Ceramides bind VDAC2 to trigger mitochondrial apoptosis

Nat Commun. 2019 Apr 23;10(1):1832. doi: 10.1038/s41467-019-09654-4.

Shashank Dadsena ¹, Svenja Bockelmann ¹, John G M Mina ² ³, Dina G Hassan ¹ ⁴, Sergei Korneev ¹, Guilherme Razzera ⁵ ⁶, Helene Jahn ¹, Patrick Niekamp ¹, Dagmar Müller ¹, Markus Schneider ¹ ⁷ ⁸, Fikadu G Tafesse ⁹, Siewert J Marrink ¹⁰, Manuel N Melo ¹¹ ¹², Joost C M Holthuis ¹³ ¹⁴ ¹⁵

Affiliations

1 Molecular Cell Biology Division, Department of Biology/Chemistry, University of Osnabrück, 49076, Osnabrück, Germany.
2 Molecular Cell Biology Division, Department of Biology/Chemistry, University of Osnabrück, 49076, Osnabrück, Germany. [email protected].
3 School of Science, Engineering and Design, Teesside University, Middlesbrough, TS1 3BX, UK. [email protected].
4 Institute of Environmental Studies and Research, Ain Shams University, Cairo, Egypt.
5 Instituto de Tecnologia Química e Biológica António Xavier, Universidade Nova de Lisboa, Av. da República, 2780-157, Oeiras, Portugal.
6 Departamento de Bioquímica, Centro de Ciências Biológicas, Universidade Federal de Santa Catarina, Florianópolis, Brazil.
7 Plant Physiology Division, Department of Biology/Chemistry, University of Osnabrück, 49076, Osnabrück, Germany.
8 Center for Cellular Nanoanalytics, Osnabrück University, Artilleriestraße 77, 49076, Osnabrück, Germany.
9 Molecular Microbiology and Immunology, Oregon Health & Science University, Portland, OR, 97239, USA.
10 Groningen Biomolecular Sciences and Biotechnology Institute and Zernike Institute for Advanced Materials, University of Groningen, Nijenborgh 7, 9747 AG, Groningen, The Netherlands.
11 Instituto de Tecnologia Química e Biológica António Xavier, Universidade Nova de Lisboa, Av. da República, 2780-157, Oeiras, Portugal. [email protected].
12 Groningen Biomolecular Sciences and Biotechnology Institute and Zernike Institute for Advanced Materials, University of Groningen, Nijenborgh 7, 9747 AG, Groningen, The Netherlands. [email protected].
13 Molecular Cell Biology Division, Department of Biology/Chemistry, University of Osnabrück, 49076, Osnabrück, Germany. [email protected].
14 Center for Cellular Nanoanalytics, Osnabrück University, Artilleriestraße 77, 49076, Osnabrück, Germany. [email protected].
15 Membrane Biochemistry and Biophysics, Bijvoet Center and Institute of Biomembranes, Utrecht University, 3584 CH, Utrecht, The Netherlands. [email protected].

PMID: 31015432 DOI: 10.1038/s41467-019-09654-4

Abstract

Ceramides draw wide attention as tumor suppressor lipids that act directly on mitochondria to trigger apoptotic cell death. However, molecular details of the underlying mechanism are largely unknown. Using a photoactivatable ceramide probe, we here identify the voltage-dependent anion channels VDAC1 and VDAC2 as mitochondrial ceramide binding proteins. Coarse-grain molecular dynamics simulations reveal that both channels harbor a ceramide binding site on one side of the barrel wall. This site includes a membrane-buried glutamate that mediates direct contact with the ceramide head group. Substitution or chemical modification of this residue abolishes photolabeling of both channels with the ceramide probe. Unlike VDAC1 removal, loss of VDAC2 or replacing its membrane-facing glutamate with glutamine renders human colon Cancer cells largely resistant to ceramide-induced Apoptosis. Collectively, our data support a role of VDAC2 as direct effector of ceramide-mediated cell death, providing a molecular framework for how ceramides exert their anti-neoplastic activity.

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