MOMP, cell suicide as a BCL-2 family business

Abstract

Apoptosis shapes development and differentiation, has a key role in tissue homeostasis, and is deregulated in cancer. In most cases, successful apoptosis is triggered by mitochondrial outer membrane permeabilization (MOMP), which defines the mitochondrial or intrinsic pathway and ultimately leads to caspase activation and protein substrate cleavage. The mitochondrial apoptotic pathway centered on MOMP is controlled by an intricate network of events that determine the balance of the cell fate choice between survival and death. Here we will review how MOMP proceeds and how the main effectors cytochrome c, a heme protein that has a crucial role in respiration, and second mitochondria-derived activator of caspase (SMAC), as well as other intermembrane space proteins, orchestrate caspase activation. Moreover, we discuss recent insights on the interplay of the upstream coordinators and initiators of MOMP, the BCL-2 family. This review highlights how our increasing knowledge on the regulation of critical checkpoints of apoptosis integrates with understanding of cancer development and has begun to translate into therapeutic clinical benefit.

Figure 1

The extrinsic and intrinsic apoptotic pathways. The extrinsic pathway is initiated by engagement of DRs via their respective ligands TNF, FASL/CD95L, or TRAIL. Together with the adaptor FAS-associated death-domain (FADD) protein and the initiator procaspase-8 (or -10) they form the death-inducing signaling complex (DISC). This assembly enables the dimerization and autoactivation of the initiator caspases, which in turn cleave and activate the executioner caspase-3 and -7, ultimately leading to apoptosis unless they are inhibited by XIAP. The intrinsic pathway can be engaged by diverse intracellular stresses that modulate BCL-2 family protein interactions that control the activation of the BCL-2 effector proteins BAX and BAK. Once activated, BAX and BAK cause MOMP, leading to the release of proapoptotic IMS proteins. Cytochrome c (Cyt c) engages APAF1 and induces its oligomerization, leading to apoptosome formation that recruits and activates the initiator procaspase-9. Active caspase-9 cleaves and activates the executioner caspase-3 and -7. Simultaneously with Cyt c, Smac is released from the IMS and inhibits XIAP. The extrinsic and intrinsic pathways are linked; caspase-8 can cleave the BH3-only protein BH3-interacting domain death agonist (Bid), leading to its active, truncated form tBid, which in turn activates BAX/BAK. Numbers in circles indicate the respective pro- and active caspase; interrupted circles represent active caspases

Figure 2

Overview of MOMP and its exceptional nuances. In general, apoptotic stress results in complete MOMP and apoptotic cell death. Scenarios of partial MOMP: iMOMP, in which case cells might survive if caspase activity is inhibited and minority MOMP, when only a small portion of mitochondria undergo MOMP. The latter version of partial MOMP results in cell survival, but caspase-dependent signaling pathways can be activated and DNA damage might occur, which might lead to malignant transformation of cells

Figure 3

Schematic view of proposed models for structure of membrane pores. (a) Proteinaceous pores consist of BAX/BAK oligomers at the inner rim. (b) Lipid pores are also initiated and stabilized by BAX/BAK oligomerization, but the pore’s edge is formed by a monolayer of lipids, allowing hydrophilic proteins to pass the pore

Figure 4

The unified model of BCL-2 protein interactions. In the 'unprimed', healthy cell, BAX and BAK reside in an inactive state that does not require active suppression of apoptosis via prosurvival BCL-2 family members. Cells 'primed for death' undergo MOMP with different kinetics upon derepression. In Mode 1, prosurvival proteins sequester BH3-only direct activators (BH3-DA). This reversible interaction can be easily overcome by BH3-only sensitizer (BH3-S) proteins. More effective inhibition of MOMP onset takes place in Mode 2, when prosurvival proteins directly sequester BAX and BAK under high-stress levels. Ultimately, when both modes of survival are overcome, BAX/BAK oligomerization leads to MOMP. Taking mitochondrial dynamics into account, in healthy cells inactive effectors BAX/ BAK support mitochondrial dynamics by promoting mitochondrial fusion. Increased activation of BAX/BAK leads to an imbalance in mitochondrial dynamics towards fission, leading to mitochondrial fragmentation