Molecular Mechanisms of Iron Metabolism and Overload in Sickle Cell Disease

Iron represents a vital element needed for normal physiologic functions across the body. A vast network of transporters is involved not only in uptake but in processing, oxidation and recycling to maintain this element in a tight balance to avoid excess storage. This complex network of transporters including heme and ferroportin among many others are responsible for facilitating inter-organ and tissue iron exchange, contributing to systemic heme homeostasis. Patients with genetic diseases such as sickle disease suffer from a chronic anemia due to the presence of an abnormal hemoglobin that requires, in most instances, a lifetime of red blood cell transfusions to overcome disease crises. These transfusions over time lead to a high iron exposure that results in a profound change to the physiology of organ systems at the cellular level requiring aggressive chelation. This exposure unfortunately leads to irreversible changes to these organs from the cardiovascular system and bone marrow, to the central nervous system. In the bone marrow, heme is synthesized, mainly within developing red blood cells, iron excess leads to impairments in cell production and differentiation due to processes needing a balanced intracellular heme concentration to prevent toxicity. In light of the extensive role of iron in the body, the aim of this review is to summarize the important metabolic pathways involved in iron homeostasis across a number of cell types and organ systems while contrasting these against effects caused by iron overload.