Apoptosis: it's BAK to VDAC.

The voltage-dependent anion channel (VDAC) of the mitochondrial outer membrane (MOM; Mannella & Kinnally, 2008)—also known as mitochondrial porin—has long been implicated in regulating the mitochondrial response to certain cell death stimuli (Galluzzi & Kroemer, 2007). This includes a potential role in MOM permeabilization (MOMP) during apoptosis, which is a necessary step in the release of cytochrome c—a critical cofactor for downstream activation of caspases—from the organelle. Although controversial, it is possible that VDAC is a component of the permeability transition pore complex, and therefore its influence could also extend to the inner membrane, regulating membrane potential and ATP production. Among the strongest indications that VDAC has a role in the regulation of cell death are the reported interactions between VDAC and members of the BCL2 family of proteins. BCL2 proteins are important regulators of the mitochondrial pathway to apoptosis (Youle & Strasser, 2008). The multi-BH-domain-containing, pro-apoptotic members BAX and BAK are the essential gateways to MOMP, and it has been suggested that both physically interact with VDAC (Galluzzi & Kroemer, 2007). In particular, Cheng and colleagues (2003) concluded that a minor VDAC isoform—known as VDAC2—acts to physically restrain BAK in the MOM in nonstimulated viable cells. However, death stimuli, including that elicited by truncated BID (tBID)—an activated, pro-apoptotic, BH3only BCL2 family protein—displaced inactive BAK from VDAC2, promoting BAK oligomerization. In view of this collective evidence, it was a surprise when gene deletion studies suggested that all three Vdac gene products are dispensable for mitochondrial-dependent cell death in mouse embryonic fibroblasts (MEFs; Baines et al 2007). In addition to necrotic cell death driven by defects in the permeability transition pore—elicited, for example, by oxidative stress or calcium overload—a range of other stresses were also unaffected by the deletion of Vdac1–Vdac3. A compelling study by the Hajnoczky group, published in this issue of EMBO reports, now reprises the role of VDAC2 in regulating BAK, but suggests a function for VDAC2 that is diametrically opposed to the antagonism of BAK by VDAC2 reported by Cheng and colleagues (2003): VDAC2 promotes tBID-induced apoptosis by recruiting newly synthesized BAK to mitochondria. What is going on? Can three such divergent conclusions—no role, antagonism and promotion of apoptosis by VDAC2—be reconciled? The answer is probably yes, but the focus is on BAK and tBID. Reconstitution experiments using purified proteins or peptides and liposomes of known lipid composition have suggested a core pathway to MOMP, defined exclusively by BCL2 family proteins (Kuwana et al, 2005; Lovell et al, 2008); however, non-BCL2 components are unquestionably layered on top of this pathway to support its execution and regulation in the complex milieu of the intact cell. The available evidence (Shore & Nguyen, 2008) supports an emerging model that focuses on BAX as the effector of MOMP, and tBID as the ‘activator’ BH3-only protein (Fig 1A, upper panel). The process starts with the generation of active tBID from inactive BID; tBID then rapidly migrates to the membrane where it probably functions as a receptor for inactive cytosolic BAX, stimulating the conformational transition of BAX to its active, monomeric, membrane-integrated form through the insertion of the transmembrane (TM) segment and integration of helices 5 and 6 into the bilayer, leaving the N terminus available for proteolysis or binding to an antibody. This pathway might be amplified by the ability of activated BAX, similarly to tBID, to recruit more mol ecules of inactive BAX from the cytosol. Activated BAX can undergo auto-oligomerization, yielding a MOMP-competent complex. In most respects, BAK probably follows a similar process Apoptosis: it’s BAK to VDAC