VDAC2 stabilizes a membrane-inserted, primed intermediate of BAX activation

Abstract

BAX, a major effector of mitochondrial apoptosis, is activated through a series of conformational transitions that lead to mitochondrial outer membrane permeabilization. Genetic studies have established VDAC2 as an essential regulator of BAX-mediated apoptosis, yet the molecular basis of this regulation remains unresolved. The absence of direct structural and biochemical characterization of VDAC2–BAX interactions has prevented mechanistic understanding of how VDAC2 influences BAX activation. Here, using complementary biochemical, biophysical and structural approaches, we reconstituted and characterized a stable VDAC2–BAX complex that was not observed with VDAC1, highlighting an isoform-specific role in BAX regulation. We show that VDAC2 captures and stabilizes a primed BAX conformation displaying the hallmarks of activation, including membrane insertion, BH3 exposure, and increased accessibility of the N-terminal activation region. By integrating AlphaFold3 predictions with molecular dynamics simulations, biochemical, biophysical and structural constraints, we derive an experimentally-supported structural model in which BAX is anchored through its α9 helix while its soluble domain partially extends over the VDAC2 pore. Together, our findings support a model in which VDAC2 facilitates BAX membrane insertion and stabilizes a membrane-inserted, activation- competent BAX intermediate. Rather than serving as a structural component of apoptotic pores, VDAC2 acts as a regulatory checkpoint in BAX activation. These results provide a molecular explanation for the emerging role of VDAC2 in mitochondrial apoptosis and establish structural basis for a previously inaccessible intermediate in the BAX activation pathway.

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BibTeX RIS

BibTeX

@article{ravishankar2026vdac2,
  title = {{VDAC2 stabilizes a membrane-inserted, primed intermediate of BAX activation}},
  author = {Varun Ravishankar and Laidy Alvero-González and Agathe Hubert and Zaiwei Zhang and Chloé Markarian and Valérie Prima and Sirine Chergui and Roberto Melero and Florian Stengel and Stéphen Manon and Jean-Pierre Duneau and Maria Queralt-Martin and Lucie Bergdoll},
  journal = {eLife},
  year = {2026},
  month = sep,
  doi = {10.7554/elife.112461.1},
  url = {https://hal.science/hal-05793965v1},
  note = {CC BY},
}

RIS

TY  - JOUR
TI  - VDAC2 stabilizes a membrane-inserted, primed intermediate of BAX activation
AU  - Varun Ravishankar
AU  - Laidy Alvero-González
AU  - Agathe Hubert
AU  - Zaiwei Zhang
AU  - Chloé Markarian
AU  - Valérie Prima
AU  - Sirine Chergui
AU  - Roberto Melero
AU  - Florian Stengel
AU  - Stéphen Manon
AU  - Jean-Pierre Duneau
AU  - Maria Queralt-Martin
AU  - Lucie Bergdoll
PY  - 2026
DA  - 2026/09/17
JO  - eLife
DO  - 10.7554/elife.112461.1
UR  - https://hal.science/hal-05793965v1
AB  - BAX, a major effector of mitochondrial apoptosis, is activated through a series of conformational transitions that lead to mitochondrial outer membrane permeabilization. Genetic studies have established VDAC2 as an essential regulator of BAX-mediated apoptosis, yet the molecular basis of this regulation remains unresolved. The absence of direct structural and biochemical characterization of VDAC2–BAX interactions has prevented mechanistic understanding of how VDAC2 influences BAX activation. Here, using complementary biochemical, biophysical and structural approaches, we reconstituted and characterized a stable VDAC2–BAX complex that was not observed with VDAC1, highlighting an isoform-specific role in BAX regulation. We show that VDAC2 captures and stabilizes a primed BAX conformation displaying the hallmarks of activation, including membrane insertion, BH3 exposure, and increased accessibility of the N-terminal activation region. By integrating AlphaFold3 predictions with molecular dynamics simulations, biochemical, biophysical and structural constraints, we derive an experimentally-supported structural model in which BAX is anchored through its α9 helix while its soluble domain partially extends over the VDAC2 pore. Together, our findings support a model in which VDAC2 facilitates BAX membrane insertion and stabilizes a membrane-inserted, activation- competent BAX intermediate. Rather than serving as a structural component of apoptotic pores, VDAC2 acts as a regulatory checkpoint in BAX activation. These results provide a molecular explanation for the emerging role of VDAC2 in mitochondrial apoptosis and establish structural basis for a previously inaccessible intermediate in the BAX activation pathway.
SN  - 2050-084X
ER  -

Abstract

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