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

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

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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
Article number1832
Number of pages12
JournalNature Communications
Volume10
Issue number1
DOIs
Publication statusPublished - 23-Apr-2019

Keywords

  • Ceramides
  • apoptosis
  • mitochondria
  • Coarse-grain molecular dynamics simulations
  • VDAC2
  • RADIATION-INDUCED APOPTOSIS
  • DEPENDENT ANION CHANNEL-1
  • SPHINGOLIPID METABOLISM
  • CELL-DEATH
  • BAX
  • MEMBRANE
  • PROTEINS
  • INHIBITION
  • TRANSPORT
  • EFFICIENT

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