Ceramides bind VDAC2 to trigger mitochondrial apoptosis

Shashank Dadsena, Svenja Bockelmann, John G.M. Mina, Dina G. Hassan, Sergei Korneev, Guilherme Razzera, Helene Jahn, Patrick Niekamp, Dagmar Müller, Markus Schneider, Fikadu G. Tafesse, Siewert J. Marrink, Manuel N. Melo, Joost C.M. Holthuis

Research output: Contribution to journalArticle

28 Scopus citations

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.

Original languageEnglish (US)
Article number1832
JournalNature communications
Volume10
Issue number1
DOIs
StatePublished - Dec 1 2019

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

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    Dadsena, S., Bockelmann, S., Mina, J. G. M., Hassan, D. G., Korneev, S., Razzera, G., Jahn, H., Niekamp, P., Müller, D., Schneider, M., Tafesse, F. G., Marrink, S. J., Melo, M. N., & Holthuis, J. C. M. (2019). Ceramides bind VDAC2 to trigger mitochondrial apoptosis. Nature communications, 10(1), [1832]. https://doi.org/10.1038/s41467-019-09654-4