Modifications de la membrane mitochondriale externe au cours de l'apoptose

Les mitochondries sont impliquées dans de nombreuses voies de signalisation de l'apoptose. Suite à la perméabilisation de leur membrane externe par des membres pro-apoptotiques de la famille Bcl-2, elles libèrent plusieurs protéines apoptogènes, dont le cytochrome c, qui contribuent à l'activation des caspases. Les mécanismes responsables de la perméabilisation membranaire mitochondriale sont encore mal compris. Leur étude a abouti à la construction de plusieurs modèles qui sont analysés dans cette revue.Mitochondria are involved in many apoptotic responses. Following permeabilization of their outer membrane, they release many apoptogenic proteins, including cytochrome c, which contribute to caspase activation. The mechanisms responsible for membrane permeability are not completely understood. Here, we briefly review the mechanisms that have been proposed to explain this phenomenon

Modifications de la membrane mitochondriale externe au cours de l'apoptose

Les mitochondries sont impliquées dans de nombreuses voies de signalisation de l'apoptose. Suite à la perméabilisation de leur membrane externe par des membres pro-apoptotiques de la famille Bcl-2, elles libèrent plusieurs protéines apoptogènes, dont le cytochrome c, qui contribuent à l'activation des caspases. Les mécanismes responsables de la perméabilisation membranaire mitochondriale sont encore mal compris. Leur étude a abouti à la construction de plusieurs modèles qui sont analysés dans cette revue

Bax oligomerization in mitochondrial membranes requires tBid (caspase-8-cleaved Bid) and a mitochondrial protein.

In response to various apoptotic stimuli, Bax, a pro-apoptotic member of the Bcl-2 family, is oligomerized and permeabilizes the mitochondrial outer membrane to apoptogenic factors, including cytochrome c. Bax oligomerization can also be induced by incubating isolated mitochondria containing endogenous Bax with recombinant tBid (caspase-8-cleaved Bid) in vitro. The mechanism by which Bax oligomerizes under these conditions is still unknown. To address this question, recombinant human full-length Bax was purified as a monomeric protein. Bax failed to oligomerize spontaneously in isolated mitochondria or in liposomes composed of either cardiolipin or lipids extracted from mitochondria. However, in the presence of tBid, the protein formed large complexes in mitochondrial membranes and induced the release of cytochrome c. tBid also induced Bax oligomerization in isolated mitochondrial outer membranes, but not in other membranes, such as plasma membranes or microsomes. Moreover, tBid-induced Bax oligomerization was inhibited when mitochondria were pretreated with protease K. The presence of the voltage-dependent anion channel was not required either for Bax oligomerization or for Bax-induced cytochrome c release. Finally, Bax oligomerization was reconstituted in proteoliposomes made from mitochondrial membrane proteins. These findings imply that tBid is necessary but not sufficient for Bax oligomerization; a mitochondrial protein is also required