Abstract
Iron and oxygen share a delicate partnership since both are indispensable for survival, but if the partnership becomes inadequate, this may rapidly terminate life. Virtually all cell components are directly or indirectly affected by cellular iron metabolism, which represents a complex, redox-based machinery that is controlled by, and essential to, metabolic requirements. Under conditions of increased oxidative stress—i.e., enhanced formation of reactive oxygen species (ROS)—however, this machinery may turn into a potential threat, the continued requirement for iron promoting adverse reactions such as the iron/H2O2-based formation of hydroxyl radicals, which exacerbate the initial pro-oxidant condition. This review will discuss the multifaceted homeodynamics of cellular iron management under normal conditions as well as in the context of oxidative stress.
Highlights
Iron and oxygen share a delicate partnership since both are indispensable for survival, but if the partnership becomes inadequate, this may rapidly terminate life
Metabolic requirements focus on proper iron supply for the mitochondrial synthesis of heme and iron-sulfur (Fe-S) clusters, functional groups which are indispensable for cell function and serve as central determinants of cellular iron “handling”
heme-oxygenase I (HO-I) and ferritin are concomitantly upregulated in cells exposed to oxidative stress [191,192], and cytosolic iron overload caused by an excessive, HO-I-based heme-degradation such as seen in malaria may be antagonized by the up-regulation of H-ferritin [193]
Summary
Ferric iron or iron contained in heme is absorbed by intestinal enterocytes via heme carrier proteins (HCP1) [1], the divalent metal transporter DMT1 (SLC11A2) [2,3] or the integrin-mobilferrin pathway [4,5]. The relase of iron-loaded ferritin could represent a non-orthodox mechanism to avoid iron overload in cells that do not express Fpn or Fpn is inhibhited by high hepcidin levels which is accompanied by increased serum ferritin levels [56]. Diseased states are accompanied by pathological changes of serum ferritin levels such as anemia-based hypoferritinemia [68,69] and the hyperferritinemia frequently associated with infection, inflammation and malignancy [21,64,68,70,71], which potentially complicates serum ferritin-based assessment of the body iron status [72] Albeit this points at a role of extracellular ferritin in cellular and systemic iron homeodynamics and evidence is increasing for a participation of serum ferritins in systemic stress responses (see Section 2.2), our understanding of the biological significance of ferritin secretion and uptake still is incomplete
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