2. Academic Validation
  3. Structural basis of apoptosis induction by the mitochondrial voltage-dependent anion channel

Structural basis of apoptosis induction by the mitochondrial voltage-dependent anion channel

  • Nat Commun. 2025 Oct 27;16(1):9481. doi: 10.1038/s41467-025-65363-1.
Melina Daniilidis # 1,  Umut Günsel # 1 2,  Georgios Broutzakis 3,  Kira D Leitl 1,  Robert Janowski 2,  Kai Fredriksson 1 4,  Dierk Niessing 2 5,  Christos Gatsogiannis 3,  Franz Hagn 6 7
Affiliations

Affiliations

  • 1 Structural Membrane Biochemistry and Bavarian NMR Center (BNMRZ), Department of Bioscience, School of Natural Sciences, Technical University of Munich, Garching, Germany.
  • 2 Molecular Targets and Therapeutics Center (MTTC), Institute of Structural Biology, Helmholtz Munich, Neuherberg, Germany.
  • 3 Institute for Medical Physics and Biophysics and Center for Soft Nanoscience, Westfälische Wilhelms Universität Münster, Münster, Germany.
  • 4 AGC Biologics, Copenhagen, Denmark.
  • 5 Institute of Pharmaceutical Biotechnology, Ulm University, Ulm, Germany.
  • 6 Structural Membrane Biochemistry and Bavarian NMR Center (BNMRZ), Department of Bioscience, School of Natural Sciences, Technical University of Munich, Garching, Germany. [email protected].
  • 7 Molecular Targets and Therapeutics Center (MTTC), Institute of Structural Biology, Helmholtz Munich, Neuherberg, Germany. [email protected].
  • # Contributed equally.
PMID: 41145501 DOI: 10.1038/s41467-025-65363-1
Abstract

The voltage-dependent anion channel (VDAC) is the main gateway for metabolites across the mitochondrial outer membrane. VDAC oligomers are connected to Apoptosis induced by various stimuli. However, the mechanistic and structural basis of Apoptosis induction by VDAC remains poorly understood. Here, using cryo-EM and NMR we show that VDAC1 oligomerization or confinement in small lipid nanodiscs triggers the exposure of its N-terminal α-helix (VDAC1-N) which becomes available for partner protein binding. NMR and X-ray crystallography data show that VDAC1-N forms a complex with the BH3 binding groove of the anti-apoptotic Bcl2 protein BclxL. Biochemical assays demonstrate that VDAC1-N exhibits a pro-apoptotic function by promoting pore formation of the executor Bcl2 protein Bak via neutralization of BclxL. This mechanism is reminiscent of BH3-only sensitizer Bcl2 proteins that are efficient inducers of Bax/Bak-mediated mitochondrial outer membrane permeabilization and ultimately Apoptosis. The VDAC pathway most likely responds to mitochondrial stress or damage.

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