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Haematologica. 2019 Jul;104(7):1342-1354. doi: 10.3324/haematol.2018.204123. Epub 2019 Jan 10.

NCOA4 maintains murine erythropoiesis via cell autonomous and non-autonomous mechanisms.

Author information

1
Division of Genomic Stability and DNA Repair, Department of Radiation Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
2
Department of Biostatistics and Translational Medicine, Medical University of Lodz, Poland.
3
Postgraduate School of Molecular Medicine, Medical University of Warsaw, Poland.
4
Department of Cell Biology, Harvard Medical School, Boston, MA, USA.
5
Department of Pathology, Boston Children's Hospital and Harvard Medical School, Boston, MA, USA.
6
Department of Radiation Oncology, Perlmutter Cancer Center, New York University School of Medicine, New York, NY, USA.
7
Division of Genomic Stability and DNA Repair, Department of Radiation Oncology, Dana-Farber Cancer Institute, Boston, MA, USA joseph_mancias@dfci.harvard.edu.

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 importance of Ncoa4-mediated ferritinophagy in regulating systemic iron homeostasis 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 systemic 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 targeted 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.

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