Iron caught on the shuttle

New and convincing evidence is provided by Sohn et al, showing that iron chelators can not only shuttle across cellular membranes but also redistribute the metal to different cell populations to be used there for metabolic purposes. This opens the door to a number of new therapeutic applications for these drugs.

Iron chelators are clinically used to treat toxic iron accumulation; however, their ability to affect cellular iron shuttling has so far been poorly understood. In this issue of Blood, Sohn and colleagues applied real-time imaging methods to study cellular and transcellular iron traffic. They could thereby identify novel pathways by which the iron chelator deferiprone¹  can relocate iron from sites of regional iron accumulation to sites of iron consumption.

Due to its unique biological properties, iron is essential for life; however, systemic or cellular iron accumulation leads to the formation of toxic radicals and tissue damage, resulting in eventual organ failure as seen in primary and secondary iron-overload disorders and several rare hereditary diseases including Friedreich ataxia.^2,3  Although phlebotomy offers an effective and safe treatment for primary iron overload, toxic iron accumulation in secondary iron-overload disorders resulting from repeated blood transfusion for the treatment of genetic hemoglobinopathies such as thalassemia or sickle cell disease can only be targeted by application of iron-chelating drugs.^4,5  The ability of these drugs to bind and remove labile iron from the circulation, thus improving siderosis of affected organs such as the heart and liver, is well known. However, hardly any evidence has been provided so far as to how, and to what extent, iron chelators may also target intracellular iron depots.

Sohn et al demonstrate that deferiprone, a membrane-permeable chelator in clinical use, harbors the ability to shuttle iron between cellular organelles and across membranes. This is shown by their use of organelle-targeted iron-fluorescence sensors and real-time imaging of cells. Likewise, by a gradient-driven force that captures iron at sites of accumulation and transfers the metal from intracellular organelles to the extracellular space and vice versa, deferiprone can facilitate the intercellular and intracellular cargo of iron across membranes (see figure).

Most interestingly, the authors visualized the unique ability of deferiprone to relocate the metal from iron-loaded cells and make it accessible to erythroid precursors, where it then can be used for heme biosynthesis. Hypothetically, this property of membrane-permeable iron chelators could be used clinically, for example in the treatment of anemia of chronic disease, in which iron is trapped in monocytes/macrophages, thus resulting in iron-restricted erythropoisis.⁶  Although application of iron chelators for the treatment of anemia appears to be obscure, the redistribution of iron from these immune cells to circulating transferrin and subsequently to erythroid cells, as may occur with deferiprone, is a desirable therapeutic aim. In addition, organelle-specific iron capturing by membrane-permeable chelators may offer a new form of targeted therapy to elevate toxic iron accumulation, for example in mitochondria to treat Friedreich ataxia,⁷  and to get the iron across the blood-brain barrier and into the circulation. Further investigations are needed so that we might learn how to modify iron chelators chemically to fulfill these expectations.⁸