Reducing oxidative protein folding alleviates senescence by minimizing ER-to-nucleus H2O2 release

Oxidative protein folding occurs in the endoplasmic reticulum (ER) to generate disulfide bonds, and the by-product is hydrogen peroxide (H2O2). 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 H2O2 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.

Automated summary

This study found that the accumulation of disulfide bonds, which are generated during oxidative protein folding, in aged human mesenchymal stem cells (hMSCs) can be alleviated by deleting protein disulfide isomerase (PDI), a key enzyme involved in oxidative protein folding. The deletion of PDI slows down the rate of oxidative protein folding and reduces the leakage of hydrogen peroxide (H2O2) from the endoplasmic reticulum (ER) into the nucleus, consequently decreasing the expression of SERPINE1, a key driver of cell senescence. Additionally, depletion of PDI also alleviates senescence in various cell models of aging. These findings reveal the previously unknown role of oxidative protein folding in promoting cell aging and provide a potential target for intervention in aging and aging-related diseases.