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Iron Metabolism and its Disorders
NCOA4-mediated ferritinophagy in macrophages is crucial to sustain erythropoiesis in mice
Ferrata Storti Foundation
Haematologica 2021 Volume 106(3):795-805
Antonella Nai,1,2 Maria Rosa Lidonnici,3 Giorgia Federico,4 Mariateresa Pettinato,1,2 Violante Olivari,1 Federica Carrillo,4,5 Simonetta Geninatti Crich,6 Giuliana Ferrari,2,3 Clara Camaschella,1 Laura Silvestri1,2# and Francesca Carlomagno4,5#
1Division of Genetics and Cell Biology, San Raffaele Scientific Institute, Milan; 2Vita- Salute San Raffaele University, Milan; 3SR-TIGET, San Raffaele Scientific Institute, Milan; 4Department of Molecular Medicine and Medicine Biotechnology (DMMBM), University of Naples Federico II, Naples; 5Institute of Endocrinology and Experimental Oncology (IEOS), CNR, Naples and 6Department of Molecular Biotechnology and Health Sciences, University of Turin, Turin, Italy
#LS and FrC contributed equally as co-senior authors.
ABSTRACT
Nuclear receptor coactivator 4 (NCOA4) promotes ferritin degrada- tion and Ncoa4-ko mice in a C57BL/6 background show microcy- tosis and mild anemia, aggravated by iron deficiency. To under- stand tissue-specific contributions of NCOA4-mediated ferritinophagy we explored the effect of Ncoa4 genetic ablation in the iron-rich Sv129/J strain. Increased body iron content protects these mice from anemia and, in basal conditions, Sv129/J Ncoa4-ko mice show only microcytosis; nev- ertheless, when fed a low-iron diet they develop a more severe anemia compared to that of wild-type animals. Reciprocal bone marrow (BM) transplantation from wild-type donors into Ncoa4-ko and from Ncoa4-ko into wild-type mice revealed that microcytosis and susceptibility to iron deficiency anemia depend on BM-derived cells. Reconstitution of ery- thropoiesis with normalization of red blood count and hemoglobin con- centration occurred at the same rate in transplanted animals independ- ently of the genotype. Importantly, NCOA4 loss did not affect terminal erythropoiesis in iron deficiency, both in total and specific BM Ncoa4-ko animals compared to controls. On the contrary, upon a low iron diet, spleen from wild-type animals with Ncoa4-ko BM displayed marked iron retention compared to (wild-type BM) controls, indicating defective macrophage iron release in the former. Thus, erythropoietin administra- tion failed to mobilize iron from stores in Ncoa4-ko animals. Furthermore, Ncoa4 inactivation in thalassemic mice did not worsen the hematologic phenotype. Overall our data reveal a major role for NCOA4-mediated ferritinophagy in macrophages to favor iron release for erythropoiesis, especially in iron deficiency.
Introduction
Nuclear receptor coactivator 4 (NCOA4), originally identified as an androgen receptor interactor,1 is a novel player in iron metabolism contributing to the regu- lation of cell and systemic iron homeostasis. NCOA4 acts as a cargo receptor that promotes “ferritinophagy”, the selective autophagy-mediated degradation of the iron storage protein ferritin.2,3 This process is induced in conditions of iron deficien- cy to facilitate iron recovery from intracellular stores.4,5
As expected, inactivation of Ncoa4 increases cell ferritin aggregates2-4 and C57BL/6 Ncoa4-knockout (ko) mice show ferritin and iron accumulation in several organs, in particular splenic macrophages.3,6 In addition, they display a mild micro- cytic anemia and develop a more severe anemia than wild-type (wt) mice when fed
Correspondence:
FRANCESCA CARLOMAGNO
francesca.carlomagno@unina.it
LAURA SILVESTRI
silvestri.laura@hsr.it
Received: October 30, 2019. Accepted: February 25, 2020. Pre-published: February 27, 2020.
https://doi.org/10.3324/haematol.2019.241232
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