Redox-stress response resistance(RRR)mediated by hyperoxidation of peroxiredoxin 2 in senescent cells  

作　　者：Jiao Meng Yuanyuan Wang Zhenyu Lv Xinhua Qiao Aojun Ye Qiaoli Zhu Chang Chen 

机构地区：[1]National Laboratory of Biomacromolecules,CAS Center for Excellence in Biomacromolecules,Institute of Biophysics,Chinese Academy of Sciences,Beijing 100101,China [2]University of Chinese Academy of Sciences,Beijing 100049,China [3]Beijing Institute for Brain Disorders,Capital Medical University,Beijing 100069,China

出　　处：《Science China(Life Sciences)》2023年第10期2280-2294,共15页中国科学（生命科学英文版）

基　　金：the Strategic Priority Research Program of the Chinese Academy of Sciences(XDB39000000);the National Key Research and Development Program of China(2022YFA1303000,2022YFA1305100,2017YFA0504000);the National Natural Science Foundation of China(91849203)。

摘　　要：Aging is closely related to redox regulation.In our previous work,we proposed a new concept,“redox-stress response capacity(RRC),”and found that the decline in RRC was a dynamic characteristic of aging.However,the mechanism of RRC decline during aging remains unknown.In this study,using the senescent human fibroblast cell model and Caenorhabditis elegans model,we identified that peroxiredoxin 2(PRDX2),as a hydrogen peroxide(H_(2)O_(2))sensor,was involved in mediating RRC.PRDX2 knockdown led to a decline of RRC and accelerated senescence in fibroblasts and prdx-2 mutant C.elegans also showed decreased RRC.The mechanism study showed that the decreased sensor activity of PRDX2 was related to the increase in hyperoxidation of PRDX2 in senescent cells.Moreover,the level of PRDX2 hyperoxidation also increased in old C.elegans.Simultaneous overexpression of both PRDX2 and sulfiredoxin(SRX)rescued the reduced RRC and delayed senescence.The increase in PRDX2 hyperoxidation in senescent cells led to a decrease in its sensor activity,resulting in the decreased cellular response to H_(2)O_(2),which is similar to the mechanism of insulin resistance due to the lower insulin receptor sensitivity.Treatment of young cells with a high level of H_(2)O_(2)to induce a higher level of PRDX2-SO_(3) resulted in mimicking the RRC decline in senescent cells,which is also similar to a model of insulin resistance induced by high levels of insulin.All these results thrillingly indicate that there is an insulin-resistance-like phenomenon in senescent cells,we named it redox-stress response resistance,RRR.RRR in senescent cells is an important new discovery that explains RRC decline during aging and reveals the internal relationship between redox regulation and aging from a new perspective.

关 键 词：peroxiredoxin 2(PRDX2) redox-stress response capacity(RRC) redox-stress response resistance(RRR) H_(2)O_(2)sensor redox relay aging oxidative stress 

分 类 号：R339.38[医药卫生—人体生理学]