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MS4A15 drives ferroptosis resistance through calcium-restricted lipid remodeling.

Cell Death Differ., DOI: 10.1038/s41418-021-00883-z (2021)
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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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Publication type Article: Journal article
Document type Scientific Article
Keywords Cell-death; Caenorhabditis-elegans; Molecular-mechanisms; Cancer-cells; Ca2+; Metabolism; Sensitivity; Receptor; Mouse; Cd20
ISSN (print) / ISBN 1350-9047
e-ISSN 1476-5403
Publisher Nature Publishing Group
Publishing Place Campus, 4 Crinan St, London, N1 9xw, England
Reviewing status Peer reviewed
Grants Innovation Platform for Academicians of Hainan Province
Chinese Scholarship Council
Helmholtz Zentrum Munich GmbH (JAS)