The central role of glutathione peroxidase 4 in the regulation of ferroptosis and its implications for pro-inflammatory cytokine-mediated beta-cell death.
Biochim Biophys Acta Mol Basis Dis
; 1867(6): 166114, 2021 06 01.
Article
en En
| MEDLINE
| ID: mdl-33662571
Pro-inflammatory cytokines are crucial mediators of beta-cell destruction in type 1 diabetes mellitus (T1DM). The involvement of ferroptosis as a form of oxidative non-apoptotic cell death in T1DM pathogenesis has not been elucidated so far. Moreover, the role of glutathione peroxidase 4 (GPx4) as an antioxidative enzyme and a major regulator of ferroptosis remains elusive. Assessment of GPx4 expression in different pancreatic islet cell types revealed a predominant expression in beta-cells. Silencing of GPx4 by RNA interference and exposure to tert-butyl hydroperoxide (tert-BHP) caused ferroptosis in rat pancreatic beta-cells as evidenced by non-apoptotic cell death in association with increased lipid peroxidation, disturbed ATP synthesis, reduced GSH content, and GPx4 degradation. GPx4 overexpression as well as the ferroptosis inhibitor ferrostatin-1 effectively attenuated beta-cell death induced by tert-BHP. Notably, beta-cell toxic cytokines did not induce ferroptosis although beta-cells underwent cell death. Inhibition of iNOS by Nω-nitro-L-arginine however led to a massive lipid peroxidation upon exposure to pro-inflammatory cytokines. Hence, nitric oxide produced during pro-inflammatory cytokine action prevents the induction of ferroptosis, thereby favouring apoptosis as a primary cell death mechanism. The extraordinarily high abundance of the phospholipid hydroperoxidase GPx4 in beta-cells in contrast to the very low expression in other islet cell types points to a susceptibility of beta-cells to the accumulation of toxic lipid peroxides. Overall, these data strongly suggest that GPx4 is indispensable for beta-cell function under physiological conditions. On the other hand, our results exclude an involvement of ferroptosis as an alternative beta-cell death mode under pro-inflammatory cytokine attack.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Peroxidación de Lípido
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Citocinas
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Apoptosis
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Mediadores de Inflamación
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Células Secretoras de Insulina
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Ferroptosis
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Fosfolípido Hidroperóxido Glutatión Peroxidasa
Límite:
Animals
Idioma:
En
Revista:
Biochim Biophys Acta Mol Basis Dis
Año:
2021
Tipo del documento:
Article
País de afiliación:
Alemania
Pais de publicación:
Países Bajos