Role of iron metabolism in heart failure: From iron deficiency to iron overload

Iron metabolism is a balancing act, and biological systems have evolved exquisite regulatory mechanisms to maintain iron homeostasis. Iron metabolism disorders are widespread health problems on a global scale and range from iron deficiency to iron-overload. Both types of iron disorders are linked to heart failure. Iron play a fundamental role in mitochondrial function and various enzyme functions and iron deficiency has a particular negative impact on mitochondria function. Given the high-energy demand of the heart, iron deficiency has a particularly negative impact on heart function and exacerbates heart failure. Iron-overload can result from excessive gut absorption of iron or frequent use of blood transfusions and is typically seen in patients with congenital anemias, sickle cell anemia and beta-thalassemia major, or in patients with primary hemochromatosis. This review provides an overview of normal iron metabolism, mechanisms underlying development of iron disorders in relation to heart failure, including iron-overload cardiomyopathy, and clinical perspective on the treatment options for iron metabolism disorders.     

Red blood cells as an organ? How deep omics characterization of the most abundant cell in the human body highlights other systemic metabolic functions beyond oxygen transport

ABSTRACT

Introduction: Recently, the classification of two ‘novel’ organs, the mesentere and interstitium, was saluted as a scientific breakthrough and disseminated into mainstream media. The novelty of these findings did not pertain to the characterization of some previously unexplored phenomena, rather to the appreciation that well-established tissues may play some hitherto unexplored functions critical to system homeostasis.

Areas covered: Here we provocatively comment on the potential classification of red blood cells – by far the most abundant host cell in the human body (~ 83% of the total cells) – as an organ involved in many functions beyond gas transport. In this perspective article, we describe some of these functions with a special emphasis on the role erythrocytes play with respect to systemic metabolic homeostasis. We thus focus on how these functions modulate the cross talk of red blood cells among each other and with other cell types including immune cells.

Expert commentary: The appreciation of RBCs as an organ impacting systemic metabolic homeostasis and other cell functions while engaging in complex metabolic activity beyond oxygen transport can foster the development of novel therapeutic interventions in pathologic hypoxemia, inflammation, neurodgenerative diseases, aging, and cancer.     

Possible roles of the hereditary hemochromatosis protein, HFE, in regulating cellular iron homeostasis

Hereditary hemochromatosis (HH) is the most common inherited disorder in people of Northern European descent. Over 83% of the cases of HH result from a single mutation of a Cys to Tyr in the HH protein. HFE. This mutation causes a recessive disease resulting in an accumulation of iron in selected tissues. Iron overload damages these organs leading to cirrhosis of the liver, diabetes, cardiomyopathy, and arthritis. The mechanism by which HFE influences iron homeostasis in cells and in the body remains elusive. Lack of functional HFE in humans produces the opposite effects in different cell types in the body. In the early stages of the disease. Kupffer cells in the liver and enterocytes in the intestine cells are iron depleted and have low intracellular ferritin levels, whereas hepatocytes in the liver are iron overloaded and have high intracellular iron levels. This review gives the background and a model as to possible mechanisms of how HFE could exert different effects on iron homeostasis in different cell types.     

Iron: Key player in cancer and cell cycle?

BackgroundIron is an essential element for growth and metabolic activities of all living organisms but remains in its oxyhydroxide ferric ion form in the surrounding. Unavailability of iron in soluble ferrous form led to development of specific pathways and machinery in different organisms to make it available for use and maintain its homeostasis. Iron homeostasis is essential as under different circumstances iron in excess as well as deprivation leads to different pathological conditions in human.ObjectiveThis review highlights the current findings related to iron excess as well as deprivation with regards to cellular proliferation.ConclusionsIron excess is extensively associated with different types of cancers viz. colorectal cancer, breast cancer etc. by producing an oxidative stressed condition and alteration of immune system. Ironically its deprivation also results in anaemic conditions and leads to cell cycle arrest at different phases with mechanism yet to be explored. Iron deprivation arrests cell cycle at G1/S and in some cases at G2/M checkpoints resulting in growth arrest. However, in some cases iron overload arrests cell cycle at G1 phase by blocking certain signalling pathways. Certain natural and synthetic iron chelators are being explored from few decades to combat diseases caused by alteration in iron homeostasis.     

A precious metal: Iron, an essential nutrient for all cells

Iron is an important cofactor required for a number of essential cell functions and hence is a vital nutrient. However, iron can also be dangerous as a catalyst of free radical reactions. Accordingly, intracellular iron homeostasis and body iron balance are tightly regulated. In this review, we presented an overview of the remarkable new insights that over the last years have been gained into the multifaceted and sophisticated molecular mechanisms controlling iron acquisition, storage and release. We also reviewed the data about nutrition-related abnormalities of iron metabolism, such as iron overload and deficiency. Finally, we discussed how pathogenic microorganisms and host cells compete for iron, a battle whose outcome has a relevant role in infectious disease.     

The roles of iron in health and disease

Iron is vital for almost all living organisms by participating in a wide variety of metabolic processes, including oxygen transport, DNA synthesis, and electron transport. However, iron concentrations in body tissues must be tightly regulated because excessive iron leads to tissue damage, as a result of formation of free radicals. Disorders of iron metabolism are among the most common diseases of humans and encompass a broad spectrum of diseases with diverse clinical manifestations, ranging from anemia to iron overload and, possibly, to neurodegenerative diseases. The molecular understanding of iron regulation in the body is critical in identifying the underlying causes for each disease and in providing proper diagnosis and treatments. Recent advances in genetics, molecular biology and biochemistry of iron metabolism have assisted in elucidating the molecular mechanisms of iron homeostasis. The coordinate control of iron uptake and storage is tightly regulated by the feedback system of iron responsive element-containing gene products and iron regulatory proteins that modulate the expression levels of the genes involved in iron metabolism. Recent identification and characterization of the hemochromatosis protein HFE, the iron importer Nramp2, the iron exporter ferroportin1, and the second transferrin-binding and -transport protein transferrin receptor 2, have demonstrated their important roles in maintaining body's iron homeostasis. Functional studies of these gene products have expanded our knowledge at the molecular level about the pathways of iron metabolism and have provided valuable insight into the defects of iron metabolism disorders. In addition, a variety of animal models have implemented the identification of many genetic defects that lead to abnormal iron homeostasis and have provided crucial clinical information about the pathophysiology of iron disorders. In this review, we discuss the latest progress in studies of iron metabolism and our current understanding of the molecular mechanisms of iron absorption, transport, utilization, and storage. Finally, we will discuss the clinical presentations of iron metabolism disorders, including secondary iron disorders that are either associated with or the result of abnormal iron accumulation.     

The iron trap: iron,malaria and anemia at the mother–child interface

Iron deficiency causes anemia, but prevents malaria for unknown reasons, thus hindering iron supplementation programs for mothers and children. Iron homeostasis is tightly regulated, including at the mother–fetus interface where iron–malaria relationships are complex. Improved iron status assays, and understanding of malaria protection mechanisms, are needed to manage these disorders.     

Nitric oxide, nitrosyl iron complexes, ferritin and frataxin: A well equipped team to preserve plant iron homeostasis

Iron is a key element in plant nutrition. Iron deficiency as well as iron overload results in serious metabolic disorders that affect photosynthesis, respiration and general plant fitness with direct consequences on crop production.More than 25% of the cultivable land possesses low iron availability due to high pH (calcareous soils). Plant biologists are challenged by this concern and aimed to find new avenues to ameliorate plant responses and keep iron homeostasis under control even at wide range of iron availability in various soils. For this purpose, detailed knowledge of iron uptake, transport, storage and interactions with cellular compounds will help to construct a more complete picture of its role as essential nutrient. In this review, we summarize and describe the recent findings involving four central players involved in keeping cellular iron homeostasis in plants: nitric oxide, ferritin, frataxin and nitrosyl iron complexes. We attempt to highlight the interactions among these actors in different scenarios occurring under iron deficiency or iron overload, and discuss their counteracting and/or coordinating actions leading to the control of iron homeostasis.     

Iron and mechanisms of emotional behavior

Iron is required for appropriate behavioral organization. Iron deficiency results in poor brain myelination and impaired monoamine metabolism. Glutamate and γ-aminobutyric acid homeostasis is modified by changes in brain iron status. Such changes produce not only deficits in memory/learning capacity and motor skills, but also emotional and psychological problems. An accumulating body of evidence indicates that both energy metabolism and neurotransmitter homeostasis influence emotional behavior, and both functions are influenced by brain iron status. Like other neurobehavioral aspects, the influence of iron metabolism on mechanisms of emotional behavior is multifactorial: brain region-specific control of behavior, regulation of neurotransmitters and associated proteins, temporal and regional differences in iron requirements, oxidative stress responses to excess iron, sex differences in metabolism, and interactions between iron and other metals. To better understand the role that brain iron plays in emotional behavior and mental health, this review discusses the pathologies associated with anxiety and other emotional disorders with respect to body iron status.     

Hepcidin与疾病关系和其临床意义的研究进展

铁是人体必需的微量元素,是血红蛋白、肌红蛋白及多种酶的重要组成成分,广泛地参与氧气输运、氧化还原反应、细胞增殖与分化、基因表达调控等基本生命过程。机体铁稳态对生命体新陈代谢的平衡起着至关重要的作用。铁稳态依赖铁吸收、转运和储存、再循环利用等代谢过程共同调节。铁调素（Hepcidin）是铁代谢调节中最关键的调节分子,成熟的铁调素是一个由25个氨基酸组成的功能性小肽类激素,可以通过调节小肠上皮细胞和巨噬细胞表面的相关铁转运蛋白来调控机体内铁的储存和利用。铁调素同时受到机体铁水平的反馈,免疫应答和红细胞生成等因素的共同调节。许多铁代谢疾病、炎症和各种原因引起的贫血与铁调素的异常表达相关。因此,对于铁调素的检测不但可以反映机体的铁代谢状况,结合其他临床指标还能够辅助诊断和有针对性地检测相关疾病的治疗效果。     

铁自噬与铁死亡及其相关疾病

铁是血红素、线粒体呼吸链复合体和各种生物酶的重要辅助因子,参与氧气运输、氧化还原反应和代谢物合成等生物过程。铁蛋白(ferritin)是一种铁存储蛋白质,通过储存和释放铁来维持机体内铁平衡。铁自噬(ferritinophagy)作为一种选择性自噬方式,介导铁蛋白降解释放游离铁,参与细胞内铁含量的调控。适度铁自噬维持细胞内铁含量稳定,但铁自噬过度会释放出大量游离铁。通过芬顿 (Fenton)反应催化产生大量的活性氧(reactive oxygen species, ROS),发生脂质过氧化造成细胞受损。因此,铁自噬在维持细胞生理性铁稳态中发挥至关重要的作用。核受体共激活因子4 (nuclear receptor co-activator 4, NCOA4)被认为是铁自噬的关键调节因子,与铁蛋白靶向结合,并传递至溶酶体中降解释放游离铁,其介导的铁自噬构成了铁代谢的重要组成部分。最新研究表明,NCOA4受体内铁含量、自噬、溶酶体和低氧等因素的调控。NCOA4介导的铁蛋白降解与铁死亡(ferroptosis)有关。铁死亡是自噬性细胞死亡过程。铁自噬通过调节细胞铁稳态和细胞ROS生成,成为诱导铁死亡的上游机制,与贫血、神经退行性疾病、癌症、缺血/再灌注损伤与疾病的发生发展密切相关。本文针对NCOA4介导的铁自噬通路在铁死亡中的功能特征,探讨NCOA4在这些疾病中的作用,可能为相关疾病的治疗提供启示。     

铁紊乱相关疾病的研究进展

铁作为一种必需的营养元素,在哺乳动物体内的重要作用越来越为人们所重视。动物体内存在着严格的铁代谢调节机制,以确保体内铁始终处于正常生理水平。如果铁代谢失调、体内铁缺乏或过负荷均会导致各种临床疾病。研究发现,肝脏抗菌多肽(hepcidin)很可能是一种控制小肠铁吸收及调节体内铁稳态的关键物质,是一种极为重要的铁调节激素。本文综述了铁的生理作用、铁缺乏引起的疾病(如:缺铁性贫血和儿童神经系统疾病)和铁过负荷引起的疾病(如:肝损伤、心血管疾病、帕金森病和癌症等),并对如何利用现代化技术手段在基因水平开展铁紊乱相关疾病的治疗做了展望。     

Intestinal iron absorption

Intestinal iron absorption is a critical process for maintaining body iron levels within the optimal physiological range. Iron in the diet is found in a wide variety of forms, but the absorption of non-heme iron is best understood. Most of this iron is moved across the enterocyte brush border membrane by the iron transporter divalent metal-ion transporter 1, a process enhanced by the prior reduction of the iron by duodenal cytochrome B and possibly other reductases. Enterocyte iron is exported to the blood via ferroportin 1 on the basolateral membrane. This transporter acts in partnership with the ferroxidase hephaestin that oxidizes exported ferrous iron to facilitate its binding to plasma transferrin. Iron absorption is controlled by a complex network of systemic and local influences. The liver-derived peptide hepcidin binds to ferroportin, leading to its internalization and a reduction in absorption. Hepcidin expression in turn responds to body iron demands and the BMP-SMAD signaling pathway plays a key role in this process. The levels of iron and oxygen in the enterocyte also exert important influences on iron absorption. Disturbances in the regulation of iron absorption are responsible for both iron loading and iron deficiency disorders in humans.     

小鼠模型在铁代谢研究中的应用

铁代谢在维持生命活动中至关重要,机体铁代谢紊乱会导致贫血和人类遗传性血色病等诸多疾病,对人体健康造成危害。在铁代谢研究领域,小鼠模型具有人群及细胞模型所不具备的优势,可以最准确的表现相应基因及通路在铁代谢调控中的生理作用。利用基因敲除及转基因小鼠模型,许多铁代谢相关的基因及调控通路被发现,有助于深入了解铁稳态调控的分子机制。这些小鼠模型为治疗铁代谢紊乱相关疾病潜在药物的开发和评估提供了理想的平台。     

Iron in infectious diseases friend or foe?: The role of gut microbiota

Iron is a trace element involved in metabolic functions for all organisms, from microorganisms to mammalians. Iron deficiency is a prevalent health problem that affects billions of people worldwide, and iron overload could have some hazardous effect. The complex microbial community in the human body, also called microbiota, influences the host immune defence against infections. An imbalance in gut microbiota, dysbiosis, changes the host's susceptibility to infections by regulating the immune system. In recent years, the number of studies on the relationship between infectious diseases and microbiota has increased. Gut microbiota is affected by different parameters, including mode of delivery, hygiene habits, diet, drugs, and plasma iron levels during the lifetime. Gut microbiota may influence iron levels in the body, and iron overload and deficiency can also affect gut microbiota composition. Novel researches on microbiota shed light on the fact that the bidirectional interactions between gut microbiota and iron play a role in the pathogenesis of many diseases, especially infections. A better understanding of these interactions may help us to comprehend the pathogenesis of many infectious and metabolic diseases affecting people worldwide and following the development of more effective preventive and/or therapeutic strategies. In this review, we aimed to present the iron-mediated host-gut microbiota interactions, susceptibility to bacterial infections, and iron-targeted therapy approaches for infections.     

Iron, oxidative stress and the example of solar ultraviolet A radiation

Iron has outstanding biological importance as it is required for a wide variety of essential cellular processes and, as such, is a vital nutrient. The element holds this central position by virtue of its facile redox chemistry and the high affinity of both redox states (iron II and iron III) for oxygen. These same properties also render iron toxic when its redox-active chelatable 'labile' form exceeds the normal binding capacity of the cell. Indeed, in contrast to iron bound to proteins, the intracellular labile iron (LI) can be potentially toxic especially in the presence of reactive oxygen species (ROS), as it can lead to catalytic formation of oxygen-derived free radicals such as hydroxyl radical that ultimately overwhelm the cellular antioxidant defense mechanisms and lead to cell damage. While intracellular iron homeostasis and body iron balance are tightly regulated to minimise the presence of potentially toxic LI, under conditions of oxidative stress and certain pathologies, iron homeostasis is severely altered. This alteration manifests itself in several ways, one of which is an increase in the intracellular level of potentially harmful LI. For example acute exposure of skin cells to ultraviolet A (UVA, 320-400 nm), the oxidising component of sunlight provokes an immediate increase in the available pool of intracellular LI that appears to play a key role in the increased susceptibility of skin cells to UVA-mediated oxidative membrane damage and necrotic cell death. The main purpose of this overview is to bring together some of the new findings related to intracellular LI distribution and trafficking under physiological and patho-physiological conditions as well as to discuss mechanisms and consequences of oxidant-induced alterations in the intracellular pool of LI, as exemplified by UVA radiation.     

Iron and the heart: A paradigm shift from systemic to cardiomyocyte abnormalities

Iron is a key micronutrient for the human body and participates in biological processes, such as oxygen transport, storage, and utilization. Iron homeostasis plays a crucial role in the function of the heart and both iron deficiency and iron overload are harmful to the heart, which is partly mediated by increased oxidative stress. Iron enters the cardiomyocyte through the classic pathway, by binding to the transferrin 1 receptor (TfR1), but also through other routes: T-type calcium channel (TTCC), divalent metal transporter 1 (DMT1), L-type calcium channel (LTCC), Zrt-, Irt-like Proteins (ZIP) 8 and 14. Only one protein, ferroportin (FPN), extrudes iron from cardiomyocytes. Intracellular iron is utilized, stored bound to cytoplasmic ferritin or imported by mitochondria. This cardiomyocyte iron homeostasis is controlled by iron regulatory proteins (IRP). When the cellular iron level is low, expression of IRPs increases and they reduce expression of FPN, inhibiting iron efflux, reduce ferritin expression, inhibiting iron storage and augment expression of TfR1, increasing cellular iron availability. Such cellular iron homeostasis explains why the heart is very susceptible to iron overload: while cardiomyocytes possess redundant iron importing mechanisms, they are equipped with only one iron exporting protein, ferroportin. Furthermore, abnormalities of iron homeostasis have been found in heart failure and coronary artery disease, however, no clear picture is emerging yet in this area. If we better understand iron homeostasis in the cardiomyocyte, we may be able to develop better therapies for a variety of heart diseases to which abnormalities of iron homeostasis may contribute.     

Neurodegeneration with brain iron accumulation — Clinical syndromes and neuroimaging

Iron participates in a wide array of cellular functions and is essential for normal neural development and physiology. However, if inappropriately managed, the transition metal is capable of generating neurotoxic reactive oxygen species. A number of hereditary conditions perturb body iron homeostasis and some, collectively referred to as neurodegeneration with brain iron accumulation (NBIA), promote pathological deposition of the metal predominantly or exclusively within the central nervous system (CNS). In this article, we discuss seven NBIA disorders with emphasis on the clinical syndromes and neuroimaging. The latter primarily entails magnetic resonance scanning using iron-sensitive sequences. The conditions considered are Friedreich ataxia (FA), pantothenate kinase 2-associated neurodegeneration (PKAN), PLA2G6-associated neurodegeneration (PLAN), FA2H-associated neurodegeneration (FAHN), Kufor-Rakeb disease (KRD), aceruloplasminemia, and neuroferritinopathy. An approach to differential diagnosis and the status of iron chelation therapy for several of these entities are presented. This article is part of a Special Issue entitled: Imaging Brain Aging and Neurodegenerative disease.     

Neurodegeneration with brain iron accumulation - clinical syndromes and neuroimaging

Iron participates in a wide array of cellular functions and is essential for normal neural development and physiology. However, if inappropriately managed, the transition metal is capable of generating neurotoxic reactive oxygen species. A number of hereditary conditions perturb body iron homeostasis and some, collectively referred to as neurodegeneration with brain iron accumulation (NBIA), promote pathological deposition of the metal predominantly or exclusively within the central nervous system (CNS). In this article, we discuss seven NBIA disorders with emphasis on the clinical syndromes and neuroimaging. The latter primarily entails magnetic resonance scanning using iron-sensitive sequences. The conditions considered are Friedreich ataxia (FA), pantothenate kinase 2-associated neurodegeneration (PKAN), PLA2G6-associated neurodegeneration (PLAN), FA2H-associated neurodegeneration (FAHN), Kufor-Rakeb disease (KRD), aceruloplasminemia, and neuroferritinopathy. An approach to differential diagnosis and the status of iron chelation therapy for several of these entities are presented. This article is part of a Special Issue entitled: Imaging Brain Aging and Neurodegenerative disease.     

Brain Iron Toxicity: Differential Responses of Astrocytes,Neurons, and Endothelial Cells

Iron accumulation or iron overload in brain is commonly associated with neurodegenerative disorders such as Parkinson’s and Alzheimer’s diseases, and also plays a role in cellular damage following hemorrhagic stroke and traumatic brain injury. Despite the brain’s highly regulated system for iron utilization and metabolism, these disorders often present following disruptions within iron metabolic pathways. Such dysregulation allows saturation of proteins involved in iron transport and storage, and may cause an increase in free ferrous iron within brain leading to oxidative damage. Not only do astrocytes, neurons, and brain endothelial cells serve unique purposes within the brain, but their individual cell types are equipped with distinct protective mechanisms against iron-induced injury. This review evaluates iron metabolism within the brain under homeostatic and pathological conditions and focuses on the mechanism(s) of brain cellular iron toxicity and differential responses of astrocytes, neurons, and brain vascular endothelial cells to excessive free iron. Special issue dedicated to Dr. Moussa Youdim. An erratum to this article can be found at