Few families can be quite so divided as the BCL-2 clan. While the anti-apoptotic members — BCL-2 and BCL-XL — fight for a cell's survival, their pro-apoptotic relatives try to send it to its death. All of the factors that decide which side triumphs are still not clear, but the problem has been tackled by Stanley Korsmeyer and co-workers, reporting in Molecular Cell.

The battleground is the mitochondrion, where the BCL-2 family regulates mitochondrial integrity and caspase activation (see figure). The pro-apoptotic family members can be divided into two groups: the 'multidomain' members, which show sequence conservation in the BCL-2 homology (BH) domains 1–3 and include BAX and BAK; and the 'BH3-domain only' group, among them BID, BIM, BAD and NOXA.

The complex interplay between the two sides is illustrated by Korsmeyer and co-workers, who now show that activated BID (tBID) can form a stable complex with BCL-2. This complex forms only when BCL-2 is functional, and correlates with the protection of cells from apoptosis. The authors also detected complexes between BCL-XL and tBID, BIM and BAD; again, the ability of BCL-XL to inhibit apoptosis mirrored its ability to bind these proteins. This, say the authors, indicates that anti-apoptotic BCL-2 proteins could sequester the BH3-domain only proteins, which prevents them from activating BAX and BAK.

Korsmeyer and co-workers next asked exactly when during the apoptotic pathway does a cell become committed to die. They compared the effects of deleting proteins that act downstream of the mitochondria ( Apaf-1 , caspase-9 or caspase-3 ) with the deletion of upstream players such as Bax and Bak. When mouse embryo fibroblasts that lacked the downstream proteins were challenged with tBID, they remained viable for 24 hours, but by 48 hours were beginning to show signs of mitochondrial dysfunction and death. By contrast, double-knockout cells that lacked Bax and Bak proved completely resistant to apoptosis that was induced by all tested BH3-domain only molecules. It seems, then, that the definitive commitment to cell death occurs proximal to the mitochondria, at the step of BAX/BAK activation.

Taken together, these results paint a picture where the BH3-domain only molecules activate the multidomain molecules to trigger a mitochondrial pathway that activates both caspase-dependent death and caspase-independent mitochondrial dysfunction.