Challenging a role for ceramide channels and microdomains in apoptosis induction using a bottom-up approach
Abstract
Ceramides are essential but potentially toxic intermediates of sphingolipid metabolism that can act directly on mitochondria to trigger apoptotic cell death, but the underlying mechanism is unclear. While one model postulates that ceramides form stable channels in the outer mitochondrial membrane that induce cell death through direct release of cytochrome c, an alternative view is that ceramides self-assemble into microdomains that facilitate membrane insertion and oligomerization of the pro-apoptotic Bcl-2 protein Bax into cytochrome c -conducting pores. To challenge these models, we here analyzed the influence of ceramides in combination with recombinant Bax on the leakiness of model membranes. We show that ceramides on their own are unable to support membrane passage of even the smallest fluorescence markers. Moreover, we find that ceramides cannot substitute for cardiolipin in facilitating membrane recruitment of Bax and its subsequent assembly into functional pores. Our data argue against a direct role of ceramides in apoptotic pore formation and indicate that the mechanism by which ceramides initiate permeabilization of the outer mitochondrial membrane is independent of ceramide channels or ceramide acting autonomously as translocation platform for Bax.
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BibTeX
@article{wessing2026challenging,
title = {{Challenging a role for ceramide channels and microdomains in apoptosis induction using a bottom-up approach}},
author = {Milena Wessing and Pia Webersinn and Sophie Klaßen and Britta Fiedler and Katia Cosentino and Joost C. M. Holthuis},
journal = {Scientific Reports},
year = {2026},
month = oct,
doi = {10.1038/s41598-026-72774-7},
url = {https://www.nature.com/articles/s41598-026-72774-7},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Challenging a role for ceramide channels and microdomains in apoptosis induction using a bottom-up approach
AU - Milena Wessing
AU - Pia Webersinn
AU - Sophie Klaßen
AU - Britta Fiedler
AU - Katia Cosentino
AU - Joost C. M. Holthuis
PY - 2026
DA - 2026/10/15
JO - Scientific Reports
DO - 10.1038/s41598-026-72774-7
UR - https://www.nature.com/articles/s41598-026-72774-7
AB - Ceramides are essential but potentially toxic intermediates of sphingolipid metabolism that can act directly on mitochondria to trigger apoptotic cell death, but the underlying mechanism is unclear. While one model postulates that ceramides form stable channels in the outer mitochondrial membrane that induce cell death through direct release of cytochrome c, an alternative view is that ceramides self-assemble into microdomains that facilitate membrane insertion and oligomerization of the pro-apoptotic Bcl-2 protein Bax into cytochrome c -conducting pores. To challenge these models, we here analyzed the influence of ceramides in combination with recombinant Bax on the leakiness of model membranes. We show that ceramides on their own are unable to support membrane passage of even the smallest fluorescence markers. Moreover, we find that ceramides cannot substitute for cardiolipin in facilitating membrane recruitment of Bax and its subsequent assembly into functional pores. Our data argue against a direct role of ceramides in apoptotic pore formation and indicate that the mechanism by which ceramides initiate permeabilization of the outer mitochondrial membrane is independent of ceramide channels or ceramide acting autonomously as translocation platform for Bax.
SN - 2045-2322
ER -