A unified model of mammalian BCL-2 protein family interactions at the mitochondria

Mol Cell. 2011 Nov 18;44(4):517-31. doi: 10.1016/j.molcel.2011.10.001. Epub 2011 Oct 27.


During apoptosis, the BCL-2 protein family controls mitochondrial outer membrane permeabilization (MOMP), but the dynamics of this regulation remain controversial. We employed chimeric proteins composed of exogenous BH3 domains inserted into a tBID backbone that can activate the proapoptotic effectors BAX and BAK to permeabilize membranes without being universally sequestered by all antiapoptotic BCL-2 proteins. We thus identified two "modes" whereby prosurvival BCL-2 proteins can block MOMP, by sequestering direct-activator BH3-only proteins ("MODE 1") or by binding active BAX and BAK ("MODE 2"). Notably, we found that MODE 1 sequestration is less efficient and more easily derepressed to promote MOMP than MODE 2. Further, MODE 2 sequestration prevents mitochondrial fusion. We provide a unified model of BCL-2 family function that helps to explain otherwise paradoxical observations relating to MOMP, apoptosis, and mitochondrial dynamics.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Apoptosis Regulatory Proteins / genetics
  • Apoptosis Regulatory Proteins / metabolism
  • Apoptosis*
  • BH3 Interacting Domain Death Agonist Protein / genetics
  • BH3 Interacting Domain Death Agonist Protein / metabolism
  • Cytochromes c / analysis
  • Gene Expression Regulation*
  • HeLa Cells
  • Humans
  • Mammals
  • Mice
  • Mice, Knockout
  • Mitochondria, Liver / metabolism*
  • Mitochondrial Membranes / metabolism*
  • Molecular Sequence Annotation
  • Permeability
  • Protein Binding
  • Recombinant Fusion Proteins / genetics
  • Recombinant Fusion Proteins / metabolism*
  • Sequence Alignment
  • Signal Transduction*
  • Transfection
  • bcl-2 Homologous Antagonist-Killer Protein / genetics
  • bcl-2 Homologous Antagonist-Killer Protein / metabolism
  • bcl-2-Associated X Protein / genetics
  • bcl-2-Associated X Protein / metabolism
  • bcl-X Protein / genetics
  • bcl-X Protein / metabolism


  • Apoptosis Regulatory Proteins
  • BH3 Interacting Domain Death Agonist Protein
  • HRK protein, human
  • Recombinant Fusion Proteins
  • bcl-2 Homologous Antagonist-Killer Protein
  • bcl-2-Associated X Protein
  • bcl-X Protein
  • Cytochromes c