Iron is essential for nearly all living organisms, and serves as a native cofactor for hundreds of mammalian proteins. Conversely, free iron is redox-active and thus can potentially damage cells by producing reactive oxygen species. Hence, cells must coordinately regulate the import, export, and storage of iron based on their physiological iron demand. Recently, NCOA4 was characterized as a selective autophagic cargo receptor for ferritin, mediating the release of stored iron via ferritinophagy. In erythroid progenitors, NCOA4 is highly upregulated by iron deficiency and during hemoglobinization. Yet, how NCOA4 contributes to cellular iron regulation in other tissues remains unclear. Reticuloendothelial macrophages (REM) recycle iron from effete erythrocytes and thereby serve as a primary iron source for red cell production, while neuronal cells represent a population of iron utilization. Employing J774 macrophages and HT-22 hippocampal cells, we studied the roles of NCOA4 in these two distinct cell types integral to whole body iron metabolism. Initially, we identified hypersensitivity of the neuronal cells to excess iron. The acute iron-induced cell death accompanied by biomarker changes reflecting ferroptosis was inhibited by ferrostatin-1. Both neuronal and macrophage cells effectively handled iron restriction until NCOA4 was co-depleted. Cells with insufficient NCOA4 featured higher ferritin levels but lower viability when extracellular iron was deprived. Proteomic profiling of HT-22 cells confirmed functional iron deficiency by NCOA4 depletion. To recapitulate the iron-recycling REM, J774 cells were fed opsonized erythrocytes. Upon erythrophagocytosis, macrophages produced temporal changes in ferritin protein abundance, which were NCOA4-dependent. Moreover, hepcidin, the central regulator for systemic iron homeostasis, and lipopolysaccharide caused repression in NCOA4 expression by macrophages. Collectively, we identify NCOA4-mediated ferritinophagy as a survival mechanism for neurons and macrophages to cope with iron deficiency, and its regulation by cues of systemic iron and inflammatory status in macrophages. These suggest that dysregulated ferritinophagy may have pathogenic implications on the development of neurodegeneration and inflammatory diseases, such as anemia of chronic disease.

NCOA4-mediated ferritinophagy: Linking cellular iron storage with systemic iron homeostasis and inflammation

2019 Fall National Meeting

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