Iron homeostasis complex

Finally, the hairpin-like peptides, hepcidins, isolated from human urine and liver [120], and from the gill of hybrid striped bass [121], are more complex, with eight cysteine residues forming four disulphide bridges. They form an unusual distorted P-sheet. Interestingly, besides their antimicrobial activity, hepcidins are the principal hormonal-regulators of iron homeostasis in humans [124]. 

The precise mechanism(s) by which a non-classical MHC class I antigen or T lymphocytes can influence iron homeostasis remain(s) elusive. Recently it has been shown that the wild-type HFE protein forms a stable complex with the transferrin receptor (TfR) [23-25]. That association seems to lower the afiinity of transferrin for its receptor, a finding still under dispute (W. Sly, personal communication). The mutant protein regardless of the mutation apparently fails to lower that afiSnity. This would provide the first molecular basis for the greater iron loading of the hepatic cells, but not for the lack of iron overload seen in the intestinal epithelial cells or the macrophages of HH patients. 

Once in the serum, aluminium can be transported bound to transferrin, and also to albumin and low-molecular ligands such as citrate. However, the transferrrin-aluminium complex will be able to enter cells via the transferrin-transferrin-receptor pathway (see Chapter 8). Within the acidic environment of the endosome, we assume that aluminium would be released from transferrin, but how it exits from this compartment remains unknown. Once in the cytosol of the cell, aluminium is unlikely to be readily incorporated into the iron storage protein ferritin, since this requires redox cycling between Fe2+ and Fe3+ (see Chapter 19). Studies of the subcellular distribution of aluminium in various cell lines and animal models have shown that the majority accumulates in the mitochondria, where it can interfere with calcium homeostasis. Once in the circulation, there seems little doubt that aluminium can cross the blood-brain barrier. 

Figure 9.2. Mechanisms of aminoglycoside toxicity. This schematic representation summarizes the principles of aminoglycoside toxicity discussed in the text. Treatment with the drugs leads to the formation of reactive oxygen species through a redox-active complex with iron and unsaturated fatty acid or by triggering superoxide production by way of NADPH oxidase. An excess of reactive oxygen species, not balanced by intracellular antioxidant systems, will cause an oxidative imbalance potentially severe enough to initiate cell death pathways. Augmenting cellular defenses by antioxidant therapy can reverse the imbalance and restore homeostasis to protect the cell.

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