Relocation of Cell Iron. A Mode of Chelation with Application to Diseases of Regional Iron Accumulation.

Abstract

Iron raises to toxic levels in mitochondria of excitable cells in some forms of neuro-degeneration with brain accumulation (NBIA), in sideroblastic anemia and in Friedreich's ataxia (FA), often leaving the cytosol iron-depleted. In anemia of chronic disease (ACD) iron is withheld by macrophages, while iron levels in extracellular fluids (e.g. plasma) are drastically reduced. Although excessive iron deposition occurring in organs of iron overloaded (IO) patients can be reduced with iron chelators, it is uncertain whether this is applicable to conditions where iron accumulates within selected tissues/cells in the absence of systemic IO.Objective. We assessed whether deferiprone (DFP), a membrane-permeant bidentate chelator in clinical use for treating systemic IO, might serve as an iron relocating agent in settings of regional iron accumulation by a. capturing labile iron accumulated in cell compartments and b. conveying the chelated iron either to other cell locations for metabolic integration or to transferrin for systemic reutilization.Methods. DFP capacity to shuttle iron intracellularly and transcellularly was assessed in macrophages (J774) and heart (H9c2) cell models using organelle-targeted fluorescent iron-sensors in conjunction with fluorescence microscopy imaging. We employed pairs of sensors targeted to different cell compartments and iron-evoked quenching and chelator-evoked dequenching as means to trace DFP mediated iron transfer. Mitochondrial iron accumulation was generated with succinylacetone or by silencing genes affecting mitochondrial iron metabolism.Results. DFP facilitated iron transfer: a. from iron-laden cell organelles to other cell compartments or to medium (and vice versa) and b. from iron loaded macrophages to pre-erythroid MEL cells (for chemically induced hemoglobin synthesis) either directly or via transfer to extracellular transferrin.Discussion The results of this study indicate that relocation of cell accumulated iron can be used as a modality of chelation for treating conditions of regional iron accumulation by applying chelators able to permeate into cell compartments but also to transfer the chelated iron to cell acceptors or to the extracellular iron carrier transferrin.