Page 64 - 2019_07 resto del Mondo-web

Ferrata Storti Foundation
Haematologica 2019 Volume 104(7):1342-1354
Red Cell Biology & its Disorders
NCOA4 maintains murine erythropoiesis via cell autonomous and non-autonomous mechanisms
Naiara Santana-Codina,1,* Sebastian Gableske,1,* Maria Quiles del Rey,1 Beata Małachowska,2,3 Mark P. Jedrychowski,1,4 Douglas E. Biancur,1
Paul J. Schmidt,5 Mark D. Fleming,5 Wojciech Fendler,1,2 J. Wade Harper,4,# Alec C. Kimmelman6,# and Joseph D. Mancias1
1Division of Genomic Stability and DNA Repair, Department of Radiation Oncology, Dana- Farber Cancer Institute, Boston, MA, USA; 2Department of Biostatistics and Translational Medicine, Medical University of Lodz, Poland; 3Postgraduate School of Molecular Medicine, Medical University of Warsaw, Poland; 4Department of Cell Biology, Harvard Medical School, Boston, MA, USA; 5Department of Pathology, Boston Children’s Hospital and Harvard Medical School, Boston, MA, USA and 6Department of Radiation Oncology, Perlmutter Cancer Center, New York University School of Medicine, New York, NY, USA
* These authors contributed equally to this work
ABSTRACT
Ncoa4 mediates autophagic degradation of ferritin, the cytosolic iron storage complex, to maintain intracellular iron homeostasis. Recent evidence also supports a role for Ncoa4 in systemic iron homeostasis and erythropoiesis. However, the specific contribution and temporal impor- tance of Ncoa4-mediated ferritinophagy in regulating systemic iron home- ostasis and erythropoiesis is unclear. Here, we show that Ncoa4 has a critical role in basal systemic iron homeostasis and both cell autonomous and non- autonomous roles in murine erythropoiesis. Using an inducible murine model of Ncoa4 knockout, acute systemic disruption of Ncoa4 impaired sys- temic iron homeostasis leading to tissue ferritin and iron accumulation, a decrease in serum iron, and anemia. Mice acutely depleted of Ncoa4 engaged the Hif2a-erythropoietin system to compensate for anemia. Mice with tar- geted deletion of Ncoa4 specifically in the erythroid compartment developed a pronounced anemia in the immediate postnatal stage, a mild hypochromic microcytic anemia at adult stages, and were more sensitive to hemolysis with higher requirements for the Hif2a-erythropoietin axis and extramedullary erythropoiesis during recovery. These studies demonstrate the importance of Ncoa4-mediated ferritinophagy as a regulator of systemic iron homeostasis and define the relative cell autonomous and non- autonomous contributions of Ncoa4 in supporting erythropoiesis in vivo.
Introduction
Iron is an essential element for life, required in a diverse set of processes including oxygen binding and transport,1 electron transport,2 and DNA synthesis and repair.3,4 The majority of cellular iron is stored in ferritin, the cellular iron storage complex composed of 24 subunits of ferritin light and heavy chain subunits (FTL, FTH1) that can chelate up to 4,500 iron atoms in a non-toxic ferrihydrite mineral core.5 Iron can be released from ferritin via a process termed ‘ferritinophagy’.6,7 FTH1 is bound by NCOA4 (Nuclear Receptor Coactivator 4) and transported to an autophagosome that fuses with a lysosome for ferritin degradation and iron release.8 NCOA4-medi- ated ferritinophagy is responsive to alterations in cellular iron levels to promote fer- ritinophagy under iron-depleted conditions or decrease ferritinophagy when iron is abundant in the cell.8
Given the established importance of NCOA4 in intracellular iron homeostasis, the role of NCOA4 in the response to systemic iron deficiency, and, particularly, its role in the pathophysiology of iron deficiency in anemia, has been of interest. Recent data from in vitro model systems of human, mouse, and zebrafish erythropoiesis support
Correspondence:
JOSEPH D. MANCIAS
joseph_mancias@dfci.harvard.edu
Received: August 10, 2018. Accepted: January 9, 2019. Pre-published: January 10, 2019.
doi:10.3324/haematol.2018.204123
Check the online version for the most updated information on this article, online supplements, and information on authorship & disclosures: www.haematologica.org/content/104/7/1342
©2019 Ferrata Storti Foundation
Material published in Haematologica is covered by copyright. All rights are reserved to the Ferrata Storti Foundation. Use of published material is allowed under the following terms and conditions: https://creativecommons.org/licenses/by-nc/4.0/legalcode. Copies of published material are allowed for personal or inter- nal use. Sharing published material for non-commercial pur- poses is subject to the following conditions: https://creativecommons.org/licenses/by-nc/4.0/legalcode, sect. 3. Reproducing and sharing published material for com- mercial purposes is not allowed without permission in writing from the publisher.
1342
haematologica | 2019; 104(7)
ARTICLE