Oxidative stress and the homeodynamics of iron metabolism

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.

Keywords: iron; metabolism; oxidative stress.

Figure 1

Cellular iron flux. Iron is transferred between communicating “labile iron pools” of the endo-/lysosomal system (ELIP), the cytosol (CLIP) and the mitochondria (MLIP). The ELIP represents the main entry site for extracellular iron such as transferrin bound iron (Fe-Tf) taken up via the TfR. Alternatively, iron containing serum ferritin may also enter the ELIP via receptor-mediated endocytosis (RME). Iron can exit from the ELIP via specific channels (DMT-1, Zip14, TRPML1) and is buffered in the cytosol (CLIP) by ferritin. Iron release from ferritin can occur via proteasomal degradation (PS) or lysosomal digestion upon autophagy (AP). Transfer of iron to the MLIP involves the iron transporter mitoferrin. The shuttling of “endosomal iron” (ES) to mitochondria by a “kiss and run” mechanism (K/R) as well as a hypothetical direct iron uptake from cytosolic ferritin has also been proposed. Note that iron can be buffered in the MLIP by mitochondrial ferritin. Ferroportin (Fpn) serves iron exit, the exact transfer mechanism not yet being resolved [39]. Fe-S clusters and heme, released from the mitochondria via ABCB7 transporter as well as labile, non-bound cytosolic iron serve as iron sensors for cytosolic IRPs. IRPs regulate the cellular labile iron pool via translational control of several iron-metabolism related proteins such as TfR, ferritin and ferroportin (Fpn). Alternative iron fluxes include heme-oxygenase 1 mediated iron liberation as well as ferritin endocytosis, transcytosis and exocytosis (EXO). The uptake of heme and extracellular NTBI is not shown. Red circles symbolize the relative iron binding capacities.

Figure 2

Iron homeodynamics and stress conditions. Cell integrity and stress tolerance demands a balanced LIP between 0 (iron depletion) and 100% (maximum loading). Under normal conditions (blue range) the LIP is controlled by IRP-2 abundance, IRP-1 preferentially exerting c-aconitase activity depending on Fe-S cluster conformation. Moderately enhanced oxidative stress will promote Fe-S cluster decomposition (see p. 820), while severe pro-oxidant regimens as well as iron overload (OVL) lead to IRP-1 degradation. Iron import via TfR and ferritin-based iron buffering control the LIP in opposite directions depending on the actual iron content and oxidant conditions (Output). It is hypothesized that ferritin exo- and endocytosis serve the “emergency control” of the LIP under conditions of either severe (or chronic) iron overload and oxidative stress or massive iron depletion, respectively.