Cell-cell contacts prevent t-BuOOH-triggered ferroptosis and cellular damage in vitro by regulation of intracellular calcium

• Verfasst von: Faust, Dagmar [VerfasserIn]
• Verfasst von: Wenz, Christine [VerfasserIn]
• Verfasst von: Holm, Stefanie [VerfasserIn]
• Verfasst von: Harms, Gregory [VerfasserIn]
• Verfasst von: Greffrath, Wolfgang [VerfasserIn]
• Verfasst von: Dietrich, Cornelia [VerfasserIn]
• Titel: Cell-cell contacts prevent t-BuOOH-triggered ferroptosis and cellular damage in vitro by regulation of intracellular calcium
• Verf.angabe: Dagmar Faust, Christine Wenz, Stefanie Holm, Gregory Harms, Wolfgang Greffrath, Cornelia Dietrich
• E-Jahr: 2024
• Jahr: September 2024
• Umfang: 17 S.
• Illustrationen: Illustrationen
• Fussnoten: Online veröffentlicht: 30. Mai 2024 ; Gesehen am 13.11.2024
• Titel Quelle: Enthalten in: Archives of toxicology
• Ort Quelle: Berlin : Springer, 1930
• Jahr Quelle: 2024
• Band/Heft Quelle: 98(2024), 9, Seite 2953-2969
• ISSN Quelle: 1432-0738
• DOI: doi:10.1007/s00204-024-03792-5
• Datenträger: Online-Ressource
• Sprache: eng
• Sach-SW: Calcium
• Sach-SW: Cell-cell contacts
• Sach-SW: Ferroptosis
• Sach-SW: t-BuOOH
• Sach-SW: Toxicity
• K10plus-PPN: 1908384565

Abstract

Tert-butyl hydroperoxide (t-BuOOH) is an organic hydroperoxide widely used as a model compound to induce oxidative stress. It leads to a plethora of cellular damage, including lipid peroxidation, DNA double-strand breaks (DNA DSBs), and breakdown of the mitochondrial membrane potential (MMP). We could show in several cell lines that t-BuOOH induces ferroptosis, triggered by iron-dependent lipid peroxidation. We have further revealed that not only t-BuOOH-mediated ferroptosis, but also DNA DSBs and loss of MMP are prevented by cell-cell contacts. The underlying mechanisms are not known. Here, we show in murine fibroblasts and a human colon carcinoma cell line that t-BuOOH (50 or 100 µM, resp.) causes an increase in intracellular Ca2+, and that this increase is key to lipid peroxidation and ferroptosis, DNA DSB formation and dissipation of the MMP. We further demonstrate that cell-cell contacts prevent t-BuOOH-mediated raise in intracellular Ca2+. Hence, we provide novel insights into the mechanism of t-BuOOH-triggered cellular damage including ferroptosis and propose a model in which cell-cell contacts control intracellular Ca2+ levels to prevent lipid peroxidation, DNA DSB-formation and loss of MMP. Since Ca2+ is a central player of toxicity in response to oxidative stress and is involved in various cell death pathways, our observations suggest a broad protective function of cell-cell contacts against a variety of exogenous toxicants.