Labile Iron: Potential Toxicity in Iron Overload Disorders

Iron homeostasis relies on a regulated network of systemic and cellular mechanisms for the acquisition, transportation and cellular utilization of the metal.¹ Once in inner body fluids, iron is swiftly captured by a chemically shielded vehicle (transferrin) that circulates and safely delivers it to cells commensurate with their metabolic needs. In the cellular milieu, most of the iron is also protein-associated, either directly or via heme or iron-sulfur-cluster moieties. However, the biosynthesis of these groups depends to a large extent on the availability of a basal level of redox-active and mobilizable iron, which we define as labile cell iron (LCI), often also referred as the labile iron pool.² The obligatory maintenance of a physiological level of labile iron is not devoid of potential liabilities, as labile iron has the capacity to catalyze the conversion of natural reactive oxygen intermediates (ROIs) of the respiratory chain (e.g., O2-·and H2O2) to noxious reactive oxygen species (ROS; e.g., OH·) that can damage proteins, lipids, and nucleic acids. This creates a continuous burden on cells to swiftly eliminate ROIs by enzymatic reactions (superoxide dismutase, peroxidases, and catalases) aided by reducing/antioxidant agents such as glutathione and the cellular reductants NADPH and NADH. Moreover, being devoid of extrusion tools to relieve themselves of iron, cells must cope with fluctuations in labile iron levels by balancing iron intake according to utilization, and also by producing the requisite amount of ferritin units to absorb “surplus” labile iron (Figure).