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Review
. 2022 Mar 25;23(7):3612.
doi: 10.3390/ijms23073612.

Iron Metabolism in Aging and Age-Related Diseases

Yao Tian  1 , Yuanliangzi Tian  1 , Zhixiao Yuan  1 , Yutian Zeng  1 , Shuai Wang  1 , Xiaolan Fan  1   2 , Deying Yang  1   2 , Mingyao Yang  1   2
Affiliations
Review

Iron Metabolism in Aging and Age-Related Diseases

Yao Tian et al. Int J Mol Sci. .

Abstract

Iron is a trace metal element necessary to maintain life and is also involved in a variety of biological processes. Aging refers to the natural life process in which the physiological functions of the various systems, organs, and tissues decline, affected by genetic and environmental factors VSports手机版. Therefore, it is imperative to investigate the relationship between iron metabolism and aging-related diseases, including neurodegenerative diseases. During aging, the accumulation of nonheme iron destroys the stability of the intracellular environment. The destruction of iron homeostasis can induce cell damage by producing hydroxyl free radicals, leading to mitochondrial dysfunction, brain aging, and even organismal aging. In this review, we have briefly summarized the role of the metabolic process of iron in the body, then discussed recent developments of iron metabolism in aging and age-related neurodegenerative diseases, and finally, explored some iron chelators as treatment strategies for those disorders. Understanding the roles of iron metabolism in aging and neurodegenerative diseases will fill the knowledge gap in the field. This review could provide new insights into the research on iron metabolism and age-related neurodegenerative diseases. .

Keywords: aging; iron chelator; iron metabolism; mitochondria; neurodegenerative diseases V体育安卓版. .

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Iron metabolism process in mammals. The absorption, circulation, storage, and regulation of iron collaborate closely together to maintain the iron homeostasis of organisms. Firstly, Fe3+ in gut lumen is reduced into Fe2+ by Dcytb positioned on the parietal membrane of intestinal epithelial cells, then transported into the iron pool in the cytoplasm through DMT1. A part of iron forms ferritin for storage, and excess iron is transported out of the cells through FPN of the basal lateral membrane, then it is oxidized into Fe3+ by Cp. Fe3+ can combine with transferrin in plasma and transport to other tissues requiring iron through blood circulation. In tissues, after combining with transferrin receptor on the surface of the tissue needing iron, protein complex Tf-TfR1 enters cells through endocytosis. The acidification of early endosomes will change the conformation of Tf-TfR1 and promote the release of Fe3+. This acidification is mainly supported by the V-ATPase on the endosome through proton exchange. Fe3+ is then reduced to Fe2+ by STEAP3 and then enters cytoplasm through DMT1 for utilization. One part of the iron can be stored as ferritin, while other part of iron can enter the mitochondria for the synthesis of iron–sulfur clusters and heme, and the rest of iron is transported out of the cells through FPN. In iron deficiency, the IRPs bind to the IREs, protecting the TfR mRNA from nuclease digestion and preventing the synthesis of ferritin. When iron is abundant, the modified IRP no longer binds to the IREs, making TfR mRNA to be destroyed and allowing the expression of ferritin. Dcytb, Duodenal cytochrome b; DMT1, Divalent metal-ion transporter 1; FPN, Ferroportin; Cp, Ceruloplasmin; V-ATPase, vacuolar H+-ATPase; STEAP, Six-transmembrane epithelial antigen of prostate 3.
Figure 2
Figure 2
Relationship between iron and aging at the molecular, cellular, organ, and individual levels. At the molecular level, excessive iron in cells can participate in the Fenton reaction to generate ROS, resulting in damage to biological macromolecules and leading to aging. At the cellular level, defects in heme and iron–sulfur cluster biosynthesis in mitochondria with aging can lead to an energy crisis in organisms and instability of genomes. In addition, decreased Frataxin and Nrp1 levels or increased PTP levels promote the iron content of mitochondria, leading to aging through ROS. At the organ level, the age-associated increase in iron deposition varies between different brain regions and cell types, and then various molecular forms (ferritin, transferrin, hemosiderin, neuromelanin) of iron can deposit in the brain, resulting in brain aging. At the individual level, model organisms (S. cerevisiae, C. elegans, D. melanogaster) can regulate the iron level of the body through different mechanisms (such as mitoferrin, ISCU/Frataxin, mTOR, natural compounds, Isc1p), eventually leading to individual aging. The red fork represents the loss of function; The red upward arrow represents the increase in content. ROS, reactive oxygen species; Nrp1, neuropilin-1; ABCB8, mitochondrial transporter ATP-binding cassette B8; PTP, permeability transition pore; ISCU, iron–sulfur cluster (ISC) assembly machinery central protein; Isc1p, inositolphosphosphingolipid phospholipase C.
Figure 3
Figure 3
Relationship between iron and Alzheimer’s disease/Parkinson’s disease. Fe3+ can be absorbed and utilized by astrocytes, neurons, oligodendrocytes, and microglia in the brain. When the iron-related proteins change in neurons, the iron homeostasis is disturbed, leading to neurodegenerative diseases. Upregulation of some iron-storage proteins such as lactoferrin and transferrin increased expression of DMT1 in dopamine neurons. Both ceruloplasmin dysfunction and a decreased level of neuromelanin can cause an accelerated onset of Parkinson’s disease. Alzheimer’s disease is characterized by the formation of Aβ plaques and NFTs in the brain. The increase of intracellular iron level promotes β-secretase and γ-secretase activities to enhance the amyloid production pathway, and finally causes Aβ aggregation around microglia. In addition, iron also binds to tau, affecting its phosphorylation and inducing hyperphosphorylated tau tangles in neurons. Aβ aggregation and neurofibrillary tangles together lead to the occurrence of AD. Apo-Tf, Apo-transferrin; Holo-Tf, Holo-transferrin; BVECs, brain vascular endothelial cells; DMT1, Divalent metal-ion transporter 1; NFTs, Neurofibrillary tangles.
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