{"doi":"10.1016/j.redox.2025.103680","title":"Redox signaling-mediated S-glutathionylation of protein disulfide isomerase A1 initiates intrinsic apoptosis and contributes to accelerated aging","abstract":"Identifying factors that contribute to the age-related onset of chronic obstructive pulmonary disease (COPD) is crucial for its prevention and treatment. The multifunctional endoplasmic reticulum (ER) chaperone protein disulfide isomerase A1 (PDIA1) shows a protective increase in expression levels in human and mouse non-COPD smokers. However, this increase slows with aging and disease progression, while increase in glutathione S-transferase π1 (GSTP1) does not. PDI has redox sensitive cysteine residues that can become S-glutathionylated (PDI-SSG) which compromise both isomerase and chaperone activity. Oxidized PDIA1 levels progressively rise with age in the lungs of murine non-smokers, with an even greater increase in smokers. To investigate whether an increased oxidized-to-native PDIA1 ratio (PDI-SSG/PDI-SH) contributes to the depletion of alveolar epithelial type 2 progenitor cells in COPD, we used the type-2-like cell line MLE12. High doses of cigarette smoke (CS) induced elevated oxidized PDIA1 levels, while a redox-refractory PDIA1 variant maintained a lower PDI-SSG/PDI-SH. Upon CS exposure, PDIA1 was S-glutathionylated by GSTP1 and predominantly localized at the ER-mitochondria interface. This mitochondrial proximity was prevented by pharmacological or genetic GSTP1 inhibition. When localized at the ER-mitochondria interface, S-glutathionylated PDIA1 decreased mitochondrial membrane potential (MMP), facilitated mitochondrial permeability transition pore opening, decreased mitochondrial respiration and triggered cytochrome c (Cyt c) release, followed by caspase-3 activation. Isolated mitochondrial studies confirmed that PDI-SSG trigger these apoptotic signals whereas native PDI does not. Our findings indicate that GSTP1-mediated S-glutathionylation of PDIA1 drives pro-apoptotic intraorganellar signaling by altering its ER distribution. Overexpression of a redox-refractory PDIA1 variant restored MMP and reduced Cyt c release, suggesting that a lower S-glutathionylated-to-native PDIA1 ratio is protective. These findings highlight a threshold-dependent regulation of PDIA1-SSG/PDIA1-SH redox signaling. We propose that the simultaneous inability to maintain high PDIA1 levels and the age-associated increase in its S-glutathionylated form in smokers accelerates AEC2 depletion and exhaustion, thereby contributing to emphysema progression.","journal":"Redox Biology","year":2025,"id":539511,"datarank":0.20794415416798362,"base_score":1.3862943611198906,"endowment":1.3862943611198906,"self_citation_contribution":0.20794415416798362,"citation_network_contribution":0.0,"self_endowment_contribution":0.20794415416798362,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":3,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9622,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":426397,"name":"Jie Zhang","orcid":"0000-0002-0466-2955","position":1,"is_corresponding":false},{"id":1426580,"name":"Amit Kumar","orcid":"0000-0003-3767-4343","position":2,"is_corresponding":false},{"id":1096530,"name":"Xuejian Huang","orcid":null,"position":3,"is_corresponding":false},{"id":918347,"name":"Theodore Lemuel Mathuram","orcid":"0000-0002-3590-4793","position":4,"is_corresponding":false},{"id":1072918,"name":"Andrew D. McCall","orcid":"0000-0002-3732-5293","position":5,"is_corresponding":false},{"id":466326,"name":"John Culpepper","orcid":null,"position":6,"is_corresponding":false},{"id":454555,"name":"Leilei Zhang","orcid":"0000-0002-9278-0459","position":7,"is_corresponding":false},{"id":1427073,"name":"Anthony D Curione","orcid":null,"position":8,"is_corresponding":false},{"id":1426581,"name":"J.Q. Xu","orcid":"0000-0003-4834-3005","position":9,"is_corresponding":false},{"id":104376,"name":"Kenneth D. Tew","orcid":"0000-0002-2117-7521","position":10,"is_corresponding":false},{"id":426398,"name":"Danyelle M. 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