) . ( 2011 ) now uncover how regulated trafficking of the proapoptotic protein bax off mitochondria and into the cytosol prevents mitochondrial permeabilization , reconciling discordant models for how antiapoptotic proteins on the mitochondrial surface inhibit proapoptotic proteins in the cytosol . the permeabilization of mitochondria is controlled by proteins belonging to the bcl-2 family , which is composed of anti- and proapoptotic members sharing homology in short stretches of amino acids called bcl-2 homology ( bh ) domains . the prosurvival members , including bcl-2 , bcl - xl , and mcl-1 , contain bh domains 14 and antagonize the prodeath members . the multidomain proteins , such as bax and bak , contain bh domains 13 and directly mediate mitochondrial permeabilization , whereas the bh3-only proteins ( e.g. , bid , bim , bad , etc . ) are thought to act as sensors of cellular stress ( danial and korsmeyer , 2004 ) . despite clearly defined roles for the bcl-2 family members , two major questions have remained : how are proapoptotic members activated , and how do the antiapoptotic members inhibit them ? the simplified rheostat model , first proposed in the early 1990s , suggests that pro- and antiapoptotic proteins directly counterbalance each other , with the more abundant protein dictating whether the cell dies or survives ( danial and korsmeyer , 2004 ) . complicating this model is the existence of two types of bh3-only proteins : the  activators  that directly activate the proapoptotic multidomains and the  sensitizers  that neutralize the antiapoptotic inhibition of the multidomain proteins ( letai et  al . , 2002 ) . a modified version of the rheostat model postulates that activator bh3-only proteins act as receptors for multidomain proapoptotic proteins on the mitochondrial outer membrane ( om ) , whereas antiapoptotic proteins act like a sponge , soaking them off of the mitochondrial surface ( lovell et  al . , a mutually exclusive model postulates that the antiapoptotic proteins directly bind and inhibit bax and bak , with bh3-only molecules acting as inhibitors of the inhibitors ( youle and strasser , 2008 ) . this latter model suffered from the lack of evidence that could explain the spatial paradox of this direct inhibition : under normal circumstances , bax is in the cytosol , whereas bcl-2 is on the surface of mitochondria . upon induction of apoptosis , bax accumulates on the mitochondrial om , undergoes conformational changes to expose a helical domain , and triggers the release of cytochrome c and other proapoptotic effectors . to gain insight into the regulation of bax , edlich et  al . , ( 2011 ) examine the localization of a mutant version of bax that is constrained in its cytosolic conformation by engineered disulfide bridges . surprisingly , this mutant protein , which does not interact with the mitochondrial antiapoptotic protein bcl - xl , localizes to mitochondria but does not induce apoptosis . following up on this observation , the authors ask whether bax normally translocates to the mitochondrial surface . using fluorescence loss in photobleaching , they monitor the localization of gfp - bax in cells and find that bax cycles on and off the mitochondria in healthy cells . the presence of antiapoptotic proteins in the mitochondrial om is required to constitutively retrotranslocate bax into the cytosol . notably , the rate of retrotranslocation is almost doubled in cells overexpressing bcl - xl and requires the physical interaction between bcl - xl and bax . once in the cytosol , bax quickly returns to its monomeric form , ready to cycle back to the mitochondrial surface . edlich and coworkers observe an acceleration of the retrotranslocation rate upon the coexpression of bcl - xl and bax . similarly , the bcl-2/bcl - xl inhibitor abt-737 , as well as bh3-only proteins , disrupts the equilibrium between cytosolic and mitochondrial bax by reducing its retrotranslocation ( figure  1 ) . this new study provides a new paradigm for understanding bax regulation during apoptosis , but how the two categories of bh3-only proteins antagonize bax retrotranslocation by bcl - xl remains an open question . one possibility is that the activators ( e.g. , bid and bim ) directly inhibit bax retrotranslocation by unmasking its 9 helix and anchoring bax in the mitochondrial om . conversely , the sensitizer ( e.g. , bad ) could obstruct the binding of bax to bcl-2 . the interplay between proapoptotic and antiapoptotic proteins is part of the normal regulation of the trafficking of bax in healthy cells . under nonapoptotic conditions , the equilibrium between the cytosolic and mitochondrial pools of bax is maintained by its bcl - xl - dependent retrotranslocation . during apoptosis , however , this balance may be tipped by bh3-only proteins , which increase the insertion of bax into the mitochondrial om ( figure  1 ) . thus , the retrotranslocation model is an important step  forward , reconciling two opposing models of how bh3-only , multidomain , and antiapoptotic proteins cooperate to dictate whether a cell lives or dies ( e.g. , cheng et  al . , 2001 ; lovell et  al . , 2008 versus willis et  al . , in addition to this new model , edlich and colleagues also find that the weak interaction between bcl - xl and bax is sufficient to extract bcl - xl from the mitochondrial om and transiently localize it to the cytosol . this highlights an unappreciated conformational change that facilitates the removal of an antiapoptotic protein from the mitochondrial om . interestingly , the rate of bcl - xl retrotranslocation increases upon treatment with abt-737 , raising the possibility that inactive bcl - xl might be predominantly cytosolic . it will be important to verify whether this is a feature common to extramitochondrial antiapoptotics , such as endoplasmic reticulum ( er)-localized bcl-2/bcl - xl , and to understand the mechanism by which interaction with bax inactivates the transmembrane domain of bcl - xl . interestingly , a fraction of inactive bax is associated with intracellular membranes , including mitochondria and er in transformed cells , but not primary hepatocytes ( scorrano et  al . , 2003 ) . understanding how oncogenic transformation influences the on and off rates of bax translocation could open new perspectives to apoptosis in cancer cells . from a teleological perspective , one might wonder why a cell would maintain a continuous flux of bax cycling on to the mitochondria and then back to the cytosol . one reason could be to prime cells to rapidly execute death , positioning bax in a ready to attack  mode such that minor changes in the kinetics of bax retrotranslocation can swiftly induce apoptosis . another possibility is that bax has additional functions that require its regulated presence on cellular membranes . interestingly , inactive bax controls transient membrane events such as mitochondrial fusion ( hoppins et  al . , 2011 ) and , however , bax can not remain on the organelle without becoming active and promoting apoptosis ( nutt et  al . the retrotranslocation model not only provides a paradigm for understanding how apoptosis is regulated , but also provides a platform for integrating the diverse functions of bax and other bcl-2 family members .
antiapoptotic bcl-2 proteins on mitochondria inhibit prodeath proteins , such as bax , which are found primarily in the cytosol . in this issue , edlich et  al . , ( 2011 ) 
 show that bax and bcl - xl interact on the mitochondrial surface and then retrotranslocate to the cytosol , effectively preventing bax - induced permeabilization of mitochondria .