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

Abstract

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.

Osteoclasts and osteoarthritis: Novel intervention targets and therapeutic potentials during aging

“…Therefore, an intimate interplay potentially exists among UPR, ER stress, oxidative stress and inflammation during aging, with PDI playing a central role in this network. Age‐related alterations in PDI have been linked to OA, oral dryness, and the senescence of epithelial, endothelial, and mesenchymal stem cells (Bhattarai et al., 2018 ; Cheng et al., 2023 ; Kim, Youn, et al., 2018 ; O'Sullivan et al., 2022 ; Tan et al., 2020 ), whereas the role of PDI in osteoclast lineage has been partially revealed. Through the suppression of ROS and the NF‐κB signaling, PDI inhibition or knockout has been shown to mitigate the inflammatory phenotype of osteoclast precursors (Xiao et al., 2018 ).…”

Molecular hallmarks of ageing in amyotrophic lateral sclerosis

“…Feeding young fruit flies with AGEs and lipofuscin inhibits the UPS, which accelerates ageing and reduces lifespan [ 112 ]. Similarly, another chaperone, the oxidoreductase protein disulphide isomerase (PDI) is protective against cellular ageing in several models including replicative senescent human mesenchymal stem cells (RS hMSCs), HGPS hMSCs, Werner syndrome (WS) hMSCs and human primary hMSCs [ 113 ]. In addition, stabilising dysfunctional proteostasis using the chemical chaperone 4‐phenyl butyrate (PBA) improves cognitive behaviour and inhibits ageing [ 114 ].…”

Thioredoxin Domain Containing 5 (TXNDC5): Friend or Foe?

“…However, it is important to note the role of thioredoxins in bacteria [26] and how their morphological changes could trigger redox alterations inside the cell that could eventually lead to disease [27]. TXNDC5 contains three Trx-like domains (a 0 , a and a ′ ) that all have redox active sites including the CGHC [2,28,29], CxxC and CxxU motifs [30][31][32]. The protein folding process can be accelerated by the three Trx-like domains of TXNDC5, which are connected by approximately 20 amino acid residues that can act independently [2].…”

“…Additionally, the three Trx-like domains appear to function independently in intact TXNDC5, as no cooperative actions were observed [3]. The redox-active sites of TXNDC5 are located separately on the molecular surface and introduce disulfide bonds to unfolded substrates more rapidly and promiscuously than other PDIs [3,28,29,33]. The three catalytic domains of TXNDC5 can bind peptides containing aromatic or alkaline residues.…”

“…Cont. Apoptotic pathways 1,4,7,26 Proteasome-mediated degradation 2,10 Protein kinase binding 3,27 Protein disulfide isomerase activity 5 Unfolded protein response 6,13,28 Cellular responses to stimuli 6,11,13,29 Regulation of actin dynamics for phagocytic cup formation 8 Plasma lipoprotein assembly, remodeling, and clearance 9 PERK regulates gene expression 11,29 Translational control 12 Signaling receptor activity 14 Metabolism of proteins 15,16,23,24 Regulation of degradation 17 MIF-mediated glucocorticoid regulation 18,26 Prolactin signaling 19 Homology directed repair 20 DNA double strand break response 20 Gene expression 21,28 Endocytosis 22 Galactose metabolism 25 Vesicle trafficking 30 Processing of capped intron-containing pre-mRNA 31 [137,[139][140][141][142][143][144][145][146][147][148][149][150][151] Esophageal squamous cell KCNH2 Potassium channels [155] Endothelial cell YAP1 Gene expression [158] Pancreas NR4A1 1 , CTNNB1 2 Gene expression 1,2 Phosphorylation 2…”