{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,13]],"date-time":"2026-06-13T14:55:17Z","timestamp":1781362517158,"version":"3.54.1"},"reference-count":44,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2023,1,5]],"date-time":"2023-01-05T00:00:00Z","timestamp":1672876800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Allen Foundation Grant"},{"DOI":"10.13039\/501100002573","name":"Yonsei University Research Fund","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":["DK079209"],"award-info":[{"award-number":["DK079209"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.mdpi.com"],"crossmark-restriction":true},"short-container-title":["Nutrients"],"abstract":"<jats:p>Anemia is the most prevalent nutrition-related disorder worldwide. Zinc is an essential trace element for various biological processes in the body, and zinc deficiency has been associated with anemia in humans. However, the molecular mechanisms by which zinc availability alters red blood cell development remain uncertain. The present study identifies the essentiality of zinc during erythroid development, particularly for normal heme biosynthesis. G1E-ER4 mouse cells were used as an in vitro model of terminal erythroid differentiation, which featured elevated cellular zinc content by development. Restriction of zinc import compromised the rate of heme and \u03b1-globin production and, thus, the hemoglobinization of the erythroid progenitors. Heme is synthesized by the incorporation of iron into protoporphyrin. The lower heme production under zinc restriction was not due to changes in iron but was attributable to less porphyrin synthesis. The requirement of adequate zinc for erythroid heme metabolism was confirmed in another erythropoietic cell model, MEL-DS19. Additionally, we found that a conventional marker of iron deficiency anemia, the ZnPP-to-heme ratio, responded to zinc restriction differently from iron deficiency. Collectively, our findings define zinc as an essential nutrient integral to erythroid heme biosynthesis and, thus, a potential therapeutic target for treating anemia and other erythrocyte-related disorders.<\/jats:p>","DOI":"10.3390\/nu15020281","type":"journal-article","created":{"date-parts":[[2023,1,6]],"date-time":"2023-01-06T02:20:30Z","timestamp":1672971630000},"page":"281","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":23,"title":["Cellular Zinc Deficiency Impairs Heme Biosynthesis in Developing Erythroid Progenitors"],"prefix":"10.3390","volume":"15","author":[{"given":"Juyoung","family":"Kim","sequence":"first","affiliation":[{"name":"Department of Food Science and Nutrition, University of Minnesota, St. Paul, MN 55108, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jaekwon","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, University of Nebraska-Lincoln, Lincoln, NE 68588, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9533-9263","authenticated-orcid":false,"given":"Moon-Suhn","family":"Ryu","sequence":"additional","affiliation":[{"name":"Department of Food Science and Nutrition, University of Minnesota, St. Paul, MN 55108, USA"},{"name":"Department of Food and Nutrition, Yonsei University, Seoul 03722, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,1,5]]},"reference":[{"key":"ref_1","unstructured":"World Health Organization (2017). Nutritional Anaemias: Tools for Effective Prevention and Control."},{"key":"ref_2","first-page":"830","article-title":"Global, Regional, and National Prevalence of Anemia and Its Causes in 204 Countries and Territories, 1990\u20132019","volume":"4","author":"Gardner","year":"2020","journal-title":"Curr. Dev. Nutr."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"E770","DOI":"10.1152\/ajpendo.1993.264.5.E770","article-title":"Zinc Metabolism and Metallothionein Expression in Bone Marrow during Erythropoiesis","volume":"264","author":"Huber","year":"1993","journal-title":"Am. J. Physiol.-Endocrinol. Metab."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"574","DOI":"10.1016\/j.ygeno.2007.06.010","article-title":"Differential Gene Expression during Terminal Erythroid Differentiation","volume":"90","author":"Koury","year":"2007","journal-title":"Genomics"},{"key":"ref_5","doi-asserted-by":"crossref","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. Investig."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"577","DOI":"10.1016\/0009-8981(56)90045-6","article-title":"Spectrochemical Determination of Magnesium, Chromium, Nickel, Copper and Zinc in Human Plasma","volume":"1","author":"Monacelli","year":"1956","journal-title":"Clin. Chim. Acta"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"92","DOI":"10.1016\/S0946-672X(00)80037-1","article-title":"Determination of Iron, Copper, Zinc, Magnesium and Selenium in Plasma and Erythrocytes in Neurosurgical Patients","volume":"14","author":"Walther","year":"2000","journal-title":"J. Trace Elem. Med. Biol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"581","DOI":"10.1016\/j.devcel.2018.07.022","article-title":"GATA\/Heme Multi-Omics Reveals a Trace Metal-Dependent Cellular Differentiation Mechanism","volume":"46","author":"Tanimura","year":"2018","journal-title":"Dev. Cell"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"749","DOI":"10.1152\/physrev.00035.2014","article-title":"The Physiological, Biochemical, and Molecular Roles of Zinc Transporters in Zinc Homeostasis and Metabolism","volume":"95","author":"Kambe","year":"2015","journal-title":"Physiol. Rev."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"2509","DOI":"10.1021\/acs.accounts.6b00414","article-title":"The Remarkable Character of Porphobilinogen Synthase","volume":"49","author":"Jaffe","year":"2016","journal-title":"Acc. Chem. Res."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"946","DOI":"10.1021\/cr050262p","article-title":"Carbonic Anhydrase as a Model for Biophysical and Physical-Organic Studies of Proteins and Protein\u2212Ligand Binding","volume":"108","author":"Krishnamurthy","year":"2008","journal-title":"Chem. Rev."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"679S","DOI":"10.3945\/ajcn.110.005744","article-title":"Zinc: An Essential but Elusive Nutrient","volume":"94","author":"King","year":"2011","journal-title":"Am. J. Clin. Nutr."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"10974","DOI":"10.1038\/srep10974","article-title":"Dietary Calcium and Zinc Deficiency Risks Are Decreasing but Remain Prevalent","volume":"5","author":"Kumssa","year":"2015","journal-title":"Sci. Rep."},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Wessells, K.R., and Brown, K.H. (2012). Estimating the Global Prevalence of Zinc Deficiency: Results Based on Zinc Availability in National Food Supplies and the Prevalence of Stunting. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0050568"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"3301","DOI":"10.1093\/jn\/132.11.3301","article-title":"Zinc Deficiency in Mice Alters Myelopoiesis and Hematopoiesis","volume":"132","author":"King","year":"2002","journal-title":"J. Nutr."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"494","DOI":"10.1080\/07315724.2005.10719495","article-title":"Chronic Zinc Deficiency in Mice Disrupted T Cell Lymphopoiesis and Erythropoiesis While B Cell Lymphopoiesis and Myelopoiesis Were Maintained","volume":"24","author":"King","year":"2005","journal-title":"J. Am. Coll. Nutr."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"581","DOI":"10.1093\/jn\/138.3.581","article-title":"Zinc, Gravida, Infection, and Iron, but Not Vitamin B-12 or Folate Status, Predict Hemoglobin during Pregnancy in Southern Ethiopia","volume":"138","author":"Gibson","year":"2008","journal-title":"J. Nutr."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1670","DOI":"10.3945\/jn.116.235127","article-title":"Serum Zinc Is a Major Predictor of Anemia and Mediates the Effect of Selenium on Hemoglobin in School-Aged Children in a Nationally Representative Survey in New Zealand","volume":"146","author":"Houghton","year":"2016","journal-title":"J. Nutr."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"703","DOI":"10.1111\/ped.13603","article-title":"Zinc Deficiency and Its Predictive Capacity for Anemia: Unique Model in School Children","volume":"60","author":"Atasoy","year":"2018","journal-title":"Pediatr. Int."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"532","DOI":"10.1016\/0002-9343(61)90137-1","article-title":"Syndrome of Iron Deficiency Anemia, Hepatosplenomegaly, Hypogonadism, Dwarfism and Geophagia","volume":"31","author":"Prasad","year":"1961","journal-title":"Am. J. Med."},{"key":"ref_21","first-page":"537","article-title":"Zinc Metabolism in Patients with the Syndrome of Iron Deficiency Anemia, Hepatosplenomegaly, Dwarfism, and Hypognadism","volume":"61","author":"Prasad","year":"1963","journal-title":"J. Lab. Clin. Med."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"608","DOI":"10.1126\/science.aah3862","article-title":"Restored Iron Transport by a Small Molecule Promotes Absorption and Hemoglobinization in Animals","volume":"356","author":"Grillo","year":"2017","journal-title":"Science"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1382","DOI":"10.1016\/0006-291X(79)91133-1","article-title":"Succinylacetone, a Potent Inhibitor of Heme Biosynthesis: Effect on Cell Growth, Heme Content and \u03b4-Aminolevulinic Acid Dehydratase Activity of Malignant Murine Erythroleukemia Cells","volume":"88","author":"Ebert","year":"1979","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Guggisberg, C.A., Kim, J., Lee, J., Chen, X., and Ryu, M.-S. (2022). NCOA4 Regulates Iron Recycling and Responds to Hepcidin Activity and Lipopolysaccharide in Macrophages. Antioxidants, 11.","DOI":"10.3390\/antiox11101926"},{"key":"ref_25","unstructured":"Parsons, P.J. (2001). Measurement of Erythrocyte Protoporphyrin Concentration by Double Extraction and Spectrofluorometry. Curr. Protoc. Toxicol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"161","DOI":"10.1093\/clinchem\/22.2.161","article-title":"Erythrocyte Porphyrin Analysis in the Detection of Lead Poisoning in Children: Evaluation of Four Micromethods","volume":"22","author":"Hanna","year":"1976","journal-title":"Clin. Chem."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1585","DOI":"10.1093\/clinchem\/23.9.1585","article-title":"Improved Ethanol Extraction Procedure for Determining Zinc Protoporphyrin in Whole Blood","volume":"23","author":"Garden","year":"1977","journal-title":"Clin. Chem."},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Ye, J., Coulouris, G., Zaretskaya, I., Cutcutache, I., Rozen, S., and Madden, T.L. (2012). Primer-BLAST: A Tool to Design Target-Specific Primers for Polymerase Chain Reaction. BMC Bioinform., 13.","DOI":"10.1186\/1471-2105-13-134"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"337","DOI":"10.1039\/C5MT00305A","article-title":"Zinc Sensing by Metal-Responsive Transcription Factor 1 (MTF1) Controls Metallothionein and ZnT1 Expression to Buffer the Sensitivity of the Transcriptome Response to Zinc","volume":"8","author":"Hardyman","year":"2016","journal-title":"Metallomics"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"34803","DOI":"10.1074\/jbc.M007339200","article-title":"The Transcription Factor MTF-1 Mediates Metal Regulation of the Mouse ZnT1 Gene","volume":"275","author":"Langmade","year":"2000","journal-title":"J. Biol. Chem."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"173","DOI":"10.3389\/fphar.2014.00173","article-title":"Special Delivery: Distributing Iron in the Cytosol of Mammalian Cells","volume":"5","author":"Philpott","year":"2014","journal-title":"Front. Pharmacol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"5350","DOI":"10.1002\/j.1460-2075.1995.tb00219.x","article-title":"Requirements for Iron-Regulated Degradation of the RNA Binding Protein, Iron Regulatory Protein 2","volume":"14","author":"Iwai","year":"1995","journal-title":"EMBO J."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"3136","DOI":"10.1182\/blood-2004-04-1603","article-title":"Global Regulation of Erythroid Gene Expression by Transcription Factor GATA-1","volume":"104","author":"Welch","year":"2004","journal-title":"Blood"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"663","DOI":"10.1016\/0016-5085(83)90023-9","article-title":"Enzymatic Formation of Zinc-Protoporphyrin by Rat Liver and Its Potential Effect on Hepatic Heme Metabolism","volume":"85","author":"Bloomer","year":"1983","journal-title":"Gastroenterology"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"e37","DOI":"10.1542\/peds.104.3.e37","article-title":"Zinc Protoporphyrin\/Heme Ratio for Diagnosis of Preanemic Iron Deficiency","volume":"104","author":"Rettmer","year":"1999","journal-title":"Pediatrics"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"768","DOI":"10.1093\/clinchem\/40.5.768","article-title":"Central Role of Zinc Protoporphyrin in Staging Iron Deficiency","volume":"40","author":"Hastka","year":"1994","journal-title":"Clin. Chem."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"176","DOI":"10.1024\/0300-9831\/a000158","article-title":"A High Prevalence of Zinc- but Not Iron-Deficiency among Women in Rural Malawi: A Cross-Sectional Study","volume":"83","author":"Siyame","year":"2013","journal-title":"Int. J. Vitam. Nutr. Res."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1218","DOI":"10.3945\/jn.116.247171","article-title":"Identification of a Hemolysis Threshold That Increases Plasma and Serum Zinc Concentration","volume":"147","author":"Killilea","year":"2017","journal-title":"J. Nutr."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"111172","DOI":"10.1016\/j.jinorgbio.2020.111172","article-title":"In Anemia Zinc Is Recruited from Bone and Plasma to Produce New Red Blood Cells","volume":"210","author":"Chen","year":"2020","journal-title":"J. Inorg. Biochem."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"2076","DOI":"10.3945\/jn.108.093575","article-title":"Zinc Transporters ZnT1 (Slc30a1), Zip8 (Slc39a8), and Zip10 (Slc39a10) in Mouse Red Blood Cells Are Differentially Regulated during Erythroid Development and by Dietary Zinc Deficiency","volume":"138","author":"Ryu","year":"2008","journal-title":"J. Nutr."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"447","DOI":"10.1093\/jn\/113.2.447","article-title":"Growth Rate, Tissue Zinc Levels and Activities of Selected Enzymes in Rats Fed a Zinc-Deficient Diet by Gastric Tube","volume":"113","author":"Faraji","year":"1983","journal-title":"J. Nutr."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"170","DOI":"10.1159\/000458572","article-title":"Effect of Age and Diet on Delta-Aminolevulinic AcidDehydratase in Red Blood Cells","volume":"23","author":"Abdulla","year":"1978","journal-title":"Enzyme"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"858S","DOI":"10.3945\/jn.115.220079","article-title":"Biomarkers of Nutrition for Development (BOND)-Zinc Review","volume":"146","author":"King","year":"2015","journal-title":"J. Nutr."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"11","DOI":"10.2147\/JBM.S29212","article-title":"Biomarkers for the Differentiation of Anemia and Their Clinical Usefulness","volume":"4","author":"Thurnham","year":"2013","journal-title":"J Blood Med"}],"updated-by":[{"DOI":"10.3390\/nu17152402","type":"correction","label":"Correction","source":"publisher","updated":{"date-parts":[[2023,1,5]],"date-time":"2023-01-05T00:00:00Z","timestamp":1672876800000}}],"container-title":["Nutrients"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6643\/15\/2\/281\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,8,3]],"date-time":"2025-08-03T22:25:06Z","timestamp":1754259906000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6643\/15\/2\/281"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,1,5]]},"references-count":44,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2023,1]]}},"alternative-id":["nu15020281"],"URL":"https:\/\/doi.org\/10.3390\/nu15020281","relation":{"correction":[{"id-type":"doi","id":"10.3390\/nu17152402","asserted-by":"object"}]},"ISSN":["2072-6643"],"issn-type":[{"value":"2072-6643","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,1,5]]}}}