{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T06:04:16Z","timestamp":1790661856116,"version":"4.1.0"},"reference-count":34,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T00:00:00Z","timestamp":1790640000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["8,2471744"],"award-info":[{"award-number":["8,2471744"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Cell Dev. Biol."],"abstract":"<jats:sec>\n                    <jats:title>Introduction<\/jats:title>\n                    <jats:p>Bronchopulmonary dysplasia (BPD) is a common chronic respiratory disease in preterm infants, characterized by impaired lung development. Mitochondrial dysfunction of alveolar type II epithelial (AT2) cells plays a critical role in the pathogenesis of BPD. Betaine is an endogenous methyl donor with anti-inflammatory and antioxidant properties. Our previous study demonstrated that plasma betaine levels were significantly decreased in preterm infants with BPD. The aim of this study was to investigate the effect of betaine on mitochondrial dysfunction of AT2 cells in BPD.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Hyperoxia-induced BPD mouse models and hyperoxia-exposed MLE-12 cells were used. Proteomic analysis was performed on lung tissues from BPD and control mice. Mitochondrial structure and function were assessed by transmission electron microscopy, immunofluorescence, Western blotting, flow cytometry, and related assays. The OPA1 inhibitor MYLS22 was used to evaluate the role of OPA1 in the protective effect of betaine.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Hyperoxia exposure induced mitochondrial structural damage in AT2 cells and impaired lung development in BPD mice. Proteomic analysis revealed that differentially expressed proteins were significantly enriched in mitochondrial dysfunction pathways in the lungs of BPD mice. Family with sequence similarity 162 member A (FAM162A), a mitochondria-associated protein involved in mitochondrial homeostasis, was prominently downregulated. Betaine significantly increased the expression of FAM162A and optic atrophy 1 (OPA1), suppressed the activating transcription factor 4 (ATF4) and C\/EBP homologous protein (CHOP) mediated integrated stress response, and alleviated cell apoptosis in AT2 cells in BPD mice. In vitro, betaine increased the expression of FAM162A and OPA1, improved mitochondrial dysfunction and decreased cell apoptosis, and the effect was abolished by the OPA1 inhibitor MYLS22 in MLE-12 cells exposed to hyperoxia.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Discussion<\/jats:title>\n                    <jats:p>Our findings revealed that betaine ameliorated OPA1-mediated mitochondrial fusion in AT2 cells and alleviated hyperoxic lung injury in newborn mice, providing new insight for the prevention and treatment of BPD.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fcell.2026.1937629","type":"journal-article","created":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T05:50:15Z","timestamp":1790661015000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Betaine restores OPA1-mediated mitochondrial fusion in alveolar epithelial type 2 cells and ameliorates hyperoxic lung injury in newborn mice"],"prefix":"10.3389","volume":"14","author":[{"given":"Jufeng","family":"Zhang","sequence":"first","affiliation":[{"name":"Department of Neonatology, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine","place":["Shanghai, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hongyu","family":"Xie","sequence":"additional","affiliation":[{"name":"Department of Neonatology, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine","place":["Shanghai, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hui","family":"Xu","sequence":"additional","affiliation":[{"name":"Department of Neonatology, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine","place":["Shanghai, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Meiling","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Neonatology, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine","place":["Shanghai, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"You","family":"You","sequence":"additional","affiliation":[{"name":"Department of Neonatology, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine","place":["Shanghai, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jingwen","family":"Lv","sequence":"additional","affiliation":[{"name":"Department of Neonatology, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine","place":["Shanghai, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Li","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Neonatology, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine","place":["Shanghai, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hongping","family":"Xia","sequence":"additional","affiliation":[{"name":"Department of Neonatology, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine","place":["Shanghai, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,9,29]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"502","DOI":"10.1001\/jamapediatrics.2021.6619","article-title":"Interventions to prevent bronchopulmonary dysplasia in preterm neonates: an umbrella review of systematic reviews and meta-analyses","volume":"176","author":"Abiramalatha","year":"2022","journal-title":"JAMA Pediatr."},{"key":"B2","doi-asserted-by":"publisher","first-page":"197","DOI":"10.1152\/physrev.00042.2024","article-title":"The evolving pathophysiology of bronchopulmonary dysplasia","volume":"106","author":"Ambalavanan","year":"2026","journal-title":"Physiol. Rev."},{"key":"B3","doi-asserted-by":"publisher","first-page":"248","DOI":"10.1001\/jama.2021.23580","article-title":"Mortality, In-Hospital morbidity, care practices, and 2-Year outcomes for extremely preterm infants in the US, 2013-2018","volume":"327","author":"Bell","year":"2022","journal-title":"JAMA"},{"key":"B4","doi-asserted-by":"publisher","first-page":"333","DOI":"10.1038\/s41392-023-01547-9","article-title":"Mitochondrial dynamics in health and disease: mechanisms and potential targets","volume":"333","author":"Chen","year":"2023","journal-title":"Signal Transduct. Target Ther."},{"key":"B5","doi-asserted-by":"publisher","first-page":"2104","DOI":"10.1002\/jcsm.13558","article-title":"Betaine delays age-related muscle loss by mitigating Mss51-induced impairment in mitochondrial respiration via yin Yang1","volume":"15","author":"Chen","year":"2024","journal-title":"J. Cachexia Sarcopenia Muscle"},{"key":"B6","doi-asserted-by":"publisher","first-page":"117301","DOI":"10.1016\/j.taap.2025.117301","article-title":"Proline betaine facilitates angiogenesis in bronchopulmonary dysplasia","volume":"498","author":"Cili","year":"2025","journal-title":"Toxicol. Appl. Pharmacol."},{"key":"B7","doi-asserted-by":"publisher","first-page":"eaat5314","DOI":"10.1126\/science.aat5314","article-title":"The integrated stress response: from mechanism to disease","volume":"368","author":"Costa-Mattioli","year":"2020","journal-title":"Science"},{"key":"B8","doi-asserted-by":"publisher","first-page":"619853","DOI":"10.3389\/fped.2020.619853","article-title":"Mitochondrial fission-mediated lung development in newborn rats with hyperoxia-induced bronchopulmonary dysplasia with pulmonary hypertension","volume":"8","author":"Dai","year":"2020","journal-title":"Front. Pediatr."},{"key":"B9","doi-asserted-by":"publisher","first-page":"706","DOI":"10.1038\/s41580-025-00854-z","article-title":"Molecular machineries shaping the mitochondrial inner membrane","volume":"26","author":"Daumke","year":"2025","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"B10","doi-asserted-by":"publisher","first-page":"755","DOI":"10.1038\/s41556-018-0133-0","article-title":"Mitochondrial dynamics in adaptive and maladaptive cellular stress responses","volume":"20","author":"Eisner","year":"2018","journal-title":"Nat. Cell Biol."},{"key":"B11","doi-asserted-by":"publisher","first-page":"58","DOI":"10.1038\/s41390-020-01224-5","article-title":"Short exposure to hyperoxia causes cultured lung epithelial cell mitochondrial dysregulation and alveolar simplification in mice","volume":"90","author":"Garcia","year":"2021","journal-title":"Pediatr. Res."},{"key":"B12","doi-asserted-by":"publisher","first-page":"5403","DOI":"10.1016\/j.cell.2025.06.001","article-title":"Systematic profiling reveals betaine as an exercise mimetic for geroprotection","volume":"188","author":"Geng","year":"2025","journal-title":"Cell"},{"key":"B13","doi-asserted-by":"publisher","first-page":"204","DOI":"10.1038\/s41580-020-0210-7","article-title":"The cell biology of mitochondrial membrane dynamics","volume":"21","author":"Giacomello","year":"2020","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"B14","doi-asserted-by":"publisher","first-page":"890","DOI":"10.1038\/s41586-023-06423-8","article-title":"Mitochondrial integrated stress response controls lung epithelial cell fate","volume":"620","author":"Han","year":"2023","journal-title":"Nature"},{"key":"B15","doi-asserted-by":"publisher","first-page":"625","DOI":"10.1007\/s10571-013-9921-z","article-title":"Betaine protects against rotenone-induced neurotoxicity in PC12 cells","volume":"33","author":"Im","year":"2013","journal-title":"Cell Mol. Neurobiol."},{"key":"B16","doi-asserted-by":"publisher","first-page":"289","DOI":"10.1080\/19768354.2018.1512523","article-title":"Betaine enhances the cellular survival via mitochondrial fusion and fission factors, MFN2 and DRP1","volume":"22","author":"Jung Kim","year":"2018","journal-title":"Anim. Cells Syst."},{"key":"B17","doi-asserted-by":"publisher","first-page":"1436","DOI":"10.1016\/j.biopha.2018.04.154","article-title":"Betaine protects mice against acetaminophen hepatotoxicity possibly via mitochondrial complex II and glutathione availability","volume":"103","author":"Khodayar","year":"2018","journal-title":"Biomed. Pharmacother."},{"key":"B18","doi-asserted-by":"publisher","first-page":"3270","DOI":"10.1016\/j.febslet.2006.05.001","article-title":"Interaction of pro-apoptotic protein HGTD-P with heat shock protein 90 is required for induction of mitochondrial apoptotic cascades","volume":"13","author":"Kim","year":"2006","journal-title":"FEBS Lett."},{"key":"B19","doi-asserted-by":"publisher","first-page":"621","DOI":"10.1016\/j.bbrc.2014.12.005","article-title":"Betaine is a positive regulator of mitochondrial respiration","volume":"456","author":"Lee","year":"2015","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"B20","doi-asserted-by":"publisher","first-page":"3918","DOI":"10.1128\/MCB.24.9.3918-3927.2004","article-title":"Identification of the hypoxia-inducible factor 1 alpha-responsive HGTD-P gene as a mediator in the mitochondrial apoptotic pathway","volume":"24","author":"Lee","year":"2004","journal-title":"Mol. Cell Biol."},{"key":"B21","doi-asserted-by":"publisher","first-page":"32","DOI":"10.1186\/s40779-024-00536-5","article-title":"Mitochondrial quality control in human health and disease","volume":"32","author":"Liu","year":"2024","journal-title":"Mil. Med. Res."},{"key":"B22","doi-asserted-by":"publisher","first-page":"1095","DOI":"10.1038\/s41401-023-01225-0","article-title":"Mammalian integrated stress responses in stressed organelles and their functions","volume":"45","author":"Lu","year":"2024","journal-title":"Acta Pharmacol. Sin."},{"key":"B23","doi-asserted-by":"publisher","first-page":"e70173","DOI":"10.1002\/fsn3.70173","article-title":"Recent advances in betaine: extraction, identification, and bioactive functions in human health","volume":"13","author":"Luo","year":"2025","journal-title":"Food Sci. Nutr."},{"key":"B24","doi-asserted-by":"publisher","first-page":"e70508","DOI":"10.1111\/acel.70508","article-title":"FAM162A is a key regulator of mitochondrial structure, dynamics, and bioenergetics, driving cellular protection and longevity","volume":"5","author":"Matamoros","year":"2026","journal-title":"Aging Cell"},{"key":"B25","doi-asserted-by":"publisher","first-page":"1167","DOI":"10.1007\/s00394-021-02738-2","article-title":"Betaine in ameliorating alcohol-induced hepatic steatosis","volume":"61","author":"Rehman","year":"2022","journal-title":"Eur. J. Nutr."},{"key":"B26","doi-asserted-by":"publisher","first-page":"100663","DOI":"10.1016\/j.crfs.2023.100663","article-title":"Role of autophagy in betaine-promoted hepatoprotection against non-alcoholic fatty liver disease in mice","volume":"8","author":"Seo","year":"2024","journal-title":"Curr. Res. Food Sci."},{"key":"B27","doi-asserted-by":"publisher","first-page":"443","DOI":"10.1186\/s12931-024-03083-8","article-title":"Activated DRP1 promotes mitochondrial fission and induces glycolysis in ATII cells under hyperoxia","volume":"25","author":"Sun","year":"2024","journal-title":"Respir. Res."},{"key":"B28","doi-asserted-by":"publisher","first-page":"78","DOI":"10.1038\/s41572-019-0127-7","article-title":"Bronchopulmonary dysplasia","volume":"78","author":"Thebaud","year":"2019","journal-title":"Nat. Rev. Dis. Prim."},{"key":"B29","doi-asserted-by":"publisher","first-page":"39","DOI":"10.1016\/j.ejphar.2019.01.043","article-title":"Betaine modulates oxidative stress, inflammation, apoptosis, autophagy, and Akt\/mTOR signaling in methionine-choline deficiency-induced fatty liver disease","volume":"848","author":"Veskovic","year":"2019","journal-title":"Eur. J. Pharmacol."},{"key":"B30","doi-asserted-by":"publisher","first-page":"e23612","DOI":"10.1096\/fj.202400088R","article-title":"Repair and regeneration of the alveolar epithelium in lung injury","volume":"38","author":"Wang","year":"2024","journal-title":"FASEB J."},{"key":"B31","doi-asserted-by":"publisher","first-page":"105950","DOI":"10.1016\/j.earlhumdev.2024.105950","article-title":"Early metabolic markers as predictors of respiratory complications in preterm infants with bronchopulmonary dysplasia","volume":"190","author":"You","year":"2024","journal-title":"Early Hum. Dev."},{"key":"B32","doi-asserted-by":"publisher","first-page":"216","DOI":"10.1039\/c8fo02004c","article-title":"Betaine increases mitochondrial content and improves hepatic lipid metabolism","volume":"10","author":"Zhang","year":"2019","journal-title":"Food Funct."},{"key":"B33","doi-asserted-by":"publisher","first-page":"1613","DOI":"10.1038\/s41390-025-04364-8","article-title":"Betaine improves hyperoxic lung injury through downregulating pulmonary macrophage pyroptosis in newborn mice","volume":"99","author":"Zhang","year":"2026","journal-title":"Pediatr. Res."},{"key":"B34","doi-asserted-by":"publisher","first-page":"1070","DOI":"10.3389\/fimmu.2018.01070","article-title":"Betaine in inflammation: mechanistic aspects and applications","volume":"9","author":"Zhao","year":"2018","journal-title":"Front. Immunol."}],"container-title":["Frontiers in Cell and Developmental Biology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fcell.2026.1937629\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T05:50:16Z","timestamp":1790661016000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fcell.2026.1937629\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,29]]},"references-count":34,"alternative-id":["10.3389\/fcell.2026.1937629"],"URL":"https:\/\/doi.org\/10.3389\/fcell.2026.1937629","relation":{},"ISSN":["2296-634X"],"issn-type":[{"value":"2296-634X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,9,29]]},"article-number":"1937629"}}