Toxic factors such as cytochrome c are locked deep within the mitochondria. In response to certain death-promoting stimuli, however, they can be released into the cytosol. The key to this cellular poison cabinet is not known, but a report in Science by Craig Thompson, Stanley Korsmeyer and colleagues now points to the pro-apoptotic proteins Bax and Bak.

Previous studies had already implicated these proteins in the release of cytochrome c from mitochondria. Activation of death receptors leads to the cleavage of a protein called Bid to its truncated, active form, tBid. This, in turn, induces the homo-oligomerization of Bax and Bak, leading to cytochrome c release.

To investigate whether Bax and Bak are required for tBid-induced apoptosis of whole cells, the authors used a retroviral vector to express tBid in mouse embryonic fibroblasts (MEFs). Whereas wild-type, Bak-deficient and Bax-deficient MEFs showed a shrunken, apoptotic morphology, the Bax , Bak double-deficient MEFs did not die.

One explanation is that tBid-induced apoptosis operates through the activation of Bax and Bak. To test this possibility, Thompson, Korsmeyer and colleagues asked whether these proteins are activated in the tBid-expressing MEFs, and they observed Bax and Bak oligomers — indicative of active protein — in the presence of tBid. Also in support of this idea, in the Bax, Bak-deficient MEFs there was no detectable redistribution of cytochrome c from the mitochondria to the cytosol.

The authors next asked whether Bax and Bak are required for cell death in situ by assessing apoptosis in mouse livers. Again, they found that tBid-dependent apoptosis requires Bax or Bak. The death-promoting stimulus used in these experiments was activation of the death receptor Fas, but the authors confirmed that Bax and Bak are also required for death in response to a host of other factors, including stress signalling from the endoplasmic reticulum.

The authors conclude, then, that the “activation of a 'multidomain' proapoptotic member, Bax or Bak, appears to be an essential gateway to mitochondrial dysfunction required for cell death in response to diverse stimuli”.