Reducing oxidative protein folding alleviates senescence by minimizing ER‐to‐nucleus H2O2 release
Cheng Fang, Qianzhao Ji, Lu Wang, Lu Wang, Chih‐Chen Wang, Guang‐Hui Liu, Lei Wang, Lei Wang
Abstract
Abstract Oxidative protein folding occurs in the endoplasmic reticulum (ER) to generate disulfide bonds, and the by‐product is hydrogen peroxide (H 2 O 2 ). However, the relationship between oxidative protein folding and senescence remains uncharacterized. Here, we find that the protein disulfide isomerase (PDI), a key oxidoreductase that catalyzes oxidative protein folding, accumulated in aged human mesenchymal stem cells (hMSCs) and deletion of PDI alleviated hMSCs senescence. Mechanistically, knocking out PDI slows the rate of oxidative protein folding and decreases the leakage of ER‐derived H 2 O 2 into the nucleus, thereby decreasing the expression of SERPINE1, which was identified as a key driver of cell senescence. Furthermore, we show that depletion of PDI alleviated senescence in various cell models of aging. Our findings reveal a previously unrecognized role of oxidative protein folding in promoting cell aging, providing a potential target for aging and aging‐related disease intervention.