Iron Overload Generates Reactive Oxygen Species With Fenton Reaction

Iron is an essential metal ion that affects different mechanisms in the intracellular and extracellular systems. The adjective essential is coming from the fact that iron is a cofactor of certain enzymes, which includes ATP production and DNA synthesis1. Concurrently, iron homeostasis must be regulated tightly due to any imbalance might lead to critical consequences. Many neurodegenerative diseases, such as Parkinson’s Disease (PD) and Alzheimer’s Disease, lead to iron accumulation in specific parts of the brain and cause several dysfunctions within2.  In both diseases, oxidative stress plays a crucial role.  The accumulated metal ions are open to being oxidized and become a reactive oxygen species (ROS). The created ROS (mainly hydroxyl ions) generate oxidative stress thus lead several types of cellular dysfunction and eventually ending with cellular death3. Regulation of oxidative stress, especially during the disease’s process, is important for understanding the mechanisms behind these metabolisms and useful for relaxing the disease’s symptoms by several methods.

Figure 1: Illustration of Fe (derived from the diet) uptake mechanism by the Enterocyte [1].

Iron from diet comes in Fe+3 (ferric ion) form and is reduced to Fe+2 (ferrous ion) just before DMT1, an iron transporter, intakes it into the enterocyte. Ferritin is a cytosol protein that is responsible for iron storage, so the accumulated Fe+2 is stored inside of it. Ferritin consists of a spherical protein shell and can fit almost 4500 iron molecules1.  When blood iron concentration is low, the Fe+2 can be oxidized back into Fe+3 and released via iron exporter Ferroportin. Transferrin (Tf) is a glycoprotein that can bind into two Fe+3 ions. It is a serum protein this functions as mainly transportation1. Released Fe+3 ions are associated with apo-Tf and leading the creation of Diferric-Tf (Transferrin that bounded into two Fe+3 ions). Regulation of iron exportation is mediated by hepcidin. Hepcidin is synthesized by the liver, and a high level of Fe in the liver or inflammatory cytokine increases transcription of hepcidin thus decreasing Fe release from the enterocyte for preventing further iron accumulation1.

Accumulation of iron can be observed in specific brain regions and is associated with many neurological diseases, such as PD, AD, and Huntington’s disease. These neurological diseases mostly occur because of neurodegeneration, which can be explained by either loss of structure or function of neurons. It is stated that iron accumulation within cells is one of the main reasons for neurodegeneration. With a basic example, overexpression of hepcidin decreases the exportation of Fe, so it provokes iron overload and eventually neurodegeneration4. The neurodegeneration via iron overload can be explained in detail especially with metabolically active Fe in mitochondria. Iron is found on considerable levels in mitochondria for heme (one form of dietary iron, composed group of enzymes and Fe+2 ion4) and Fe-S cluster synthesis. The regulation of mitochondria’ iron level is mediated by mitochondrial ferritin and its distribution is quite common1. To approach this issue therapeutically, iron chelators are agents that are used for the regulation of redox-active-free irons. These metal chelations cause the irons to bind to their high-affinity binding site, thus preventing any toxicity reaction by basically not letting ions roam freely5. From the perspective of PD, chelation agents are used for balancing iron metabolism within the brain. To succeed, the user agent must successfully pass through the blood-brain barrier (BBB). Plus, they must be able to specifically bind the metal ions, at least it must be the preferred one (in that case, it must be able to specifically bind to iron ions)5.

PD studies focused on mitochondria and their energy metabolism. As an example, for its iron chelation ability, lactoferrin is used for decreasing the neurodegeneration rate of PD patients. When the cells are exposed to a low level of oxidative stress, lactoferrin, as an iron chelator, relieved potential cell damage and relaxed the symptoms of PD by protecting the cells from ROS damage as an iron scavenging ability6. (Unfortunately, the external explanation of the mechanism and methods behind this is not the main subject of this article. For further information, related research and review articles can be examined.) PD is a neurodegenerative disorder that is diagnosed with the death of dopaminergic neurons of the substantia nigra. Death of the dopaminergic neurons led to a decrease in the released neurotransmitter dopamine levels7. These dopaminergic neurons are open for degeneration due to their high requirement of energy and extensive branching. To replenish its energy demand and precise dopamine secretion, iron is essential for the neurons. This means that these cells need a high amount of iron, consistently, to function properly. Consequently, this need might lead to a dangerous reaction, known as the Fenton reaction.

Figure 2: Equation of Fenton and Fenton-like reaction8. Fenton reaction is clarified as the oxidation of a ferrous ion into a ferric ion, whereby reduces hydrogen peroxide into a hydroxyl ion. Hydrogen peroxide (H2O2) is produced within the cell by dopamine metabolism and the electron transfer chain. So, the iron that is normally aimed for usage for essential reactions might generate hydroxyl radicals through the Fenton reaction with a reduction of H2O2, and increased oxidative stress damaging the cell itself [4,7].

Hereby, iron is found in different tissues as in free or stored forms. In free form, iron can easily be oxidized or reduced to form highly active oxygen species. So, the uptake and release of iron are tightly regulated for preventing these kinds of molecule formation. Dysregulation of the iron metabolism alters the Fe+2 and Fe+3 ratio to abnormal levels, which herewith causes oxidative stress to disturb cellular membranes and tissues. As an illustration, iron chelators are currently being used for regulating iron metabolism in several diseases for treatment and relieving their symptoms. Comprehending iron metabolism might be the key to treatments, notably neurodegenerative diseases.

References:

  1. Richardson DR. Molecular Mechanisms of Iron Uptake by Cells and the Use of Iron Chelators for the Treatment of Cancer. Curr Med Chem. 2005;12(23):2711-2729. doi:10.2174/092986705774462996
  2. Leveugle B, Faucheux BA, Bouras C, et al. Cellular distribution of the iron-binding protein lactotransferrin in the mesencephalon of Parkinson’s disease cases. Acta Neuropathol. 1996;91(6):566-572. doi:10.1007/s004010050468
  3. Sokolov A V., Miliukhina I V., Belsky YP, Belska N V., Vasilyev VB. Potential role of lactoferrin in early diagnostics and treatment of Parkinson’s disease. Med Acad J. 2020;20(1):37-44. doi:10.17816/maj33848
  4. Uranga RM, Salvador GA. Unravelling the Burden of Iron in Neurodegeneration: Intersections with Amyloid Beta Peptide Pathology. Oxid Med Cell Longev. 2018;2018. doi:10.1155/2018/2850341
  5. Hider RC, Ma Y, Molina-Holgado F, Gaeta A, Roy S. Iron chelation as a potential therapy for neurodegenerative disease. Biochem Soc Trans. 2008;36(6):1304-1308. doi:10.1042/BST0361304
  6. Rousseau E, Michel PP, Hirsch EC. The iron-binding protein lactoferrin protects vulnerable dopamine neurons from degeneration by preserving mitochondrial calcium homeostasis. Mol Pharmacol. 2013;84(6):888-898. doi:10.1124/mol.113.087965
  7. Nunez MT, Chana-Cuevas P. New perspectives in iron chelation therapy for the treatment of Parkinson’s disease. Neural Regen Res. 2019;14(11):1905-1906. doi:10.4103/1673-5374.259614
  8. Ranji-Burachaloo H, Gurr PA, Dunstan DE, Qiao GG. Cancer Treatment through Nanoparticle-Facilitated Fenton Reaction. ACS Nano. 2018;12(12):11819-11837. doi:10.1021/acsnano.8b07635

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