Cell-cell contacts prevent t-BuOOH-triggered ferroptosis and cellular damage in vitro by regulation of intracellular calcium.
Arch Toxicol
; 98(9): 2953-2969, 2024 Sep.
Article
em En
| MEDLINE
| ID: mdl-38814333
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.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Peroxidação de Lipídeos
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Cálcio
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Terc-Butil Hidroperóxido
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Quebras de DNA de Cadeia Dupla
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Potencial da Membrana Mitocondrial
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Ferroptose
Limite:
Animals
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Humans
Idioma:
En
Revista:
Arch Toxicol
Ano de publicação:
2024
Tipo de documento:
Article
País de afiliação:
Alemanha