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

Melina Daniilidis, Umut Günsel, Georgios Broutzakis, Kira D. Leitl, Robert Janowski, Kai Fredriksson, Dierk Niessing, Christos Gatsogiannis and Franz Hagn ()
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Melina Daniilidis: Technical University of Munich
Umut Günsel: Technical University of Munich
Georgios Broutzakis: Westfälische Wilhelms Universität Münster
Kira D. Leitl: Technical University of Munich
Robert Janowski: Helmholtz Munich
Kai Fredriksson: Technical University of Munich
Dierk Niessing: Helmholtz Munich
Christos Gatsogiannis: Westfälische Wilhelms Universität Münster
Franz Hagn: Technical University of Munich

Nature Communications, 2025, vol. 16, issue 1, 1-16

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-025-65363-1

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