Reducing oxidative protein folding alleviates senescence by minimizing ER‐to‐nucleus H 2 O 2 release

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. image Protein disulfide isomerase (PDI), a key oxidoreductase that catalyzes oxidative protein folding, accumulates in aged human mesenchymal stem cells. Depletion of PDI slows the rate of oxidative protein folding, decreases the leakage of ER‐derived H 2 O 2 into the nucleus, and alleviates cell senescence. PDI accumulates in aged human mesenchymal stem cells and depletion of PDI alleviates cell senescence. PDI deficiency slows the rate of oxidative protein folding and reduces the level of its byproduct H 2 O 2 in both the ER and nucleus. Increased H 2 O 2 levels induce the expression of SERPINE1, a component of the senescence‐associated secretory phenotype (SASP), which accelerates cell senescence.