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

作者：Naiara Santana-Codina, Sebastian Gableske, Maria Quiles del Rey, Beata Małachowska, Mark P. Jedrychowski, Douglas E. Biancur, Paul J. Schmidt, Mark D. Fleming, Wojciech Fendler, J. Wade Harper, Alec C. Kimmelman, Joseph D. Mancias · 发表于：Haematologica · 年份：2019 · DOI：10.3324/haematol.2018.204123 · 被引用次数：57 · 研究领域：Iron Metabolism and Disorders、Hemoglobinopathies and Related Disorders、Autophagy in Disease and Therapy

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.