{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,14]],"date-time":"2026-10-14T23:08:44Z","timestamp":1792019324051,"version":"4.4.0"},"reference-count":37,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2023,1,19]],"date-time":"2023-01-19T00:00:00Z","timestamp":1674086400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001321","name":"National Research Foundation","doi-asserted-by":"publisher","award":["2022R1F1A106351711"],"award-info":[{"award-number":["2022R1F1A106351711"]}],"id":[{"id":"10.13039\/501100001321","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002573","name":"Yonsei University","doi-asserted-by":"publisher","award":["2021-22-0341"],"award-info":[{"award-number":["2021-22-0341"]}],"id":[{"id":"10.13039\/501100002573","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R21HD106043"],"award-info":[{"award-number":["R21HD106043"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01HD094809"],"award-info":[{"award-number":["R01HD094809"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Nutr."],"abstract":"<jats:sec>\n                    <jats:title>Introduction<\/jats:title>\n                    <jats:p>Neurons require iron to support their metabolism, growth, and differentiation, but are also susceptible to iron-induced oxidative stress and cytotoxicity. Ferritin, a cytosolic iron storage unit, mediates cellular adaptation to fluctuations in iron delivery. NCOA4 has been characterized as a selective autophagic cargo receptor facilitating the mobilization of intracellular iron from ferritin. This process named ferritinophagy results in the degradation of ferritin and the consequent release of iron into the cytosol.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      Here we demonstrate that NCOA4 is important for the adaptation of the HT22 mouse hippocampal neuronal cell line to cellular iron restriction. Additionally, we determined the pathophysiological implications of impaired ferritinophagy\n                      <jats:italic>via<\/jats:italic>\n                      functional analysis of the omics profile of HT22 cells deficient in NCOA4.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>NCOA4 silencing impaired ferritin turnover and was cytotoxic when cells were restricted of iron. Quantitative proteomics identified IRP2 accumulation among the most prominent protein responses produced by NCOA4 depletion in HT22 cells, which is indicative of functional iron deficiency. Additionally, proteins of apoptotic signaling pathway were enriched by those responsive to NCOA4 deficiency. Transcriptome profiles of NCOA4 depletion revealed neuronal cell death, differentiation of neurons, and development of neurons as potential diseases and bio functions affected by impaired ferritinophagy, particularly, when iron was restricted.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Discussion<\/jats:title>\n                    <jats:p>These findings identify an integral role of NCOA4-mediated ferritinophagy in the maintenance of iron homeostasis by HT22 cells, and its potential implications in controlling genetic pathways of neurodevelopment and neurodegenerative diseases.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fnut.2023.1054852","type":"journal-article","created":{"date-parts":[[2023,1,19]],"date-time":"2023-01-19T00:11:52Z","timestamp":1674087112000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":19,"title":["Quantitative omics analyses of NCOA4 deficiency reveal an integral role of ferritinophagy in iron homeostasis of hippocampal neuronal HT22 cells"],"prefix":"10.3389","volume":"10","author":[{"given":"Emily F.","family":"Bengson","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cole A.","family":"Guggisberg","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas W.","family":"Bastian","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael K.","family":"Georgieff","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Moon-Suhn","family":"Ryu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2023,1,19]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"S34","DOI":"10.1301\/nr.2006.may.s34-s43","article-title":"Long-lasting neural and behavioral effects of iron deficiency in infancy","volume":"64","author":"Lozoff","year":"2006","journal-title":"Nutr Rev."},{"key":"B2","doi-asserted-by":"publisher","first-page":"1136","DOI":"10.1001\/archpsyc.65.10.1136","article-title":"Maternal iron deficiency and the risk of schizophrenia in offspring","volume":"65","author":"Insel","year":"2008","journal-title":"Arch Gen Psychiatry."},{"key":"B3","doi-asserted-by":"publisher","first-page":"161","DOI":"10.1186\/1471-244X-13-161","article-title":"Association between psychiatric disorders and iron deficiency anemia among children and adolescents: a nationwide population-based study","volume":"13","author":"Chen","year":"2013","journal-title":"BMC Psychiatry."},{"key":"B4","doi-asserted-by":"publisher","first-page":"1559S","DOI":"10.3945\/ajcn.117.155804","article-title":"Current understanding of iron homeostasis.","volume":"106","author":"Anderson","year":"2017","journal-title":"Am J Clin Nutr."},{"key":"B5","doi-asserted-by":"publisher","first-page":"1069","DOI":"10.1038\/ncb3053","article-title":"Selective VPS34 inhibitor blocks autophagy and uncovers a role for NCOA4 in ferritin degradation and iron homeostasis in vivo.","volume":"16","author":"Dowdle","year":"2014","journal-title":"Nat Cell Biol."},{"key":"B6","doi-asserted-by":"publisher","first-page":"105","DOI":"10.1038\/nature13148","article-title":"Quantitative proteomics identifies NCOA4 as the cargo receptor mediating ferritinophagy.","volume":"509","author":"Mancias","year":"2014","journal-title":"Nature."},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.10308","article-title":"Ferritinophagy via NCOA4 is required for erythropoiesis and is regulated by iron dependent HERC2-mediated proteolysis.","volume":"4","author":"Mancias","year":"2015","journal-title":"eLife."},{"key":"B8","doi-asserted-by":"publisher","first-page":"75","DOI":"10.1016\/j.bcmd.2017.09.009","article-title":"Ferritin iron regulators, PCBP1 and NCOA4, respond to cellular iron status in developing red cells.","volume":"69","author":"Ryu","year":"2018","journal-title":"Blood Cells Mol Dis."},{"key":"B9","doi-asserted-by":"publisher","first-page":"2547","DOI":"10.1182\/blood.2021013452","article-title":"Modulation of the HIF2\u03b1-NCOA4 axis in enterocytes attenuates iron loading in a mouse model of hemochromatosis.","volume":"139","author":"Das","year":"2022","journal-title":"Blood."},{"key":"B10","doi-asserted-by":"publisher","first-page":"2691","DOI":"10.1182\/blood.2020006321","article-title":"NCOA4 is regulated by HIF and mediates mobilization of murine hepatic iron stores after blood loss.","volume":"136","author":"Li","year":"2020","journal-title":"Blood."},{"key":"B11","doi-asserted-by":"publisher","first-page":"795","DOI":"10.3324\/haematol.2019.241232","article-title":"NCOA4-mediated ferritinophagy in macrophages is crucial to sustain erythropoiesis in mice.","volume":"106","author":"Nai","year":"2021","journal-title":"Haematologica."},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.3390\/antiox11101926","article-title":"NCOA4 regulates iron recycling and responds to hepcidin activity and lipopolysaccharide in macrophages.","volume":"11","author":"Guggisberg","year":"2022","journal-title":"Antioxidants."},{"key":"B13","doi-asserted-by":"publisher","first-page":"1786","DOI":"10.1172\/JCI90519","article-title":"PCBP1 and NCOA4 regulate erythroid iron storage and heme biosynthesis.","volume":"127","author":"Ryu","year":"2017","journal-title":"J Clin Invest."},{"key":"B14","doi-asserted-by":"publisher","first-page":"1342","DOI":"10.3324\/haematol.2018.204123","article-title":"NCOA4 maintains murine erythropoiesis via cell autonomous and non-autonomous mechanisms.","volume":"104","author":"Santana-Codina","year":"2019","journal-title":"Haematologica."},{"key":"B15","doi-asserted-by":"publisher","first-page":"411","DOI":"10.1016\/j.celrep.2015.12.065","article-title":"NCOA4 deficiency impairs systemic iron homeostasis.","volume":"14","author":"Bellelli","year":"2016","journal-title":"Cell Rep."},{"key":"B16","doi-asserted-by":"publisher","first-page":"142","DOI":"10.1016\/j.spen.2006.08.002","article-title":"Brain iron metabolism.","volume":"13","author":"Rouault","year":"2006","journal-title":"Semin Pediatr Neurol."},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.3389\/fnins.2019.00238","article-title":"NCOA4-mediated ferritinophagy: a potential link to neurodegeneration.","volume":"13","author":"Quiles Del Rey","year":"2019","journal-title":"Front Neurosci."},{"key":"B18","doi-asserted-by":"publisher","first-page":"267","DOI":"10.1016\/j.lfs.2008.12.008","article-title":"HT22 hippocampal neuronal cell line possesses functional cholinergic properties.","volume":"84","author":"Liu","year":"2009","journal-title":"Life Sci."},{"key":"B19","doi-asserted-by":"publisher","first-page":"1297","DOI":"10.3969\/j.issn.1673-5374.2013.14.006","article-title":"Differentiation renders susceptibility to excitotoxicity in HT22 neurons.","volume":"8","author":"He","year":"2013","journal-title":"Neural Regen Res."},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1186\/1471-2105-13-134","article-title":"Primer-BLAST: a tool to design target-specific primers for polymerase chain reaction.","volume":"13","author":"Ye","year":"2012","journal-title":"BMC Bioinformatics."},{"key":"B21","doi-asserted-by":"publisher","first-page":"264","DOI":"10.1159\/000448514","article-title":"Iron deficiency impairs developing hippocampal neuron gene expression, energy metabolism, and dendrite complexity.","volume":"38","author":"Bastian","year":"2016","journal-title":"Dev Neurosci."},{"key":"B22","doi-asserted-by":"publisher","first-page":"802","DOI":"10.1523\/JNEUROSCI.1504-18.2018","article-title":"Chronic energy depletion due to iron deficiency impairs dendritic mitochondrial motility during hippocampal neuron development.","volume":"39","author":"Bastian","year":"2019","journal-title":"J Neurosci."},{"key":"B23","doi-asserted-by":"publisher","first-page":"747","DOI":"10.1093\/jn\/nxab429","article-title":"Choline supplementation partially restores dendrite structural complexity in developing iron-deficient mouse hippocampal neurons.","volume":"152","author":"Bastian","year":"2022","journal-title":"J Nutr."},{"key":"B24","doi-asserted-by":"publisher","first-page":"129","DOI":"10.1586\/epr.12.15","article-title":"High-pH reversed-phase chromatography with fraction concatenation for 2D proteomic analysis.","volume":"9","author":"Yang","year":"2012","journal-title":"Expert Rev Proteomics."},{"key":"B25","doi-asserted-by":"publisher","first-page":"139","DOI":"10.1093\/bioinformatics\/btp616","article-title":"edgeR: a bioconductor package for differential expression analysis of digital gene expression data.","volume":"26","author":"Robinson","year":"2010","journal-title":"Bioinformatics."},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkac194","article-title":"DAVID: a web server for functional enrichment analysis and functional annotation of gene lists (2021 update).","volume":"50","author":"Sherman","year":"2022","journal-title":"Nucleic Acids Res."},{"key":"B27","doi-asserted-by":"publisher","first-page":"15545","DOI":"10.1073\/pnas.0506580102","article-title":"Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles.","volume":"102","author":"Subramanian","year":"2005","journal-title":"Proc Natl Acad Sci USA."},{"key":"B28","doi-asserted-by":"publisher","first-page":"722","DOI":"10.1126\/science.1176326","article-title":"An E3 ligase possessing an iron-responsive hemerythrin domain is a regulator of iron homeostasis.","volume":"326","author":"Salahudeen","year":"2009","journal-title":"Science."},{"key":"B29","doi-asserted-by":"publisher","first-page":"S43","DOI":"10.1111\/j.1753-4887.2011.00432.x","article-title":"Long-term brain and behavioral consequences of early iron deficiency.","author":"Georgieff","year":"2011","journal-title":"Nutr Rev."},{"key":"B30","doi-asserted-by":"publisher","first-page":"1607","DOI":"10.1007\/s00018-013-1509-8","article-title":"Iron deposits in the chronically inflamed central nervous system and contributes to neurodegeneration.","volume":"71","author":"Andersen","year":"2014","journal-title":"Cell Mol Life Sci."},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.3389\/fnins.2019.00180","article-title":"Iron in neurodegeneration - cause or consequence?","volume":"13","author":"Ndayisaba","year":"2019","journal-title":"Front Neurosci."},{"key":"B32","doi-asserted-by":"publisher","first-page":"1195","DOI":"10.1093\/brain\/awz072","article-title":"Absence of iron-responsive element-binding protein 2 causes a novel neurodegenerative syndrome.","volume":"142","author":"Costain","year":"2019","journal-title":"Brain."},{"key":"B33","doi-asserted-by":"publisher","first-page":"3428","DOI":"10.1073\/pnas.1519473113","article-title":"Disrupted iron homeostasis causes dopaminergic neurodegeneration in mice.","volume":"113","author":"Matak","year":"2016","journal-title":"Proc Natl Acad Sci USA."},{"key":"B34","doi-asserted-by":"publisher","first-page":"1155","DOI":"10.1038\/onc.2009.413","article-title":"Tid1 is a new regulator of p53 mitochondrial translocation and apoptosis in cancer.","volume":"29","author":"Ahn","year":"2010","journal-title":"Oncogene."},{"key":"B35","doi-asserted-by":"publisher","first-page":"400","DOI":"10.1016\/j.bbabio.2003.06.005","article-title":"The possible role of cytochrome c oxidase in stress-induced apoptosis and degenerative diseases.","volume":"1655","author":"Kadenbach","year":"2004","journal-title":"Biochim Biophys Acta."},{"key":"B36","doi-asserted-by":"publisher","first-page":"3586","DOI":"10.1093\/emboj\/18.13.3586","article-title":"Role of cytochrome c and dATP\/ATP hydrolysis in Apaf-1-mediated caspase-9 activation and apoptosis.","volume":"18","author":"Hu","year":"1999","journal-title":"EMBO J."},{"key":"B37","doi-asserted-by":"publisher","first-page":"1490","DOI":"10.1182\/blood.2021010995","article-title":"CD63 is regulated by iron via the IRE-IRP system and is important for ferritin secretion by extracellular vesicles.","volume":"138","author":"Yanatori","year":"2021","journal-title":"Blood."}],"container-title":["Frontiers in Nutrition"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fnut.2023.1054852\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,1,19]],"date-time":"2023-01-19T00:11:59Z","timestamp":1674087119000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fnut.2023.1054852\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,1,19]]},"references-count":37,"alternative-id":["10.3389\/fnut.2023.1054852"],"URL":"https:\/\/doi.org\/10.3389\/fnut.2023.1054852","relation":{},"ISSN":["2296-861X"],"issn-type":[{"value":"2296-861X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,1,19]]},"article-number":"1054852"}}