experiments. However, a negative cross-linking result does not exclude interactions.
Nevertheless, these data show that Bax forms large oligomers in the outer
mitochondrial membrane in cells undergoing apoptosis. These oligomers are larger
then those shown to be required to permeabilize liposomes to cytochrome c and could
therefore be the cytochrome c-conducting channel in the outer mitochondrial
membrane of apoptotic cells. Whether the Bax oligomers in the mitochondrial
membrane are composed of Bax exclusively or contain additional proteins is still
Figure 4. Models for permeabilization of the outer mitochondrial membrane during
apoptosis.
Several models have been proposed for how the proapoptotic multidomain proteins, such as
Bax and Bak, induce the release of proteins, including cytochrome c, from the intermembrane
space. (A) Bax forms a chimeric channel with VDAC. (B) Bax interacts with ANT in the inner
membrane; either it forms a chimeric channel or the interactions induce or regulate a Bax
channel. (C) A channel is formed by Bax oligomers. Whether these oligomers in the
mitochondria are composed of Bax only, or contain other, not yet identified proteins, is unclear.
However, those proteins are not VDAC or ANT. (D) Insertion of Bax destabilizes the
membrane, inducing ‘lipic holes’ in the membrane. (E) The multidomain proteins trigger
opening of the permeability transition pore, resulting in matrix swelling and rupture of the
outer membrane. Models A-C propose formation of channels that could induce the release of
specific proteins, whereas models D and E would permeabilize the membrane in an unspecific
way, releasing proteins in an uncontrolled manner.
MITOCHONDRIA IN APOPTOSIS INDUCTION 133