Journal
CELL DEATH AND DIFFERENTIATION
Volume 29, Issue 3, Pages 670-686Publisher
SPRINGERNATURE
DOI: 10.1038/s41418-021-00883-z
Keywords
-
Categories
Funding
- Helmholtz Zentrum Munich GmbH (JAS)
- Chinese Scholarship Council [201609505007]
- Innovation Platform for Academicians of Hainan Province
Ask authors/readers for more resources
This study uncovers a crucial link between ferroptosis and calcium through the identification of the novel tetraspanin MS4A15; MS4A15 blocks ferroptosis by depleting luminal calcium stores and reprogramming membrane phospholipids; Increasing luminal calcium levels can sensitize refractory cancer cell lines.
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.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available