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Review
. 2014 Jan 16;21(1):114-23.
doi: 10.1016/j.chembiol.2013.10.009. Epub 2013 Nov 21.

Death upon a kiss: mitochondrial outer membrane composition and organelle communication govern sensitivity to BAK/BAX-dependent apoptosis

Thibaud T Renault  1 , Jerry E Chipuk  2
Affiliations
Review

Death upon a kiss: mitochondrial outer membrane composition and organelle communication govern sensitivity to BAK/BAX-dependent apoptosis

Thibaud T Renault et al. Chem Biol. .

Abstract

For stressed cells to induce the mitochondrial pathway of apoptosis, a cohort of pro-apoptotic BCL-2 proteins must collaborate with the outer mitochondrial membrane to permeabilize it. BAK and BAX are the two pro-apoptotic BCL-2 family members that are required for mitochondrial outer membrane permeabilization. While biochemical and structural insights of BAK/BAX function have expanded in recent years, very little is known about the role of the outer mitochondrial membrane in regulating BAK/BAX activity. In this review, we will highlight the impact of mitochondrial composition (both protein and lipid) and mitochondrial interactions with cellular organelles on BAK/BAX function and cellular commitment to apoptosis. A better understanding of how BAK/BAX and mitochondrial biology are mechanistically linked will likely reveal novel insights into homeostatic and pathological mechanisms associated with apoptosis.

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Figures

Figure 1
Figure 1. Mechanisms of BAK/BAX activation within the BCL-2 family
Pro-apoptotic effectors (e.g., BAX, in blue) require multiple conformational changes to induce MOMP. Activation-associated BAK/BAX conformational changes are induced by interactions with direct activator BH3-only proteins (e.g., BIM, in yellow). These conformational changes are: exposure of the N-terminus, exposure of the α9 helix revealing the BH3 domain and, in some cases, homo-dimerization. Subsequently, multimerization of these dimers leads to pore formation and apoptosis. Anti-apoptotic proteins (e.g., BCL-2, in red) prevent MOMP in two ways: (1) anti-apoptotic proteins actively sequester pro-apoptotic BH3-only proteins; and (2) anti-apoptotic proteins bind to the exposed BH3 domain of BAK and BAX to prevent dimerization and oligomerization. Sensitization is when BH3-only proteins (e.g., BIM, in yellow) are binding anti-apoptotic proteins, preventing the future inhibition of pro-apoptotic proteins. De-repression is when a BH3-only protein (e.g., BAD, in green) releases activated BAK/BAX monomers and/or direct activator proteins, from anti-apoptotic proteins, leading to MOMP.
Figure 2
Figure 2. Competing models of pore formation during apoptosis
In the literature, there are several models describing the composition of the pore responsible for cytochrome c release. Early models of apoptosis suggested that BAK and BAX can positively influence proteinaceous or lipidic pore formation. For example, it has been shown that BAX increases the permeability of VDAC1 function in the OMM; alternatively, BAK/BAX may cooperate with ceramide channels. On the other hand, biochemical studies have shown that BAK and BAK directly promote pore formation in the absence of additional proteins. More recently, accumulating evidence suggests that BAK/BAX and mitochondrial lipids cooperate to promote BAK/BAX activation and pore formation.
Figure 3
Figure 3. Mitochondrial lipids regulate BAK/BAX activation and MOMP
BAK/BAX activation requires several conformational changes, including intra-molecular (N-terminus exposure, core conformational changes revealing the BH3 domain) and intermolecular (homo-dimerization and oligomerization) rearrangements. Several lipids are described to cooperate with BID, BAK and BAX. As a first example, cardiolipin favors BID interactions with BAK and BAX, which promotes intra-molecular conformational changes. Given the abundance of cardiolipin in the IMM and contact sites, additional roles for cardiolipin in BAK/BAX core rearrangements and oligomerization remain to be resolved. Additionally, sphingosine-1-phosphate and hexadecenal are demonstrated to participate in BAK and BAX activation, respectively. The exact step(s) of BAK/BAX activation controlled by these sphingolipid metabolites also remains to be defined. Little is known about the negative regulatory aspects of lipids on BAK and BAX activation, except for phosphatidylethanolamine which inhibits BAX oligomerization in vitro.
Figure 4
Figure 4. Inter-organellar communication influences mitochondrial lipid composition and MOMP
As the permeabilization of the OMM is effected and affected by lipids, interactions between the OMM and other cellular membranes likely influence BAK/BAX activation and MOMP. For example, lipids originating at the Golgi complex and ER influence the composition of mitochondrial membranes (e.g., sphingomyelin, ceramide, phosphatidylserine). Likewise, this transfer increases the diversity of mitochondrial lipids as mitochondria themselves are able to further metabolize lipids which directly impact on BAK/BAX activation (e.g., sphingosine-1-phosphate, hexadecenal, phosphatidylethanolamine). Lipid transfer is likely assisted by a combination of shared membrane structures and proteinaceous tethers between the ER and mitochondria (e.g., the ERMES complex and Mfn-2 dimers). In addition to a role in lipid exchange, ER-mitochondria interactions also allow for calcium buffering between organelles which is known to modulate the sensitivity of mitochondria to the BCL-2 family.
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