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Xin, S. ; Müller, C. ; Pfeiffer, S. ; Kraft, V. ; Merl-Pham, J. ; Bao, X.* ; Feederle, R. ; Jin, X.* ; Hauck, S.M. ; Schmitt-Kopplin, P. ; Schick, J.

MS4A15 drives ferroptosis resistance through calcium-restricted lipid remodeling.

Cell Death Differ., DOI: 10.1038/s41418-021-00883-z (2022)
Verlagsversion DOI PMC
Open Access Hybrid
Creative Commons Lizenzvertrag
Ferroptosis is an iron-dependent form of cell death driven by biochemical processes that promote oxidation within the lipid compartment. Calcium (Ca2+) is a signaling molecule in diverse cellular processes such as migration, neurotransmission, and cell death. Here, we uncover a crucial link between ferroptosis and Ca2+ through the identification of the novel tetraspanin MS4A15. MS4A15 localizes to the endoplasmic reticulum, where it blocks ferroptosis by depleting luminal Ca2+ stores and reprogramming membrane phospholipids to ferroptosis-resistant species. Specifically, prolonged Ca2+ depletion inhibits lipid elongation and desaturation, driving lipid droplet dispersion and formation of shorter, more saturated ether lipids that protect phospholipids from ferroptotic reactive species. We further demonstrate that increasing luminal Ca2+ levels can preferentially sensitize refractory cancer cell lines. In summary, MS4A15 regulation of anti-ferroptotic lipid reservoirs provides a key resistance mechanism that is distinct from antioxidant and lipid detoxification pathways. Manipulating Ca2+ homeostasis offers a compelling strategy to balance cellular lipids and cell survival in ferroptosis-associated diseases.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Schlagwörter Cell-death; Caenorhabditis-elegans; Molecular-mechanisms; Cancer-cells; Ca2+; Metabolism; Sensitivity; Receptor; Mouse; Cd20
Sprache englisch
Veröffentlichungsjahr 2022
Prepublished im Jahr 2021
HGF-Berichtsjahr 2021
ISSN (print) / ISBN 1350-9047
e-ISSN 1476-5403
Zeitschrift Cell Death and Differentiation
Verlag Nature Publishing Group
Verlagsort Campus, 4 Crinan St, London, N1 9xw, England
Begutachtungsstatus Peer reviewed
Institut(e) Institute of Molecular Toxicology and Pharmacology (TOX)
Research Unit BioGeoChemistry and Analytics (BGC)
CF Metabolomics & Proteomics (CF-MPC)
CF Monoclonal Antibodies (CF-MAB)
POF Topic(s) 30203 - Molecular Targets and Therapies
30202 - Environmental Health
30201 - Metabolic Health
Forschungsfeld(er) Enabling and Novel Technologies
Environmental Sciences
Helmholtz Diabetes Center
PSP-Element(e) G-505200-006
G-504800-001
G-505200-001
G-505700-001
G-502210-001
A-630700-001
Förderungen Innovation Platform for Academicians of Hainan Province
Chinese Scholarship Council
Helmholtz Zentrum Munich GmbH (JAS)
DOI 10.1038/s41418-021-00883-z
WOS ID WOS:000708331700002
Scopus ID 85117222753
PubMed ID 34663908
Erfassungsdatum 2021-10-27
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