Decisive steps in the initiation of programmed cell death revealed

The key step in apoptosis is the release of the protein cytochrome c and other apoptotic factors from the mitochondria into the cell interior. After this step, apoptosis induction is irreversible and cell's fate is sealed. In order to allow this process, the mitochondrial membrane must be permeable. The research team has examined how the mitochondrial membrane becomes permeable. Their experiments on artificial membrane systems showed that the Bax protein initially is inserted into the membrane as a single molecule. Once inserted, these monomers join up in the shortest time with a second molecule of Bax to form a stable complex, the so-called Bax dimers. From these dimers larger complexes are formed. "Surprisingly, Bax complexes have no standard size, but we observed a mixture of different-sized Bax species," says Dr. Katia Cosentino, a member of Professor García-Sáez team, "and these species are mostly based on dimer units." These Bax complexes form the pores through which the cytochrome c exits the mitochondrial membrane.

The process of pore formation is finely controlled by other proteins. Some enable the assembly of Bax elements, while others induce their dismantling. "The differing size of the Bax complexes in the pore formation is likely part of the reason why earlier investigations on pore formation conveyed in contradictory results" says Katia Cosentino. The researchers can now make some initial recommendations for medical intervention in the apoptotic process: In order to promote this cell "suicide," it should be enough to initiate the first step of activating Bax proteins -- because the subsequent steps of self-organization will then happen automatically. Conversely, from these new insights into the mechanism of pore formation can be concluded that apoptosis can be prevented when drugs force the dismantling of the Bax-dimers into their individual elements.