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Here, newborn mice are used to understand how hyperoxia stimulates an early aberrant wave of AT2 cell proliferation that occurs between Postnatal Days (PNDs) 0 and 4. RNA-sequencing analysis of AT2 cells isolated from PND4 mice revealed hyperoxia stimulates expression of mitochondrial-specific methylenetetrahydrofolate dehydrogenase 2 and other genes involved in mitochondrial one-carbon coupled folate metabolism and serine synthesis. The same genes are induced when AT2 cells normally proliferate on PND7 and when they proliferate in response to the mitogen fibroblast growth factor 7. However, hyperoxia selectively stimulated their expression via the stress-responsive activating transcription factor 4 (ATF4). Administration of the mitochondrial superoxide scavenger mitoTEMPO during hyperoxia suppressed ATF4 and thus early AT2 cell proliferation, but it had no effect on normative AT2 cell proliferation seen on PND7. Because ATF4 and methylenetetrahydrofolate dehydrogenase are detected in hyperplastic AT2 cells of preterm infant humans and baboons with bronchopulmonary dysplasia, dampening mitochondrial oxidative stress and ATF4 activation may provide new opportunities for controlling excess AT2 cell proliferation in neonatal lung disease.<\/jats:p>","DOI":"10.1165\/rcmb.2021-0363oc","type":"journal-article","created":{"date-parts":[[2022,1,19]],"date-time":"2022-01-19T18:33:55Z","timestamp":1642617235000},"page":"402-414","update-policy":"https:\/\/doi.org\/10.1164\/crossmarkpolicies","source":"Crossref","is-referenced-by-count":8,"title":["Neonatal Hyperoxia Activates Activating Transcription Factor 4 to Stimulate Folate Metabolism and Alveolar Epithelial Type 2 Cell Proliferation"],"prefix":"10.1093","volume":"66","author":[{"given":"Min","family":"Yee","sequence":"first","affiliation":[{"name":"Department of Pediatrics"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew N.","family":"McDavid","sequence":"additional","affiliation":[{"name":"Department of Biostatistics and Computational Biology, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ethan David","family":"Cohen","sequence":"additional","affiliation":[{"name":"Department of Pediatrics"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Heidie L.","family":"Huyck","sequence":"additional","affiliation":[{"name":"Department of Pediatrics"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cory","family":"Poole","sequence":"additional","affiliation":[{"name":"Department of Pediatrics"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brian J.","family":"Altman","sequence":"additional","affiliation":[{"name":"Department of Biomedical Genetics, School of Medicine and Dentistry, University of Rochester, Rochester, New York; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"William M.","family":"Maniscalco","sequence":"additional","affiliation":[{"name":"Department of Pediatrics"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gail H.","family":"Deutsch","sequence":"additional","affiliation":[{"name":"Department of Pathology, Seattle Children\u2019s Hospital, University of Washington, Seattle, Washington"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9185-3994","authenticated-orcid":false,"given":"Gloria S.","family":"Pryhuber","sequence":"additional","affiliation":[{"name":"Department of Pediatrics"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5094-696X","authenticated-orcid":false,"given":"Michael A.","family":"O\u2019Reilly","sequence":"additional","affiliation":[{"name":"Department of Pediatrics"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2022,4,1]]},"reference":[{"key":"2026012204015088600_bib1","doi-asserted-by":"crossref","first-page":"S2","DOI":"10.1186\/1742-4755-10-S1-S2","article-title":"Born too soon: the global epidemiology of 15 million preterm births","volume":"10","author":"Blencowe","year":"2013","journal-title":"Reprod Health"},{"key":"2026012204015088600_bib2","doi-asserted-by":"crossref","first-page":"623","DOI":"10.1146\/annurev.physiol.67.040403.102229","article-title":"Lung vascular development: implications for the pathogenesis of bronchopulmonary dysplasia","volume":"67","author":"Stenmark","year":"2005","journal-title":"Annu Rev Physiol"},{"key":"2026012204015088600_bib3","doi-asserted-by":"crossref","first-page":"335","DOI":"10.1016\/0014-4800(82)90046-6","article-title":"A baboon model of bronchopulmonary dysplasia. 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