{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T23:54:15Z","timestamp":1791417255880,"version":"4.3.3"},"reference-count":121,"publisher":"Wiley","license":[{"start":{"date-parts":[[2025,1,27]],"date-time":"2025-01-27T00:00:00Z","timestamp":1737936000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["physoc.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["The Journal of Physiology"],"abstract":"<jats:sec><jats:title>Abstract<\/jats:title><jats:p>The mechanisms that drive placental dysfunction in pregnancies complicated by hypoxia and fetal growth restriction remain poorly understood. Changes to mitochondrial respiration contribute to cellular dysfunction in conditions of hypoxia and have been implicated in the pathoaetiology of pregnancy complications, such as pre\u2010eclampsia. We used bespoke isobaric hypoxic chambers and a combination of functional, molecular and imaging techniques to study cellular metabolism and mitochondrial dynamics in sheep undergoing hypoxic pregnancy. We show that hypoxic pregnancy in sheep triggers a shift in capacity away from \u03b2\u2010oxidation and complex I\u2010mediated respiration, while maintaining total oxidative phosphorylation capacity. There are also complex\u2010specific changes to electron transport chain composition and a switch in mitochondrial dynamics towards fission. Hypoxic placentas show increased activation of the non\u2010canonical mitochondrial unfolded protein response pathway and enhanced insulin like growth factor 2 signalling. Combined, therefore, the data show that the hypoxic placenta undergoes significant metabolic and morphological adaptations to maintain cellular energy balance. Chronic hypoxia during pregnancy in sheep activated placental mitochondrial stress pathways, leading to alterations in mitochondrial respiration, mitochondrial energy metabolism and mitochondrial dynamics, as seen in the placenta of women with pre\u2010eclampsia.\n<jats:boxed-text content-type=\"graphic\" position=\"anchor\"><jats:graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" mimetype=\"image\/png\" position=\"anchor\" specific-use=\"enlarged-web-image\" xlink:href=\"graphic\/tjp16522-gra-0001-m.png\"><jats:alt-text>image<\/jats:alt-text><\/jats:graphic><\/jats:boxed-text><\/jats:p><\/jats:sec><jats:sec><jats:title>Key points<\/jats:title><jats:p><jats:list list-type=\"bullet\">\n<jats:list-item><jats:p>Hypoxia shifts mitochondrial respiration away from \u03b2\u2010oxidation and complex I.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>Complex\u2010specific changes occur in the electron transport chain composition.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>Activation of the non\u2010canonical mitochondrial unfolded protein response pathway is heightened in hypoxic placentas.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>Enhanced insulin like growth factor 2 signalling is observed in hypoxic placentas.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>Hypoxic placentas undergo significant functional adaptations for energy balance.<\/jats:p><\/jats:list-item>\n<\/jats:list><\/jats:p><\/jats:sec>","DOI":"10.1113\/jp287897","type":"journal-article","created":{"date-parts":[[2025,1,27]],"date-time":"2025-01-27T14:43:46Z","timestamp":1737989026000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["Placental mitochondrial metabolic adaptation maintains cellular energy balance in pregnancy complicated by gestational hypoxia"],"prefix":"10.1113","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1647-4166","authenticated-orcid":false,"given":"Wen","family":"Tong","sequence":"first","affiliation":[{"name":"Department of Physiology, Development and Neuroscience University of Cambridge Cambridge UK"},{"name":"Centre for Trophoblast Research University of Cambridge Cambridge UK"},{"name":"Strategic Research Initiative in Reproduction University of Cambridge Cambridge UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1060-513X","authenticated-orcid":false,"given":"Beth J.","family":"Allison","sequence":"additional","affiliation":[{"name":"Department of Physiology, Development and Neuroscience University of Cambridge Cambridge UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kirsty L.","family":"Brain","sequence":"additional","affiliation":[{"name":"Department of Physiology, Development and Neuroscience University of Cambridge Cambridge UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8008-5144","authenticated-orcid":false,"given":"Olga V.","family":"Patey","sequence":"additional","affiliation":[{"name":"Department of Physiology, Development and Neuroscience University of Cambridge Cambridge UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8843-9952","authenticated-orcid":false,"given":"Youguo","family":"Niu","sequence":"additional","affiliation":[{"name":"Department of Physiology, Development and Neuroscience University of Cambridge Cambridge UK"},{"name":"Centre for Trophoblast Research University of Cambridge Cambridge UK"},{"name":"Strategic Research Initiative in Reproduction University of Cambridge Cambridge UK"},{"name":"Cardiovascular Strategic Research Initiative University of Cambridge Cambridge UK"},{"name":"Department of Aerospace Physiology Fourth Military Medical University Xi'an China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kimberley J.","family":"Botting","sequence":"additional","affiliation":[{"name":"Department of Physiology, Development and Neuroscience University of Cambridge Cambridge UK"},{"name":"Centre for Trophoblast Research University of Cambridge Cambridge UK"},{"name":"Strategic Research Initiative in Reproduction University of Cambridge Cambridge UK"},{"name":"Cardiovascular Strategic Research Initiative University of Cambridge Cambridge UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5542-0545","authenticated-orcid":false,"given":"Sage G.","family":"Ford","sequence":"additional","affiliation":[{"name":"Department of Physiology, Development and Neuroscience University of Cambridge Cambridge UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tess A.","family":"Garrud","sequence":"additional","affiliation":[{"name":"Department of Physiology, Development 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B.","family":"Wooding","sequence":"additional","affiliation":[{"name":"Department of Physiology, Development and Neuroscience University of Cambridge Cambridge UK"},{"name":"Centre for Trophoblast Research University of Cambridge Cambridge UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qiang","family":"Lyu","sequence":"additional","affiliation":[{"name":"Department of Aerospace Physiology Fourth Military Medical University Xi'an China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lin","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Aerospace Physiology Fourth Military Medical University Xi'an China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6802-455X","authenticated-orcid":false,"given":"Jin","family":"Ma","sequence":"additional","affiliation":[{"name":"Department of Aerospace Physiology Fourth Military Medical University Xi'an China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3718-7783","authenticated-orcid":false,"given":"Alice P.","family":"Sowton","sequence":"additional","affiliation":[{"name":"Department of Physiology, Development and Neuroscience University of Cambridge Cambridge UK"},{"name":"Centre for Trophoblast Research University of Cambridge Cambridge UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katie A.","family":"O'Brien","sequence":"additional","affiliation":[{"name":"Department of Physiology, Development and Neuroscience University of Cambridge Cambridge UK"},{"name":"Centre for Trophoblast Research University of Cambridge Cambridge UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tereza","family":"Cindrova\u2010Davies","sequence":"additional","affiliation":[{"name":"Department of Physiology, Development and Neuroscience University of Cambridge Cambridge UK"},{"name":"Centre for Trophoblast Research University of Cambridge Cambridge UK"},{"name":"Strategic Research Initiative in Reproduction University of Cambridge Cambridge UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0869-7426","authenticated-orcid":false,"given":"Hong Wa","family":"Yung","sequence":"additional","affiliation":[{"name":"Department of Physiology, Development and Neuroscience University of Cambridge Cambridge UK"},{"name":"Centre for Trophoblast Research University of Cambridge Cambridge UK"},{"name":"Strategic Research Initiative in Reproduction University of Cambridge Cambridge UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8677-4143","authenticated-orcid":false,"given":"Graham J.","family":"Burton","sequence":"additional","affiliation":[{"name":"Department of Physiology, Development and Neuroscience University of Cambridge Cambridge UK"},{"name":"Centre for Trophoblast Research University of Cambridge Cambridge UK"},{"name":"Strategic Research Initiative in Reproduction University of Cambridge Cambridge UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew J.","family":"Murray","sequence":"additional","affiliation":[{"name":"Department of Physiology, Development and Neuroscience University of Cambridge Cambridge UK"},{"name":"Centre for Trophoblast Research University of Cambridge Cambridge UK"},{"name":"Cardiovascular Strategic Research Initiative University of Cambridge Cambridge UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1308-1204","authenticated-orcid":false,"given":"Dino A.","family":"Giussani","sequence":"additional","affiliation":[{"name":"Department of Physiology, Development and Neuroscience University of Cambridge Cambridge UK"},{"name":"Centre for Trophoblast Research University of Cambridge Cambridge UK"},{"name":"Strategic Research Initiative in Reproduction University of Cambridge Cambridge UK"},{"name":"Cardiovascular Strategic Research Initiative University of Cambridge Cambridge UK"},{"name":"Department of Aerospace Physiology Fourth Military Medical University Xi'an China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,1,27]]},"reference":[{"key":"e_1_2_5_2_1","doi-asserted-by":"crossref","first-page":"52","DOI":"10.1016\/j.placenta.2017.01.114","article-title":"Review: Alterations in placental glycogen deposition in complicated pregnancies: Current preclinical and clinical evidence","volume":"54","author":"Akison L. 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