Send to

Choose Destination
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

Division of Genomic Stability and DNA Repair, Department of Radiation Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
Department of Biostatistics and Translational Medicine, Medical University of Lodz, Poland.
Postgraduate School of Molecular Medicine, Medical University of Warsaw, Poland.
Department of Cell Biology, Harvard Medical School, Boston, MA, USA.
Department of Pathology, Boston Children's Hospital and Harvard Medical School, Boston, MA, USA.
Department of Radiation Oncology, Perlmutter Cancer Center, New York University School of Medicine, New York, NY, USA.
Division of Genomic Stability and DNA Repair, Department of Radiation Oncology, Dana-Farber Cancer Institute, Boston, MA, USA


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.

Supplemental Content

Full text links

Icon for HighWire Icon for PubMed Central
Loading ...
Support Center