Reductive Stress in the Endoplasmic Reticulum Caused by Ero1α <i>S</i>-Nitrosation Accelerates Senescence

Abstract

Oxidative stress in aging has attracted much attention, however, the role of reductive stress in aging remains largely unknown. We report that the endoplasmic reticulum (ER) undergoes reductive stress during replicative senescence as detected by specific glutathione and H2O2 fluorescent probes. We constructed an ER reductive stress cell model by ER-specific catalase overexpression and observed accelerated senescence phenotypes accompanied with proteostasis disruption and compromise of the ER unfolded protein response. S-nitrosation of ER sulfhydryl oxidase Ero1α led to decreased activity in catalyzing oxidative protein folding and lower levels of H2O2 and GSSG/GSH, therefore resulting in reductive stress. Expression of a constitutively active Ero1α restored an oxidizing state in the ER and successfully rescued senescence 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. Funding Information: This work was supported by the National Key R&D Program (2017YFA0504000), the National Natural Science Foundation of China (91849203, 31900893, 32022033), the Strategic Priority Research Program of the Chinese Academy of Sciences (XDB39000000, XDB37020303), and the Youth Innovation Promotion Association, CAS, to L.W. Declaration of Interests: The authors declare no competing interests.