Mitochondria in apoptosis: Bcl-2 family members and mitochondrial dynamics

Abstract

Mitochondria participate in apoptosis through a range of mechanisms that vary between vertebrates and invertebrates. In vertebrates, they release intermembrane space proteins, such as cytochrome c, to promote caspase activation in the cytosol. This process is the result of the loss of integrity of the outer mitochondrial membrane caused by proapoptotic members of the Bcl-2 family. This event is always accompanied by a fissioning of the organelle. Fission of mitochondria has also been reported to participate in apoptosis in Drosophila and Caenorhabditis elegans. However, in these organisms, mitochondrial membrane permeabilization does not occur and the mechanism by which mitochondrial dynamics participates in cell death remains elusive.

Figure 1. Structure of Bcl-2 family proteins

A) The Bcl-2 family is divided into three groups based on their Bcl-2 Homology domains (BH). Pro- and antiapoptotic proteins contain 4 BH domains, while BH3-only proteins, as their name indicates, contain only the BH3 domain. B) Structure of Bax showing the alpha-helix 9 (transmembrane domain) embedded in the hydrophobic groove (left structure). A 180° rotation (structure on the right) shows the alpha-helices 1 and 6. The red circle represents the binding site for the Bim BH3 domain.

Figure 2. Bax moves back and forth from the cytosol to the mitochondrial outer membrane

In healthy cells, Bax (blue) and Bclx-L (red) are translocated from the cytosol to the outer mitochondrial membrane (OMM) where they attach loosely. The triangle in Bax represents its BH3 domain, which needs to be exposed in order for Bcl-x_L-mediated retrotranslocation to occur. OMM: outer mitochondrial membrane.

Figure 3. Model for Bax activation and mitochondrial outer membrane permeabilization: the role of membrane hemifission and hemifusion intermediates

A) During apoptosis, Drp1 and Bax are recruited to mitochondrial foci. As a result MOMP occurs concomitantly with mitochondrial fission. The release of cytochrome c promotes caspase activation in the cytosol. A magnification of what occurs at the level of mitochondrial fission sites is shown in (B). According to the ‘embeded together model’, tBid first inserts in the outer mitochondrial membrane (OMM) to expose its BH3 domain. Upon interaction with the Bid BH3 domain, Bax is in turn recruited to the OMM where it inserts and oligomerizes. This process does not occur randomly at the OMM surface. Bax mainly oligomerizes at mitochondrial fission sites and at contact sites between the OMM and the IMM. C) (Left) A detailed structure of the hemifission intermediate that forms before fission of the organelle. The membrane forms a non bilayer structure that represents a privileged site for the formation of a membrane hole. Upon its oligomerization in the OMM, Bax forms a lipidic pore or triggers the formation of a hole at the edge of the hemifission intermediate. (Right) A detailed structure of the membrane at OMM and inner mitochondrial membrane (IMM) contact sites. The model postulates that Bax forms a pore in the membrane at the edges of membrane hemifusion intermediates that may form between the OMM and the IMM.