NCOA4 impairs systemic iron homeostasis

NCOA4 protein is involved in iron metabolism. Indeed, under low iron conditions, NCOA4 accumulates and promotes, as cargo receptor, the autophagic degradation of the iron-storage macromolecule ferritin. This process, called ferritinophagy, is critical to restore the appropriate cellular iron levels and could impair systemic iron homeostasis. Consistently, we have demonstrated that mice carrying genetic ablation of NCOA4 were unable to mobilize iron from deposits, featuring tissue iron overload as well as mild anemia. Because of impaired ferritinophagy, NCOA4 null mice displayed a severe mycrocitic hypocromic anemia and ineffective erythropoiesis when fed with an iron low diet. Conversely, they poorly tolerated an iron rich diet, dying prematurely for iron toxicity. Since in previous studies we discovered that nuclear NCOA4 is a chromatin binding protein that acts as a negative regulator of DNA replication origin activation, inhibiting the MCM2-7 DNA helicase, we also investigated whether NCOA4 could regulate DNA replication as a function of iron bioavailability. Treatment with iron chelators promoted a G1-arrest, blocking DNA replication origins activation. In cell fractionation experiments, we observed that iron depletion induced nuclear translocation of NCOA4, and by ChIP and co-immunoprecipitation assays we demonstrated that NCOA4 increased its binding to DNA replication origins and to MCM2-7 complex, respectively. Silencing of NCOA4 induced an unscheduled activation of DNA replication under iron-depleted conditions that promotes replication stress and reduction of cell viability. In conclusion, our data indicate NCOA4 as a novel inter player coupling DNA replication origin activation to cellular iron levels.