A novel mechanism for the uptake of enterobactin-chelated ferric ions by the mitochondria and subsequent reduction to ferrous ions inside

Abstract Conventional knowledge of mitochondrial iron metabolism talks about the export of iron in its doubly charged state once it is reduced inside the cell until it reaches the mitochondria. At physiological oxygen tension and pH 7.4, the comparatively soluble Fe(II) is easily available. Fe(III) hydrolyses to generate insoluble ferric hydroxides. Iron must be regularly chaperoned because of its near insolubility and potential toxicity due to redox activity. All tissues pick up iron through the binding of transferrin (Tf) to the transferrin receptor 1 (TfR1), followed by the complex’s internalisation through receptor-mediated endocytosis. The low pH created by the operation of a proton pump within the endosome reduces Tf’s affinity for iron. Importantly, the TfR1 promotes iron escape from Tf in the pH range (pH 5-5.5) reached by the endosome. A "trap," such as pyrophosphate, is needed in vitro for iron release from Tf. However, a physiological chelator that can play this role has not yet been discovered. Fe(III) is hypothesised to be reduced to Fe(II) in erythroid cells by a ferrireductase known as the six-transmembrane epithelial antigen of the prostate 3 in the endosomal membrane after being released from Tf in the endosome. Following this, the divalent metal transporter-1 (DMT1) transports Fe(II) through the endosomal membrane and, it is generally accepted that this generates the cytosolic labile or chelatable iron pool. This reservoir of iron is believed to provide the metal for metabolic requirements, including as iron intake by the mitochondrion for haem and ISC synthesis, as well as storage in the cytosolic protein ferritin. The possibility of Fe(III) entering the mitochondria has not been explored before. A series of dockings shows that binding of the alpha subunit to a complex of Fe(III) with enterobactin is as stable as the binding with of the same chelator with Fe(II). Enterobactin is a bacterial iron chelator thought to play an integral role in host iron metabolism. Our results suggest an interesting possibility of iron being trafficked to the mitochondria as Fe(III). We propose a potential mechanism of Fe(III) trafficking and subsequent reduction to Fe(II) inside the mitochondria.