Ferritins are highly conserved supramolecular protein nanostructures to form shell-like protein structures of 24 subunits, within which thousands of iron atoms are stored as an insoluble inorganic ferric iron core. In-vitro, the mechanisms of iron oxidation and mineral core formation have been extensively investigated. There is a common understanding that the major pathway of iron mobilization from ferritin involves a lysosomal proteolytic degradation of ferritin and the dissolution of the iron mineral core. However, it is still unclear whether other auxiliary iron mobilization mechanisms involving physiological reducing agents and/or cellular reductases contribute to the release of iron from ferritin. In-vitro iron mobilization from ferritin in cell-free systems can be achieved using different reducing agents capable of easily reducing the ferritin iron core to produce soluble ferrous ions that are subsequently chelated by strong Fe(II)-chelating agents. However, the physiological significance of the iron reductive mobilization has not been proven. We report on experiments showing the presence of cell lysate significantly increases rates of the reductive mobilization of iron cations from ferritin by NADH or NADPH is greatly accelerated in comparison to buffered solutions. In contrast to the reductive mobilization of iron from ferritin catalyzed by flavins the cell lysate catalyzed process the concentration of dissolved oxygen shown only a moderate effect on the rate of the process. The process of iron mobilization is catalyzed by cellular oxidoreductase proteins, most likely flavoenzymes. The results of these experiments indicate that in living cells there is a continuous futile cycle of oxidation of cytosolic iron(II) cations by ferritin and their reductive mobilization by cytosolic NADH or/or NADPH. The concentration of labile iron cations in the cytosol is determined by relative rates of these two processes, the concentration of ferritin, and its iron loading.

Reductive mobilization of iron from ferritin in cell lysate

ACS Spring Meeting 2021

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