{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,28]],"date-time":"2026-07-28T08:01:58Z","timestamp":1785225718409,"version":"3.55.0"},"reference-count":94,"publisher":"Wiley","issue":"5","license":[{"start":{"date-parts":[[2026,2,16]],"date-time":"2026-02-16T00:00:00Z","timestamp":1771200000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,2,16]],"date-time":"2026-02-16T00:00:00Z","timestamp":1771200000000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100000925","name":"National Health and Medical Research Council","doi-asserted-by":"publisher","award":["GNT2026065"],"award-info":[{"award-number":["GNT2026065"]}],"id":[{"id":"10.13039\/501100000925","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["physoc.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["The Journal of Physiology"],"published-print":{"date-parts":[[2026,3]]},"abstract":"<jats:sec>\n                    <jats:title>Abstract<\/jats:title>\n                    <jats:p>\n                      Fetal growth restriction (FGR) affects \u223c10% of pregnancies worldwide and is often associated with placental insufficiency. Iron is essential for maternal haematopoietic adaptations and placental processes such as mitochondrial iron\u2013sulphur (Fe\u2010S) cluster assembly, haem synthesis and erythropoiesis. This study aimed to characterise iron transport and downstream utilisation in FGR. Placental tissues from term uncomplicated (\n                      <jats:italic>n<\/jats:italic>\n                      \u00a0=\u00a019) and FGR (\n                      <jats:italic>n<\/jats:italic>\n                      \u00a0=\u00a018) pregnancies were analysed. Maternal iron status was retrospectively assessed from clinical records. Placental mRNA and protein expression of iron\u2010dependent pathways were analysed via RT\u2010qPCR, LC\u2010MS and western blotting. Placental iron content was assessed histologically, and haem levels were measured by an activity assay. FGR pregnancies showed significantly elevated maternal serum ferritin and lower red cell distribution width, although these remained within normal clinical values. Placental iron uptake transporters TFRC and DMT1 were significantly upregulated, while the iron exporter to the fetus, ferroportin, was reduced, indicating increased iron retention in the FGR placenta. Despite altered transporter expression, Fe\n                      <jats:sup>3<\/jats:sup>\n                      <jats:sup>+<\/jats:sup>\n                      iron levels were unchanged, suggesting iron utilisation over storage. Subsequent investigations identified reduced mitochondrial Fe\u2010S synthesis components (FDXR, FDX2, NDUFAB1, HSPA9), and a prioritisation of mitochondrial and cytosolic haem synthesis enzymes in FGR. Protein levels of haemoglobin subunits (HBG1, HBG2, HBB, HBA1) and erythrocyte membrane markers (EPB41, EPB42, SPTA1, SPTB, ANK1) were decreased. These findings reveal a compensatory response in FGR placentae, with increased iron uptake and utilisation favouring haem synthesis over Fe\u2010S cluster formation, possibly to support oxygen handling under poor placental vascularisation and reduced fetal oxygenation, with potential consequences for mitochondrial energy metabolism.\n                      <jats:boxed-text content-type=\"graphic\" position=\"anchor\">\n                        <jats:graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" mimetype=\"image\/png\" position=\"anchor\" specific-use=\"enlarged-web-image\" xlink:href=\"graphic\/tjp70370-gra-0001-m.png\">\n                          <jats:alt-text>image<\/jats:alt-text>\n                        <\/jats:graphic>\n                      <\/jats:boxed-text>\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Key points<\/jats:title>\n                    <jats:p>\n                      <jats:list list-type=\"bullet\">\n                        <jats:list-item>\n                          <jats:p>Iron plays a critical role in placental function, and while iron\u2010dependent pathway components are well\u2010characterised, their integrated response and adaptive reprogramming in fetal growth restriction (FGR) remain poorly understood.<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>In FGR, maternal iron status was unchanged, however, placental iron uptake proteins were increased and ferroportin reduced, suggesting that the placenta retains iron.<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>\n                            FGR placentae showed altered\n                            <jats:italic>de novo<\/jats:italic>\n                            mitochondrial iron\u2013sulphur cluster (Fe\u2010S) formation and a bottleneck in late\u2010stage Fe\u2010S cluster assembly.\n                          <\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>This shift in Fe\u2010S synthesis prioritises mitochondrial and cytosolic haem synthesis pathways, consistent with increased haem utilisation and breakdown.<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>Globin subunits were lower in protein abundance and impaired placental erythrocyte structure in FGR.<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>Dysregulation of erythrocyte membrane proteins in FGR placentae suggests altered erythrocyte structure, potentially representing an adaptive response to inadequate vascularisation, attempting to optimise oxygen delivery to the fetus.<\/jats:p>\n                        <\/jats:list-item>\n                      <\/jats:list>\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1113\/jp289451","type":"journal-article","created":{"date-parts":[[2026,2,16]],"date-time":"2026-02-16T16:39:39Z","timestamp":1771259979000},"page":"2229-2249","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Placental iron utilisation in fetal growth restriction: alterations in mitochondrial haem synthesis and iron\u2013sulphur cluster assembly pathways"],"prefix":"10.1113","volume":"604","author":[{"given":"Veronica B.","family":"Botha","sequence":"first","affiliation":[{"name":"School of Biomedical Sciences and Pharmacy University of Newcastle  Callaghan New South Wales Australia"},{"name":"School of Medicine and Public Health University of Newcastle  Callaghan New South Wales Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Heather C.","family":"Murray","sequence":"additional","affiliation":[{"name":"School of Biomedical Sciences and Pharmacy University of Newcastle  Callaghan New South Wales Australia"},{"name":"Precision Medicine Program Hunter Medical Research Institute  New Lambton Heights New South Wales Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Siddharth","family":"Acharya","sequence":"additional","affiliation":[{"name":"School of Biomedical Sciences and Pharmacy University of Newcastle  Callaghan New South Wales Australia"},{"name":"School of Medicine and Public Health University of Newcastle  Callaghan New South Wales Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kirsty G.","family":"Pringle","sequence":"additional","affiliation":[{"name":"School of Biomedical Sciences and Pharmacy University of Newcastle  Callaghan New South Wales Australia"},{"name":"Women's Health Research Program Hunter Medical Research Institute  New Lambton Heights New South Wales Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roger","family":"Smith","sequence":"additional","affiliation":[{"name":"School of Medicine and Public Health University of Newcastle  Callaghan New South Wales Australia"},{"name":"Mothers and Babies Research Program Hunter Medical Research Institute  New Lambton Heights New South Wales Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joshua J.","family":"Fisher","sequence":"additional","affiliation":[{"name":"School of Medicine and Public Health University of Newcastle  Callaghan New South Wales Australia"},{"name":"Mothers and Babies Research Program Hunter Medical Research Institute  New Lambton Heights New South Wales Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,2,16]]},"reference":[{"key":"e_1_2_5_2_1","doi-asserted-by":"publisher","DOI":"10.1097\/AOG.0b013e3181c2bde8"},{"key":"e_1_2_5_3_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature19949"},{"key":"e_1_2_5_4_1","doi-asserted-by":"publisher","DOI":"10.3390\/cells11213464"},{"key":"e_1_2_5_5_1","doi-asserted-by":"publisher","DOI":"10.1242\/jeb.029454"},{"key":"e_1_2_5_6_1","doi-asserted-by":"publisher","DOI":"10.3945\/ajcn.117.155804"},{"key":"e_1_2_5_7_1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.genom.1.1.75"},{"key":"e_1_2_5_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajog.2020.11.005"},{"key":"e_1_2_5_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.mcpro.2021.100071"},{"key":"e_1_2_5_10_1","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms15124"},{"key":"e_1_2_5_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.placenta.2025.04.008"},{"key":"e_1_2_5_12_1","doi-asserted-by":"publisher","DOI":"10.1074\/mcp.M114.044305"},{"key":"e_1_2_5_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.placenta.2011.11.013"},{"key":"e_1_2_5_14_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajog.2017.11.577"},{"key":"e_1_2_5_15_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMra1401038"},{"key":"e_1_2_5_16_1","doi-asserted-by":"publisher","DOI":"10.3324\/haematol.2014.116483"},{"key":"e_1_2_5_17_1","doi-asserted-by":"publisher","DOI":"10.1093\/nutrit\/nuw009"},{"key":"e_1_2_5_18_1","doi-asserted-by":"publisher","DOI":"10.1159\/000481447"},{"key":"e_1_2_5_19_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12884-018-1963-2"},{"key":"e_1_2_5_20_1","doi-asserted-by":"publisher","DOI":"10.3324\/haematol.2013.091991"},{"key":"e_1_2_5_21_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.semcdb.2022.03.039"},{"key":"e_1_2_5_22_1","doi-asserted-by":"publisher","DOI":"10.1093\/jn\/nxab093"},{"issue":"1","key":"e_1_2_5_23_1","first-page":"S6","article-title":"Overview of iron metabolism in health and disease","volume":"21","author":"Dev S.","year":"2017","journal-title":"Hemodialysis International"},{"key":"e_1_2_5_24_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.stem.2018.04.015"},{"key":"e_1_2_5_25_1","doi-asserted-by":"publisher","DOI":"10.1095\/biolreprod60.4.861"},{"key":"e_1_2_5_26_1","doi-asserted-by":"publisher","DOI":"10.21037\/atm.2019.09.58"},{"key":"e_1_2_5_27_1","article-title":"Methodology for biological sample collection, processing, and storage in the Newcastle 1000 pregnancy cohort: Protocol for a longitudinal, prospective population\u2010based study in Australia","volume":"13","author":"Fisher J. J.","year":"2024","journal-title":"Journal of Medical Internet Research Research Protocols"},{"key":"e_1_2_5_28_1","doi-asserted-by":"publisher","DOI":"10.3389\/fphys.2019.01536"},{"key":"e_1_2_5_29_1","doi-asserted-by":"publisher","DOI":"10.1387\/ijdb.103070cg"},{"key":"e_1_2_5_30_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cels.2016.02.015"},{"key":"e_1_2_5_31_1","doi-asserted-by":"publisher","DOI":"10.1002\/uog.15884"},{"key":"e_1_2_5_32_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms232213880"},{"issue":"4","key":"e_1_2_5_33_1","first-page":"276","article-title":"Iron homeostasis: Transport, metabolism, and regulation","volume":"19","author":"Guo S.","year":"2016","journal-title":"Current Opinion in Clinical Nutrition and Metabolic Care"},{"key":"e_1_2_5_34_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood.2021014308"},{"key":"e_1_2_5_35_1","doi-asserted-by":"publisher","DOI":"10.1002\/ajh.25341"},{"key":"e_1_2_5_36_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbamcr.2012.04.009"},{"key":"e_1_2_5_37_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0092-8674(04)00343-5"},{"key":"e_1_2_5_38_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.biochem.9b00539"},{"key":"e_1_2_5_39_1","doi-asserted-by":"publisher","DOI":"10.1002\/pd.4045"},{"key":"e_1_2_5_40_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.placenta.2016.12.012"},{"key":"e_1_2_5_41_1","doi-asserted-by":"publisher","DOI":"10.1097\/00006250-200003000-00026"},{"key":"e_1_2_5_42_1","doi-asserted-by":"publisher","DOI":"10.1242\/dev.134866"},{"key":"e_1_2_5_43_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood.2023022190"},{"key":"e_1_2_5_44_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbamcr.2012.04.008"},{"key":"e_1_2_5_45_1","doi-asserted-by":"publisher","DOI":"10.1515\/cclm-2014-0585"},{"key":"e_1_2_5_46_1","doi-asserted-by":"publisher","DOI":"10.1038\/srep36193"},{"key":"e_1_2_5_47_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.tibs.2020.02.001"},{"key":"e_1_2_5_48_1","doi-asserted-by":"publisher","DOI":"10.1007\/978-3-030-41769-7_11"},{"key":"e_1_2_5_49_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI38499"},{"key":"e_1_2_5_50_1","doi-asserted-by":"publisher","DOI":"10.1023\/A:1020714915767"},{"key":"e_1_2_5_51_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1753-4887.2011.00428.x"},{"key":"e_1_2_5_52_1","doi-asserted-by":"publisher","DOI":"10.1007\/s43032-020-00393-2"},{"key":"e_1_2_5_53_1","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.15991"},{"key":"e_1_2_5_54_1","doi-asserted-by":"publisher","DOI":"10.1053\/j.semperi.2008.04.010"},{"key":"e_1_2_5_55_1","doi-asserted-by":"publisher","DOI":"10.1038\/s42003-022-03529-z"},{"key":"e_1_2_5_56_1","doi-asserted-by":"publisher","DOI":"10.1021\/acsomega.3c02719"},{"issue":"1","key":"e_1_2_5_57_1","first-page":"123","article-title":"Detecting outliers when fitting data with nonlinear regression \u2013 a new method based on robust nonlinear regression and the false discovery rate","volume":"7","author":"Motulsky H. J.","year":"2006","journal-title":"BioMed Central Bioinformatics [Electronic Resource]"},{"key":"e_1_2_5_58_1","doi-asserted-by":"publisher","DOI":"10.1002\/pmic.202300253"},{"key":"e_1_2_5_59_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.mcpro.2023.100503"},{"key":"e_1_2_5_60_1","doi-asserted-by":"publisher","DOI":"10.3389\/fphys.2019.01329"},{"key":"e_1_2_5_61_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-019-55313-5"},{"key":"e_1_2_5_62_1","unstructured":"NSW Health Pathology. (2019).NSWHP Reference Ranges: Adult (CRPOAH Reference Ranges Adult\u2010 February 2019). South Eastern Syndey Local Health District Sydney Australia. Available at:https:\/\/seslhd.health.gov.au\/sites\/default\/files\/2019\u201004\/NSWHP%20Reference%20Ranges%20Adult%202019.pdf"},{"key":"e_1_2_5_63_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.placenta.2021.12.018"},{"key":"e_1_2_5_64_1","doi-asserted-by":"publisher","DOI":"10.3389\/fcell.2022.894591"},{"key":"e_1_2_5_65_1","doi-asserted-by":"publisher","DOI":"10.2217\/bmm-2021-0364"},{"key":"e_1_2_5_66_1","doi-asserted-by":"publisher","DOI":"10.1111\/jog.12371"},{"key":"e_1_2_5_67_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0268-960X(98)90022-4"},{"key":"e_1_2_5_68_1","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.01685-08"},{"key":"e_1_2_5_69_1","doi-asserted-by":"publisher","DOI":"10.1080\/17474086.2016.1268047"},{"key":"e_1_2_5_70_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.exphem.2020.07.011"},{"key":"e_1_2_5_71_1","doi-asserted-by":"publisher","DOI":"10.1093\/humupd\/dmaa014"},{"key":"e_1_2_5_72_1","doi-asserted-by":"publisher","DOI":"10.1002\/uog.20419"},{"key":"e_1_2_5_73_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bcp.2023.115725"},{"key":"e_1_2_5_74_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.redox.2021.102164"},{"key":"e_1_2_5_75_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.stem.2008.01.001"},{"key":"e_1_2_5_76_1","doi-asserted-by":"publisher","DOI":"10.1530\/REP-20-0271"},{"key":"e_1_2_5_77_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI127341"},{"key":"e_1_2_5_78_1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-pathol-012513-104720"},{"key":"e_1_2_5_79_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature04512"},{"key":"e_1_2_5_80_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbamcr.2011.11.002"},{"key":"e_1_2_5_81_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.placenta.2009.12.020"},{"key":"e_1_2_5_82_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.placenta.2020.05.003"},{"key":"e_1_2_5_83_1","doi-asserted-by":"publisher","DOI":"10.1530\/REP-16-0287"},{"key":"e_1_2_5_84_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.mehy.2004.11.047"},{"key":"e_1_2_5_85_1","doi-asserted-by":"publisher","DOI":"10.3390\/antiox12051074"},{"key":"e_1_2_5_86_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jshs.2022.11.007"},{"key":"e_1_2_5_87_1","doi-asserted-by":"publisher","DOI":"10.1159\/000362888"},{"key":"e_1_2_5_88_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.modpat.2023.100398"},{"key":"e_1_2_5_89_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41390-023-02805-w"},{"key":"e_1_2_5_90_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.placenta.2021.09.003"},{"key":"e_1_2_5_91_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00018-024-05192-5"},{"key":"e_1_2_5_92_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bcp.2022.115141"},{"key":"e_1_2_5_93_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.mvr.2009.01.010"},{"key":"e_1_2_5_94_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkad842"},{"key":"e_1_2_5_95_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0301-2115(03)00168-4"}],"container-title":["The Journal of Physiology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/physoc.onlinelibrary.wiley.com\/doi\/pdf\/10.1113\/JP289451","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/physoc.onlinelibrary.wiley.com\/doi\/full-xml\/10.1113\/JP289451","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/physoc.onlinelibrary.wiley.com\/doi\/pdf\/10.1113\/JP289451","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,28]],"date-time":"2026-07-28T07:39:51Z","timestamp":1785224391000},"score":1,"resource":{"primary":{"URL":"https:\/\/physoc.onlinelibrary.wiley.com\/doi\/10.1113\/JP289451"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,2,16]]},"references-count":94,"journal-issue":{"issue":"5","published-print":{"date-parts":[[2026,3]]}},"alternative-id":["10.1113\/JP289451"],"URL":"https:\/\/doi.org\/10.1113\/jp289451","archive":["Portico"],"relation":{},"ISSN":["0022-3751","1469-7793"],"issn-type":[{"value":"0022-3751","type":"print"},{"value":"1469-7793","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,2,16]]},"assertion":[{"value":"2025-06-16","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-01-14","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-02-16","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}