The third model of Bax/Bak activation: A Bcl-2 family feud finally resolved?

Xu Luo, Katelyn L. O'Neill, Kai Huang

Research output: Contribution to journalReview articlepeer-review

27 Scopus citations


Bax and Bak, two functionally similar, pro-apoptotic proteins of the Bcl-2 family, are known as the gateway to apoptosis because of their requisite roles as effectors of mitochondrial outer membrane permeabilization (MOMP), a major step during mitochondria-dependent apoptosis. The mechanism of how cells turn Bax/Bak from inert molecules into fully active and lethal effectors had long been the focal point of a major debate centered around two competing, but not mutually exclusive, models: direct activation and indirect activation. After intensive research efforts for over two decades, it is now widely accepted that to initiate apoptosis, some of the BH3-only proteins, a subclass of the Bcl-2 family, directly engage Bax/Bak to trigger their conformational transformation and activation. However, a series of recent discoveries, using previously unavailable CRISPR-engineered cell systems, challenge the basic premise that undergirds the consensus and provide evidence for a novel and surprisingly simple model of Bax/Bak activation: the membrane (lipids)-mediated spontaneous model. This review will discuss the evidence, rationale, significance, and implications of this new model.

Original languageEnglish (US)
Article number935
StatePublished - 2020


  • Activator
  • Apoptosis
  • Auto-activation
  • BH3 mimetics
  • BH3-only proteins
  • Bad
  • Bak
  • Bax
  • Bcl-2 family
  • Bcl-xL
  • Bid
  • Bim
  • De novo activation
  • Direct activation
  • Indirect activation
  • Mcl-1
  • Membrane-mediated Spontaneous activation
  • Mitochondrial outer membrane
  • Retro-translocation
  • Sensitizer

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Microbiology(all)
  • Pharmacology, Toxicology and Pharmaceutics(all)


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