Membrane remodeling induced by the dynamin-related protein Drp1 stimulates Bax oligomerization.

In response to many apoptotic stimuli, oligomerization of Bax is essential for mitochondrial outer membrane permeabilization and the ensuing release of cytochrome c. These events are accompanied by mitochondrial fission that appears to require Drp1, a large GTPase of the dynamin superfamily. Loss of Drp1 leads to decreased cytochrome c release by a mechanism that is poorly understood.

Granzyme a, a stealth killer in the mitochondrion.

The induction of caspase-independent cell death by killer lymphocytes involves the serine protease granzyme A (GzmA). In this issue, Martinvalet et al. (2008) show that GzmA penetrates the mitochondrial matrix without perturbing normal mitochondrial functions.

Contributions to Bax insertion and oligomerization of lipids of the mitochondrial outer membrane.

Under many apoptotic conditions, Bax undergoes conformational rearrangements, leading to its insertion in the mitochondrial outer membrane as a transmembrane oligomer. At the same time, mitochondria undergo fragmentation and activated Bax was reported to localize to fission sites. We studied how lipid composition and membrane curvature regulate Bax activation.

Bax activation and stress-induced apoptosis delayed by the accumulation of cholesterol in mitochondrial membranes.

Activation of Bax or Bak is essential for the completion of many apoptotic programmes. Under cytotoxic conditions, these proteins undergo a series of conformational rearrangements that end up with their oligomerization. We found that unlike inactive monomeric Bax, active oligomerized Bax is partially resistant to trypsin digestion, providing a convenient read out to monitor Bax activation.

Mechanisms of mitochondrial outer membrane permeabilization.

In response to many apoptotic stimuli, Bcl-2 family pro-apoptotic members, such as Bax and Bak, are activated. This results in their oligomerization, permeabilization of the outer mitochondrial membrane, and release of many proteins that are normally confined in the mitochondrial inter-membrane space. Among these proteins are cytochrome c, Smac/DIABLO, OMI/HtrA2, AIF and endonuclease G.

[Changes in the outer mitochondrial membranes during apoptosis].

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.

Regulation of Bcl-2 proteins and of the permeability of the outer mitochondrial membrane.

In many apoptotic responses, pro-apoptotic members of the Bcl-2 family trigger the permeabilization of the outer mitochondrial membrane, thereby allowing the release of mitochondrial apoptogenic factors that contribute to caspase activation in the cytosol. The mechanisms that lead to the activation of pro-apoptotic Bcl-2 family members and to the permeabilization of the outer mitochondrial membrane are not yet completely understood. Here, we attempt to summarize our current view of the mechanisms that lead to these events, regarding both additional proteins that were recently suggested to be involved, and the roles of lipids.

Newcomers in the process of mitochondrial permeabilization.

Under stress conditions, apoptogenic factors normally sequestered in the mitochondrial intermembrane space are released into the cytosol, caspases are activated and cells die by apoptosis. Although the precise mechanism that leads to the permeabilization of mitochondria is still unclear, the activation of multidomain pro-apoptotic proteins of the Bcl-2 family, such as Bax and Bak, is evidently crucial. Regulation of Bax and Bak by other members of the family has been known for a long time, but recent evidence suggests that additional unrelated proteins participate in the process, both as inhibitors and activators.