How do BCL-2 proteins induce mitochondrial outer membrane permeabilization?

Trends Cell Biol. 2008 Apr;18(4):157-64. doi: 10.1016/j.tcb.2008.01.007. Epub 2008 Mar 7.


The mitochondrial pathway of apoptosis proceeds when molecules sequestered between the outer and inner mitochondrial membranes are released to the cytosol by mitochondrial outer membrane permeabilization (MOMP). This process is controlled by the BCL-2 family, which is composed of both pro- and anti-apoptotic proteins. Although there is no disagreement that BCL-2 proteins regulate apoptosis, the mechanism leading to MOMP remains controversial. Current debate focuses on what interactions within the family are crucial to initiate MOMP. Specifically, do the BH3-only proteins directly engage BAX and/or BAK activation or do these proteins solely promote apoptosis by neutralization of anti-apoptotic BCL-2 proteins? We describe these models and contend that BH3-only proteins must perform both functions to efficiently engage MOMP and apoptosis.

Publication types

  • Review

MeSH terms

  • Animals
  • Apoptosis
  • Apoptosis Regulatory Proteins / metabolism
  • Gene Expression Regulation*
  • Humans
  • Membrane Proteins / metabolism*
  • Mitochondrial Membranes / metabolism*
  • Models, Biological
  • Protein Structure, Tertiary
  • Proto-Oncogene Proteins c-bcl-2 / metabolism*
  • bcl-2 Homologous Antagonist-Killer Protein / metabolism
  • bcl-2-Associated X Protein / metabolism


  • Apoptosis Regulatory Proteins
  • Membrane Proteins
  • Proto-Oncogene Proteins c-bcl-2
  • bcl-2 Homologous Antagonist-Killer Protein
  • bcl-2-Associated X Protein