Multiple Proton Translocation Paths Reveal a Novel Function of Ferritin as a Source of Protons for Cellular Metabolism

Ferritin stores iron as Fe[Formula: see text] after being oxidized in the presence of molecular oxygen. The Fe[Formula: see text] ions typically enter into the ferroxidase as hexahydrate, where the oxidation of Fe[Formula: see text]to Fe[Formula: see text] occurs. The studies predict probable residues involved in the entry of molecular oxygen by sequence and structural comparison with other proteins. This study identified the probable [Formula: see text]-H paths for electron transfer and proton translocation in ferritin through structural analysis. The identification of multiple proton translocation paths and the use of hexahydrate iron as substrate by ferritin indicate that during the oxidation of Fe[Formula: see text] to Fe[Formula: see text], all the water molecules of iron may be utilized. The resulting byproducts, protons and hydroxyl ions may be one of the sources for the proton gradient required to drive oxidative phosphorylation by electron transport complexes in mitochondria. Also, it may be required to acidify lysosomes and generate nitroperoxy species.