ER reductive stress caused by Ero1α S-nitrosation accelerates senescence.
Free Radic Biol Med
; 180: 165-178, 2022 02 20.
Article
em En
| MEDLINE
| ID: mdl-35033630
ABSTRACT
Oxidative stress in aging has attracted much attention; however, the role of reductive stress in aging remains largely unknown. Here, we report that the endoplasmic reticulum (ER) undergoes reductive stress during replicative senescence, as shown by specific glutathione and H2O2 fluorescent probes. We constructed an ER-specific reductive stress cell model by ER-specific catalase overexpression and observed accelerated senescent phenotypes accompanied by disrupted proteostasis and a compromised ER unfolded protein response (UPR). Mechanistically, S-nitrosation of the pivotal ER sulfhydryl oxidase Ero1α led to decreased activity, therefore resulting in reductive stress in the ER. Inhibition of inducible nitric oxide synthase decreased the level of Ero1α S-nitrosation and decreased cellular senescence. Moreover, the expression of constitutively active Ero1α restored an oxidizing state in the ER and successfully rescued the senescent phenotypes. Our results uncover a new mechanism of senescence promoted by ER reductive stress and provide proof-of-concept that maintaining the oxidizing power of the ER and organelle-specific precision redox regulation could be valuable future geroprotective strategies.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Estresse do Retículo Endoplasmático
/
Peróxido de Hidrogênio
Idioma:
En
Revista:
Free Radic Biol Med
Assunto da revista:
BIOQUIMICA
/
MEDICINA
Ano de publicação:
2022
Tipo de documento:
Article
País de afiliação:
China