Redox homeostasis

Iron chelators can also be used to selectively bind iron in areas where oxidative stress is observed, thereby preventing the iron from taking part in Fenton reactions without interfering with normal iron homeostasis. Charkoudian et al. have developed boronic acid and boronic ester masked prochelators, which do not bind metals unless exposed to hydrogen peroxide (237,238). The binding of these chelators to iron(III) prevents redox cycling. Similar studies of these systems have been performed by a separate group (239,240). 

Figure 18.6 Schematic representation of the physiological role of prion protein (Prpc) in copper homeostasis and redox signalling. (From Crichton and Ward, 2006. Reproduced with permission from John Wiley Sons., Inc.)...

There is considerable evidence that defective homeostasis of redox-active metals, i.e. iron and copper, together with oxidative stress, contributes to the neuropathology of AD. The characteristic histology of AD is the deposition of both Ap, as neurotic plaques (Figure 18.12a), and of the protein tau, as neurofibrillary tangles NFT (Figure 18.12b), predominantly in the cerebral cortex and hippocampus. 

In many crucial biological processes, such as oxygen transport, electron transport, intermediary metabolism, metals play an important part. Therefore, disorders of metal homeostasis, metal bioavailability or toxicity caused by metal excess, are responsible for a large number of human diseases. We have already mentioned disorders of iron metabolism (see Chapter 7) and of copper metabolism (see Chapter 14). The important role, particularly of redox metals such as copper and iron, and also of zinc, in neurodegenerative diseases, such as Parkinson s disease, Alzheimer s disease, etc. has also been discussed (see Chapter 18). We will not further discuss them here. 

A considerable number of transcription factors have reactive cysteine residues, which enable them to respond to the redox conditions in the cell. Since cadmium perturbs redox homeostasis, it can affect this class of transcription factors. If cadmium can displace the tetra-coordinate zinc atoms in zinc finger-containing transcription factors, it will affect them as well. Many of the pathways involving activation and inactivation of transcription factors involve kinases and phosphatases, themselves under the intricate control of calcium fluxes. It is therefore no surprise that cadmium will exert effects on the activity of transcription factors, the activation of proto-oncogenes, and thereby on gene expression (Figure 20.8i and i ). 

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. 

Chapter 7 has reported on the importance of iron in biological species. Because iron is the most abundant transition metal found in biological species, one would expect a wide variety of iron-containing proteins and metalloenzymes. Only a few of these have been treated in any detail in this chapter. Little or no mention has been made of how or why iron ions evolved to be the most biologically abundant transition metal ions probably their usefulness in redox situations and for electron transport has something to do with their popularity. Iron homeostasis in biological species has not been discussed, although this... 

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.

There are specific fiuorescent dyes for specific pathologies created by specific drug classes, such as phospholipidosis from cationic amphiphilic drugs [18, 19], mitochondrial DNA depletion by nucleoside reverse transcriptase inhibitors that also inhibit mitochondrial DNA polymerase gamma and redox cyclers that produce reactive oxygen species. The complex mechanism of statin-induced toxicity is demonstrated vith early sublethal effects on apoptosis, mitochondrial function and calcium homeostasis [20]. 

Calabrese V, Colombrita C, Scapagnini G, Calvani M, Giuffrida Stella AM. Butterfield DA. 2006a. Acetylcamitine and cellular stress response Role in nutritional redox homeostasis and regulation of longevity genes. J Nutr Biochem 17 73-88. 

Multiminicore disease may also result from mutations in another protein found in the lumen of the ER/SR, selenoprotein N (Ferreiro 2002b). The function of selenoprotein N is currently unknown but may be to participate in regulation of redox homeostasis. An intriguing question is the relationship between RyRl and selenoprotein N such that mutations in either protein can produce similar changes in muscle structure and function. 

P17. Popov, I., Volker, H., and Lewin, G., Photochemiluminescent detection of antiradical activity. V., Application in combination with the hydrogen peroxide-initiated chemiluminescence of blood plasma proteins to evaluate antioxidant homeostasis in humans. Redox Rep. 6,43—48 (2001). 

Betaine is used in liver diseases to combat alcoholic cirrhosis. Betaine may also be valuable in the treatment of disorders of the skin. The underlying mechanisms of the action of betaine are not clear, but it has recently been suggested that they may play a role in the maintenance of redox homeostasis.4... 

The IRP-1 is present at similar levels in both AD and control brains. In contrast, IRP-2 co-localizes with redox-active Fe in NFT, senile plaque neurites, and neuropil threads. Hence, alterations in IRP-2 might be directly linked to impaired iron homeostasis in AD [28]. 

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