Mitochondrial Outer Membrane Permeabilization


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.



Cassidy‐Stone A, Chipuk JE, Ingerman E et al. (2008) Chemical inhibition of the mitochondrial division dynamin reveals its role in Bax/Bak‐dependent mitochondrial outer membrane permeabilization. Developmental Cell 14(2): 193–204.

Chao JR, Parganas E, Boyd K et al. (2008) Hax1‐mediated processing of HtrA2 by Parl allows survival of lymphocytes and neurons. Nature 452(7183): 98–102.

Chen H, Detmer SA, Ewald AJ et al. (2003) Mitofusins Mfn1 and Mfn2 coordinately regulate mitochondrial fusion and are essential for embryonic development. Journal of Cell Biology 160(2): 189–200.

Chipuk JE, Fisher JC, Dillon CP et al. (2008) Mechanism of apoptosis induction by inhibition of the anti‐apoptotic BCL‐2 proteins. Proceedings of the National Academy of Sciences of the USA 105(51): 20327–20332.

Chipuk JE, Kuwana T, Bouchier‐Hayes L et al. (2004) Direct activation of Bax by p53 mediates mitochondrial membrane permeabilization and apoptosis. Science 303(5660): 1010–1014.

Cory S and Adams JM (2002) The Bcl2 family: regulators of the cellular life‐or‐death switch. Nature Reviews. Cancer 2(9): 647–656.

Du C, Fang M, Li Y, Li L and Wang X (2000) Smac, a mitochondrial protein that promotes cytochrome c‐dependent caspase activation by eliminating IAP inhibition. Cell 102(1): 33–42.

Earnshaw WC, Martins LM and Kaufmann SH (1999) Mammalian caspases: structure, activation, substrates, and functions during apoptosis. Annual Review of Biochemistry 68: 383–424.

Hanahan D and Weinberg RA (2000) The hallmarks of cancer. Cell 100(1): 57–70.

Karbowski M, Norris KL, Cleland MM, Jeong SY and Youle RJ (2006) Role of Bax and Bak in mitochondrial morphogenesis. Nature 443(7112): 658–662.

Kazama H, Ricci JE, Herndon JM et al. (2008) Induction of immunological tolerance by apoptotic cells requires caspase‐dependent oxidation of high‐mobility group box‐1 protein. Immunity 29(1): 21–32.

Knudson CM, Tung KS, Tourtellotte WG, Brown GA and Korsmeyer SJ (1995) Bax‐deficient mice with lymphoid hyperplasia and male germ cell death. Science 270(5233): 96–99.

Kroemer G, Galluzzi L, Vandenabeele P et al. (2009) Classification of cell death: recommendations of the Nomenclature Committee on Cell Death 2009. Cell Death and Differentiation 16(1): 3–11.

Lindsten T, Ross AJ, King A et al. (2000) The combined functions of proapoptotic Bcl‐2 family members bak and bax are essential for normal development of multiple tissues. Molecular Cell 6(6): 1389–1399.

Nakano K and Vousden KH (2001) PUMA, a novel proapoptotic gene, is induced by p53. Molecular Cell 7(3): 683–694.

Oda E, Ohki R, Murasawa H et al. (2000) Noxa, a BH3‐only member of the Bcl‐2 family and candidate mediator of p53‐induced apoptosis. Science 288(5468): 1053–1058.

Puthalakath H, Villunger A, O'Reilly LA et al. (2001) Bmf: a proapoptotic BH3‐only protein regulated by interaction with the myosin V actin motor complex, activated by anoikis. Science 293(5536): 1829–1832.

Reed JC (2006) Proapoptotic multidomain Bcl‐2/Bax‐family proteins: mechanisms, physiological roles, and therapeutic opportunities. Cell Death and Differentiation 13(8): 1378–1386.

Ricci JE, Munoz‐Pinedo C, Fitzgerald P et al. (2004) Disruption of mitochondrial function during apoptosis is mediated by caspase cleavage of the p75 subunit of complex I of the electron transport chain. Cell 117(6): 773–786.

Riedl SJ and Shi Y (2004) Molecular mechanisms of caspase regulation during apoptosis. Nature Reviews. Molecular Cell Biology 5(11): 897–907.

Saelens X, Festjens N, Vande Walle L et al. (2004) Toxic proteins released from mitochondria in cell death. Oncogene 23(16): 2861–2874.

Sheridan C, Delivani P, Cullen SP and Martin SJ (2008) Bax‐ or Bak‐induced mitochondrial fission can be uncoupled from cytochrome c release. Molecular Cell 31(4): 570–585.

Smirnova E, Griparic L, Shurland DL and van der Bliek AM (2001) Dynamin‐related protein Drp1 is required for mitochondrial division in mammalian cells. Molecular Biology of the Cell 12(8): 2245–2256.

Tsujimoto Y and Shimizu S (2007) Role of the mitochondrial membrane permeability transition in cell death. Apoptosis 12(5): 835–840.

Wei MC, Zong WX, Cheng EH et al. (2001) Proapoptotic BAX and BAK: a requisite gateway to mitochondrial dysfunction and death. Science 292(5517): 727–730.

Willis SN, Fletcher JI, Kaufmann T et al. (2007) Apoptosis initiated when BH3 ligands engage multiple Bcl‐2 homologs, not Bax or Bak. Science 315(5813): 856–859.

Yamaguchi R, Lartigue L, Perkins G et al. (2008) Opa1‐mediated cristae opening is Bax/Bak and BH3 dependent, required for apoptosis, and independent of Bak oligomerization. Molecular Cell 31(4): 557–569.

Yoon Y, Krueger EW, Oswald BJ and McNiven MA (2003) The mitochondrial protein hFis1 regulates mitochondrial fission in mammalian cells through an interaction with the dynamin‐like protein DLP1. Molecular and Cellular Biology 23(15): 5409–5420.

Zha J, Harada H, Yang E, Jockel J and Korsmeyer SJ (1996) Serine phosphorylation of death agonist BAD in response to survival factor results in binding to 14‐3‐3 not BCL‐X(L). Cell 87(4): 619–628.

Zou H, Li Y, Liu X and Wang X (1999) An APAF‐1.cytochrome c multimeric complex is a functional apoptosome that activates procaspase‐9. Journal of Biological Chemistry 274(17): 11549–11556.

Further Reading

Cartron PF, Gallenne T, Bougras G et al. (2004) The first alpha helix of Bax plays a necessary role in its ligand‐induced activation by the BH3‐only proteins Bid and PUMA. Molecular Cell 16(5): 807–818.

Chen L, Willis SN, Wei A et al. (2005) Differential targeting of prosurvival Bcl‐2 proteins by their BH3‐only ligands allows complementary apoptotic function. Molecular Cell 17(3): 393–403.

Chipuk JE and Green DR (2008) How do BCL‐2 proteins induce mitochondrial outer membrane permeabilization? Trends in Cell Biology 18(4): 157–164.

Cohen GM (1997) Caspases: the executioners of apoptosis. Biochemical Journal 326(part 1): 1–16.

Fesik SW (2005) Promoting apoptosis as a strategy for cancer drug discovery. Nature Reviews. Cancer 5(11): 876–885.

Kerr JF, Wyllie AH and Currie AR (1972) Apoptosis: a basic biological phenomenon with wide‐ranging implications in tissue kinetics. British Journal of Cancer 26(4): 239–257.

Kim H, Rafiuddin‐Shah M, Tu HC et al. (2006) Hierarchical regulation of mitochondrion‐dependent apoptosis by BCL‐2 subfamilies. Nature Cell Biology 8(12): 1348–1358.

Kuwana T, Bouchier‐Hayes L, Chipuk JE et al. (2005) BH3 domains of BH3‐only proteins differentially regulate Bax‐mediated mitochondrial membrane permeabilization both directly and indirectly. Molecular Cell 17(4): 525–535.

Letai AG (2008) Diagnosing and exploiting cancer's addiction to blocks in apoptosis. Nature Reviews. Cancer 8(2): 121–132.

Letai A, Bassik MC, Walensky LD et al. (2002) Distinct BH3 domains either sensitize or activate mitochondrial apoptosis, serving as prototype cancer therapeutics. Cancer Cell 2(3): 183–192.

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Parsons, Melissa J, and Green, Douglas R(Sep 2009) Mitochondrial Outer Membrane Permeabilization. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0021576]