Mitochondrial Outer Membrane Permeabilization

Melissa J Parsons, St. Jude Children's Research Hospital, Memphis, TN, USA
Douglas R Green, St. Jude Children's Research Hospital, Memphis, TN, USA

Published online: September 2009

DOI: 10.1002/9780470015902.a0021576

Defects in apoptosis have dire consequences and can contribute to the development of autoimmune disorders, neurological diseases and cancer. At the centre of the intrinsic apoptotic signalling pathway lies the mitochondrion, which is not only the bioenergetic centre of the cell, but also the cell's reservoir of pro-death factors such as cytochrome c. These proteins reside in the mitochondrial intermembrane space (IMS), and their release from the IMS induces a signalling cascade that leads to the demise of the cell. The critical event governing the release of pro-apoptotic molecules from the IMS is mitochondrial outer membrane permiabilization (MOMP). Although two models exist to explain the execution of MOMP, both models incorporate the widely accepted idea that MOMP is achieved through the coordinated actions of pro- and antiapoptotic members of the Bcl-2 (B-cell lymphoma) family of proteins. In addition, non-Bcl-2 family proteins, mitochondrial dynamics and mitochondrial bioenergetics are also involved in MOMP.

Key Concepts:

  • Apoptosis is one mechanism of cell death, which is characterized by distinct morphological features and occurs in response to specific physiological cues.
  • Apoptosis is a signalling cascade that leads to the demise of the cell.
  • The intrinsic apoptotic signalling cascade is one of the two main apoptotic pathways.
  • Mitochondrial outer membrane permeabilization (MOMP) is the key step in apoptosis that involves the mitochondria.
  • Bcl-2 family proteins are both pro- and antiapoptotic in nature, and are the main regulators of MOMP.
  • Bak or Bax is necessary for MOMP.
  • MOMP leads to the release of pro-death factors from the intermembrane space (IMS), which engage caspases to carry out the apoptotic signalling cascade.
  • Mitochondrial bioenergetics are disrupted during MOMP.

Keywords: apoptosis; Bak; Bax; Bcl-2; mitochondria

Figure 1. The Bcl-2 family. The Bcl-2 protein family is broken into antiapoptotic family members, which contain four BH homology domains, and pro-apoptotic family members, which contain either three BH homology domains (multidomain effectors) or only the third BH domain (BH3-only). Illustrated are cartoon schematics of the different groups, and a list of the members of each group. Most members have a C-terminal hydrophobic domain (TM) that aids association with the mitochondrial membrane. Exceptions are A1 and many of the BH3-only proteins (Bid, Bad, Bmf, Noxa and Puma).
Figure 2. Bcl-2 family protein interactions. The BH3-only proteins Bid, Bim and Puma can neutralize all antiapoptotic Bcl-2 proteins. BH3-only proteins such as Bad can neutralize only Bcl-2, Bcl-xL and Bcl-w, whereas Noxa can only neutralize Mcl-1 and A1.
Figure 3. Two competing models for Bak/Bax activation. Left, the direct activator model states that Bid and/or Bim are responsible for directly activating Bak and/or Bax (indicated by the yellow star) to induce MOMP, whereas the other BH3-only proteins (such as Bad) function to promote Bak/Bax activation by neutralizing the antiapoptotic family members. Right, the displacement model states that Bak and Bax are constitutively in an active conformation, and that sequestration by antiapoptotic proteins is the main mechanism by which Bak/Bax oligomerization and MOMP are prevented. Neutralization of the antiapoptotic proteins by BH3-only proteins releases active Bak and Bax to induce MOMP.
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Related Sub-Topics:

Cell Membranes | Cell Compartments and Cellular Organelles | Cell Energetics | Cell Death and Cellular Senescence | Protein Degradation | Mechanisms of Cell Death, Senescence and Metabolism | Biomolecular Interactions | Proteins: Structure, Function, Metabolism | Enzymes: Structure and Action Mechanism | Cell Structure | Bioenergetics
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Article Title: Mitochondrial Outer Membrane Permeabilization
 
How to Cite close
Parsons, Melissa J, and Green, Douglas R(Sep 2009) Mitochondrial Outer Membrane Permeabilization. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0021576]