GPX4 degradation contributes to fluoride-induced neuronal ferroptosis and cognitive impairment via mtROS-chaperone-mediated autophagy.
Sci Total Environ
; 927: 172069, 2024 Jun 01.
Article
em En
| MEDLINE
| ID: mdl-38582117
ABSTRACT
Ferroptosis is a newly recognized type of programmed cell death that is implicated in the pathophysiological process of neurological disorders. Our previous studies have revealed that exposure to high concentrations of fluoride for long periods of time induces hippocampal neural injury and cognitive deficits. However, whether ferroptosis is involved in fluoride-induced neuronal death and the underlying mechanism remain unknown. In this study, the results indicated that exposure to high fluoride triggered ferroptosis in SH-SY5Y cells and in the hippocampus of mice. Fluoride exposure accelerated the lysosomal degradation of GPX4 and led to neuronal ferroptosis, while GPX4 overexpression protected SH-SY5Y cells against fluoride-induced neurotoxicity. Intriguingly, the enhanced chaperone-mediated autophagy (CMA) induced by fluoride stimulation was responsible for GPX4 degradation because the inhibition of CMA activity by LAMP2A knockdown effectively prevented fluoride-induced GPX4 loss. Furthermore, mitochondrial ROS (mtROS) accumulation caused by fluoride contributed to CMA activation-mediated GPX4 degradation and subsequent neuronal ferroptosis. Notably, the ferroptosis-specific inhibitor ferrostatin-1 (Fer-1) or the ROS scavenger N-acetyl-L-cysteine (NAC) alleviated fluoride-evoked hippocampal neuronal death and synaptic injury as well as cognitive deficits in mice. The present studies indicates that ferroptosis is a novel mechanism of fluoride-induced neurotoxicity and that chronic fluoride exposure facilitates GPX4 degradation via mtROS chaperone-mediated autophagy, leading to neuronal ferroptosis and cognitive impairment.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Contexto em Saúde:
6_ODS3_enfermedades_notrasmisibles
Base de dados:
MEDLINE
Assunto principal:
Espécies Reativas de Oxigênio
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Disfunção Cognitiva
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Fluoretos
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Autofagia Mediada por Chaperonas
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Ferroptose
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Fosfolipídeo Hidroperóxido Glutationa Peroxidase
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Neurônios
Limite:
Animals
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Humans
Idioma:
En
Revista:
Sci Total Environ
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Sci. total environ
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Science of the total environment
Ano de publicação:
2024
Tipo de documento:
Article