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 () and Joost C. M. Holthuis ()
Additional contact information
Shashank Dadsena: University of Osnabrück
Svenja Bockelmann: University of Osnabrück
John G. M. Mina: University of Osnabrück
Dina G. Hassan: University of Osnabrück
Sergei Korneev: University of Osnabrück
Guilherme Razzera: Universidade Nova de Lisboa
Helene Jahn: University of Osnabrück
Patrick Niekamp: University of Osnabrück
Dagmar Müller: University of Osnabrück
Markus Schneider: University of Osnabrück
Fikadu G. Tafesse: Oregon Health & Science University
Siewert J. Marrink: University of Groningen
Manuel N. Melo: Universidade Nova de Lisboa
Joost C. M. Holthuis: University of Osnabrück

Nature Communications, 2019, vol. 10, issue 1, 1-12

Abstract: 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.

Date: 2019
References: Add references at CitEc
Citations: View citations in EconPapers (1)

Downloads: (external link)
https://www.nature.com/articles/s41467-019-09654-4 Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-019-09654-4

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-019-09654-4

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().