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Avoiding Mitochondrial Apoptosis by the Bcl-2-Driven Bax Oligomerization on Membrane Surfaces

Ayscough, Sophie E. LU ; Clifton, Luke A. ; Ådén, Jörgen ; Köhler, Sebastian LU ; Paracini, Nicolò LU orcid ; Doutch, James ; Bragginton, Éilís C. ; Leung, Anna E. ; Bogojevic, Oliver LU and Poon, Jia Fei LU , et al. (2026) In ACS Chemical Biology 21(3). p.565-576
Abstract

The Bcl-2 family of proteins governs mitochondrial outer membrane (MOM) permeabilization, a critical step in apoptosis that is dysfunctional in many cancers. Although cellular studies have long implicated direct interactions between the pore-forming apoptotic Bax protein and its opponent, the antiapoptotic Bcl-2 protein in apoptosis regulation, the underlying basic principles behind this control remained unresolved. To provide in-depth insight, we carried out a systematic biophysical study in which we utilized neutron reflectometry (NR) and ATR-FTIR to elucidate the molecular communication between those proteins in and around the mitochondrial membrane environment. The spatial and temporal changes across model MOM surfaces were resolved... (More)

The Bcl-2 family of proteins governs mitochondrial outer membrane (MOM) permeabilization, a critical step in apoptosis that is dysfunctional in many cancers. Although cellular studies have long implicated direct interactions between the pore-forming apoptotic Bax protein and its opponent, the antiapoptotic Bcl-2 protein in apoptosis regulation, the underlying basic principles behind this control remained unresolved. To provide in-depth insight, we carried out a systematic biophysical study in which we utilized neutron reflectometry (NR) and ATR-FTIR to elucidate the molecular communication between those proteins in and around the mitochondrial membrane environment. The spatial and temporal changes across model MOM surfaces were resolved during the interaction of Bax with Bcl-2. The NR-derived membrane surface Bax distributions suggested that Bcl-2 mediated Bax sequestration through both Bcl-2/Bax heterodimerization and Bax/Bax oligomerization. Kinetic analysis revealed a two-step process: rapid formation of Bcl-2/Bax heterodimers, followed by slower Bax oligomerization on these complexes. Importantly, this sequestration mechanism was also observed in the presence of cardiolipin, a lipid known to promote the formation of an apoptotic pore by Bax in the absence of Bcl-2. These findings suggest a fundamental mechanism by which cancer cells may evade apoptosis by exploiting Bcl-2’s ability to neutralize Bax through structural entrapment, even if excess Bax is present, either in response to treatment or natural death signals.

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organization
publishing date
type
Contribution to journal
publication status
published
subject
in
ACS Chemical Biology
volume
21
issue
3
pages
12 pages
publisher
The American Chemical Society (ACS)
external identifiers
  • pmid:41705766
  • scopus:105033400038
ISSN
1554-8929
DOI
10.1021/acschembio.5c00913
language
English
LU publication?
yes
additional info
Publisher Copyright: © 2026 The Authors. Published by American Chemical Society
id
522aa651-239e-4aa8-8ccb-0385ca8108b0
date added to LUP
2026-04-23 14:37:36
date last changed
2026-05-07 15:30:53
@article{522aa651-239e-4aa8-8ccb-0385ca8108b0,
  abstract     = {{<p>The Bcl-2 family of proteins governs mitochondrial outer membrane (MOM) permeabilization, a critical step in apoptosis that is dysfunctional in many cancers. Although cellular studies have long implicated direct interactions between the pore-forming apoptotic Bax protein and its opponent, the antiapoptotic Bcl-2 protein in apoptosis regulation, the underlying basic principles behind this control remained unresolved. To provide in-depth insight, we carried out a systematic biophysical study in which we utilized neutron reflectometry (NR) and ATR-FTIR to elucidate the molecular communication between those proteins in and around the mitochondrial membrane environment. The spatial and temporal changes across model MOM surfaces were resolved during the interaction of Bax with Bcl-2. The NR-derived membrane surface Bax distributions suggested that Bcl-2 mediated Bax sequestration through both Bcl-2/Bax heterodimerization and Bax/Bax oligomerization. Kinetic analysis revealed a two-step process: rapid formation of Bcl-2/Bax heterodimers, followed by slower Bax oligomerization on these complexes. Importantly, this sequestration mechanism was also observed in the presence of cardiolipin, a lipid known to promote the formation of an apoptotic pore by Bax in the absence of Bcl-2. These findings suggest a fundamental mechanism by which cancer cells may evade apoptosis by exploiting Bcl-2’s ability to neutralize Bax through structural entrapment, even if excess Bax is present, either in response to treatment or natural death signals.</p>}},
  author       = {{Ayscough, Sophie E. and Clifton, Luke A. and Ådén, Jörgen and Köhler, Sebastian and Paracini, Nicolò and Doutch, James and Bragginton, Éilís C. and Leung, Anna E. and Bogojevic, Oliver and Poon, Jia Fei and Nagy, Tamás Milán and Wacklin-Knecht, Hanna P. and Gröbner, Gerhard}},
  issn         = {{1554-8929}},
  language     = {{eng}},
  month        = {{03}},
  number       = {{3}},
  pages        = {{565--576}},
  publisher    = {{The American Chemical Society (ACS)}},
  series       = {{ACS Chemical Biology}},
  title        = {{Avoiding Mitochondrial Apoptosis by the Bcl-2-Driven Bax Oligomerization on Membrane Surfaces}},
  url          = {{http://dx.doi.org/10.1021/acschembio.5c00913}},
  doi          = {{10.1021/acschembio.5c00913}},
  volume       = {{21}},
  year         = {{2026}},
}