NCOA4 deficiency impairs systemic iron homeostasis

NCOA4 has been recently identified as a cargo receptor mediating autophagic ferritin degradation. Here, we show that NCOA4 deficiency in a knock out mouse model leads to iron accumulation in liver and spleen, pointing to a systemic alteration of iron homeostasis. Null mice show increased levels of transferrin saturation, serum ferritin and liver hepcidin with decreased duodenal ferroportin. Although NCOA4 null mice display iron overload signs, they suffer from a mild microcytic hypochromic anaemia. Under an iron-deprived diet regimen (2-3 mg/kg), they fail to release iron from ferritin storages and rapidly develop a severe microcytic hypochromic anaemia, with ineffective erythropoiesis associated with increased erythropoietin levels. On the contrary, when fed with an iron-enriched diet (2 gr/kg), knock out mice die prematurely, featuring signs of liver damage. In primary embryonic fibroblasts from NCOA4 null mice, the absence of NCOA4 protein induced accumulation of ferritin impeding its targeting to autophagosomes; the adoptive expression of NCOA4 COOH-terminal portion (aa 239-614) was sufficient to restore this function. All together these data suggest that NCOA4 plays a central role in balancing iron levels in vivo by controlling ferritin turnover to prevent excessive iron accumulation and ensure an efficient erythropoiesis.