Further Elucidation of the Mechanism of Iron Transport Form Plasma Transferrin to Mitochondrial Ferrochelatase: Further Evidence for the “Kiss and Run” Hypothesis

Abstract

Normal hemoglobinization of immature red blood cells (RBC) requires iron (Fe) uptake from transferrin (Tf), mediated by Tf receptors (TfR). Following the binding of Fe(III)2-Tf to TfR on the erythroid cell membrane, the Tf-TfR complexes are internalized via endocytosis, following which Fe is released from Tf by a process involving endosomal acidification and reduction by Steap3. Fe2+ is then transported across the endosomal membrane by the divalent metal transporter 1 (DMT1). Unfortunately, the post-endosomal path of Fe within cells remains elusive or is, at best, controversial. It has been commonly accepted that a low molecular weight intermediate chaperones Fe in transit from endosomes to mitochondria and other sites of utilization; however, this much sought Fe binding intermediate has never been identified.