title: NCOA4 Deficiency Impairs Systemic Iron Homeostasis.
abstract: The cargo receptor NCOA4 mediates autophagic ferritin degradation. Here we show that NCOA4 deficiency in a knockout mouse model causes iron accumulation in the liver and spleen, increased levels of transferrin saturation, serum ferritin, and liver hepcidin, and decreased levels of duodenal ferroportin. Despite signs of iron overload, NCOA4-null mice had mild microcytic hypochromic anemia. Under an iron-deprived diet (2-3 mg/kg), mice failed to release iron from ferritin storage and developed severe microcytic hypochromic anemia and ineffective erythropoiesis associated with increased erythropoietin levels. When fed an iron-enriched diet (2 g/kg), mice died prematurely and showed signs of liver damage. Ferritin accumulated in primary embryonic fibroblasts from NCOA4-null mice consequent to impaired autophagic targeting. Adoptive expression of the NCOA4 COOH terminus (aa 239-614) restored this function. In conclusion, NCOA4 prevents iron accumulation and ensures efficient erythropoiesis, playing a central role in balancing iron levels in vivo.
authors.affiliation: Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Università degli Studi di Napoli Federico II, and Istituto di Endocrinologia ed Oncologia Sperimentale del Consiglio Nazionale delle Ricerche, 80131 Napoli, Italy.
authors.forename: Roberto
authors.initials: R
authors.lastname: Bellelli
authors.affiliation: Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Università degli Studi di Napoli Federico II, and Istituto di Endocrinologia ed Oncologia Sperimentale del Consiglio Nazionale delle Ricerche, 80131 Napoli, Italy.
authors.forename: Giorgia
authors.initials: G
authors.lastname: Federico
authors.affiliation: Dipartimento di Medicina, Università degli Studi di Verona-Azienda Ospedaliera Universitaria Integrata Verona, 37134 Verona, Italy.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Matte'
authors.affiliation: Istituto Toscano Tumori-Core Research Laboratory and Consiglio Nazionale delle Ricerche-Istituto di Fisiologia Clinica, 53100 Siena, Italy.
authors.forename: David
authors.initials: D
authors.lastname: Colecchia
authors.affiliation: Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Università degli Studi di Napoli Federico II, and Istituto di Endocrinologia ed Oncologia Sperimentale del Consiglio Nazionale delle Ricerche, 80131 Napoli, Italy; Centro di Ingegneria Genetica-Advanced Biotechnologies, 80145 Naples, Italy.
authors.forename: Achille
authors.initials: A
authors.lastname: Iolascon
authors.affiliation: Istituto Toscano Tumori-Core Research Laboratory and Consiglio Nazionale delle Ricerche-Istituto di Fisiologia Clinica, 53100 Siena, Italy.
authors.forename: Mario
authors.initials: M
authors.lastname: Chiariello
authors.affiliation: Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Università degli Studi di Napoli Federico II, and Istituto di Endocrinologia ed Oncologia Sperimentale del Consiglio Nazionale delle Ricerche, 80131 Napoli, Italy.
authors.forename: Massimo
authors.initials: M
authors.lastname: Santoro
authors.affiliation: Dipartimento di Medicina, Università degli Studi di Verona-Azienda Ospedaliera Universitaria Integrata Verona, 37134 Verona, Italy.
authors.forename: Lucia
authors.initials: L
authors.lastname: De Franceschi
authors.affiliation: Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Università degli Studi di Napoli Federico II, and Istituto di Endocrinologia ed Oncologia Sperimentale del Consiglio Nazionale delle Ricerche, 80131 Napoli, Italy. Electronic address: francesca.carlomagno@unina.it.
authors.forename: Francesca
authors.initials: F
authors.lastname: Carlomagno
mesh_terms: D000747:Anemia, Hypochromic / Q000378:metabolism / Q000473:pathology; D000818:Animals; D001343:Autophagy / Q000187:drug effects; D002460:Cell Line; D004386:Duodenum / Q000378:metabolism / Q000473:pathology; D004912:Erythrocytes / Q000166:cytology / Q000378:metabolism; D004920:Erythropoiesis / Q000187:drug effects; D005260:Female; D005293:Ferritins / Q000378:metabolism; D064451:Hepcidins / Q000378:metabolism; D007501:Iron / Q000378:metabolism*; D019190:Iron Overload / Q000401:mortality / Q000473:pathology; D019266:Iron, Dietary / Q000494:pharmacology; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D056918:Nuclear Receptor Coactivators / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D010088:Oxidoreductases / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D013154:Spleen / Q000378:metabolism / Q000473:pathology; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D064451:Hepcidins; D019266:Iron, Dietary; C508724:NcoA4 protein, mouse; D056918:Nuclear Receptor Coactivators; D017382:Reactive Oxygen Species; D005293:Ferritins; D007501:Iron; D010088:Oxidoreductases
keywords: NCOA4; autophagy; ferritin; hypochromic anemia; iron