The Role Of The Labile Iron Pool In Free Radical Production

The labile iron pool within cells is defined as a pool of redox-active, mostly low molecular weight iron complexes, originally proposed to be a pool of iron in transit between extracellular and intracellular forms of iron. Operationally, it is a pool of chelatable iron, both Fe2+ and Fe3+, associated with a diverse population of ligands such as organic anions (phosphates and carboxylates), polypeptides, and surface components of membranes (e.g., phospholipid head groups) [13]. This means that the LIP can participate in redox-cycling, with clear implications for production of reactive oxygen species, notably hydroxyl radical, and that it can be scavenged by chelators which are able to penetrate the cell. The levels of LIP in cultured cells are maintained within a relatively narrow range of concentrations [20,21], in the interests of cellular iron homeostasis, allowing the cells to meet their metabolic requirements for iron while maintaining their potential for ROS formation at an appropriate level. Logically, cytosolic LIP levels will be sensed by the IRPs [19] and, subsequently, readjusted; when LIP levels are low, the IRPs will up-regulate iron uptake via the transferrin receptor and the endosomal transmembrane cation transporter DMT 1 while downregulating the synthesis of the intracellular iron storage protein, ferritin; when LIP levels are high in iron repletion, IRPs will be inactivated, leading to increased translation of ferritin and down-regulation of the iron importer proteins.

The LIP reflects the readily available iron within the cell and is believed to be the key regulator of internal and external iron exchange, and its labile nature is underlined by its capacity to promote the formation of reactive oxygen species, levels of LIP and ROS following similar 'rises and falls' as a function of cellular iron homeostasis. For example, it was shown that accompanying rising LIP levels there was a demonstrable rise in ROS production, lipid peroxidation, and eventual cell death [22]. Using repression of ferritin synthesis it was shown that the upregulation of steady state LIP significantly increased protein oxidation [23].

The production of both ROS and RNS (including nitric oxide and peroxyni-trite) results in covalent modification of proteins by products of lipid peroxidation including acrolein and 4-hydroxy-2 nonenal (HNE), involving Michael addition (Figure 7) to lysine, cysteine and histidine residues[24]. The ROS/RNS induced

Protein

Protein

Protein

Protein

Protein

Figure 7. The Michael-type addition of 4-hydroxy-2 nonenal to proteins. X: the sulfhydryl group of cysteine, the imidazole group of histidine or the amino group of lysine. (Reproduced with permission from [24]).

protein misfolding finally results in the formation of protein aggregates. On account of ineffective functioning of the cytoplasmic protein elimination system, involving ubiquitination and digestion by the proteasome (Figure 8), this leads to the formation of the typical intracellular inclusion bodies which are the postmortem hallmark of many neurodegenerative diseases.

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