Iron homeostasis and oxidative stress: An intimate relationship

Iron is a transition metal and essential constituent of almost all living cells and organisms. As component of various metalloproteins it is involved in critical biochemical processes such as transport of oxygen in tissues, electron transfer reactions during respiration in mitochondria, synthesis and repair of DNA, metabolism of xenobiotics, etc. However, when present in excess within cells and tissues, iron disrupts redox homeostasis and catalyzes the propagation of reactive oxygen species (ROS), leading to oxidative stress. ROS are critical for physiological signaling pathways, but oxidative stress is associated with tissue injury and disease. At the cellular level, oxidative stress may lead to ferroptosis, an iron-dependent form of cell death. In this review, we focus on the intimate relationship between iron metabolism and oxidative stress in health and disease. We discuss aspects of redox- and iron-mediated signaling, toxicity, ferroptotic cell death, homeostatic pathways and pathophysiological implications.     

Role of peroxisomes in ROS/RNS-metabolism: Implications for human disease

Peroxisomes are cell organelles that play a central role in lipid metabolism. At the same time, these organelles generate reactive oxygen and nitrogen species as byproducts. Peroxisomes also possess intricate protective mechanisms to counteract oxidative stress and maintain redox balance. An imbalance between peroxisomal reactive oxygen species/reactive nitrogen species production and removal may possibly damage biomolecules, perturb cellular thiol levels, and deregulate cellular signaling pathways implicated in a variety of human diseases. Somewhat surprisingly, the potential role of peroxisomes in cellular redox metabolism has been underestimated for a long time. However, in recent years, peroxisomal reactive oxygen species/reactive nitrogen species metabolism and signaling have become the focus of a rapidly evolving and multidisciplinary research field with great prospects. This review is mainly devoted to discuss evidence supporting the notion that peroxisomal metabolism and oxidative stress are intimately interconnected and associated with age-related diseases. We focus on several key aspects of how peroxisomes contribute to cellular reactive oxygen species/reactive nitrogen species levels in mammalian cells and how these cells cope with peroxisome-derived oxidative stress. We also provide a brief overview of recent strategies that have been successfully employed to detect and modulate the peroxisomal redox status. Finally, we highlight some gaps in our knowledge and propose potential avenues for further research. This article is part of a Special Issue entitled: Metabolic Functions and Biogenesis of peroxisomes in Health and Disease.     

FGF/FGFR signaling: From lung development to respiratory diseases

The fibroblast growth factor/fibroblast growth factor receptor (FGF/FGFR) signaling system regulates a variety of biological processes, including embryogenesis, angiogenesis, wound repair, tissue homeostasis, and cancer. It exerts these regulatory functions by controlling proliferation, differentiation, migration, survival, and metabolism of target cells. The morphological structure of the lung is a complex tree-like network for effective oxygen exchange, and the airway terminates in the middle and distal ends of many alveoli. FGF/FGFR signaling plays an important role in the pathophysiology of lung development and pathogenesis of various human respiratory diseases. Here, we mainly review recent advances in FGF/FGFR signaling during human lung development and respiratory diseases, including lung cancer, acute lung injury (ALI), pulmonary arterial hypertension (PAH), chronic obstructive pulmonary disease (COPD), asthma, and pulmonary fibrosis.     

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。     

Iron and its sensitive balance in the cell

Iron is vital in life because it is an important component of molecules that undergoes redox reactions or transport oxygen. However, the existence of two stable and inter-convertible forms of iron, iron(III) and iron(II), makes possible one electron being transferred to or captured from other species to form radicals. In particular, superoxide and hydroxyl radicals may be formed in these reactions, both with capacity of attacking other molecules. DNA is one important target and a vast literature exists showing that attack of hydroxyl radical to DNA leads to cell death cellular necrosis, apoptosis, mutation and malignant transformation. Therefore, a fine balance must exist at various levels of an organism to maintain iron concentration in a narrow range, above and below which deleterious effects of distinct nature occur. This review will deal with the formation of oxygen reactive species in iron participating reactions, defenses in the organism against these species, the different mechanisms of iron homeostasis and iron deficiency and iron overload related diseases.     

动物储铁蛋白研究进展

铁元素是生物体中必不可少的微量元素,在生物的生长发育中发挥着重要作用。铁蛋白是一种分布广泛的球形蛋白,能够以稳定的形式储存大量铁。铁蛋白通过储存和释放铁来维持机体内铁平衡。铁蛋白不仅是机体中重要的铁储存蛋白,同时也能有效保护生物体免受来自氧自由基的损伤。与此同时,铁蛋白含量可以作为一些疾病预防检测的明确指标。对铁的代谢吸收及铁对基因调控的研究,进一步说明了维持铁平衡对生物体有重要意义。     

The neurotoxicity of iron,copper and cobalt in Parkinson’s disease through ROS-mediated mechanisms

Parkinson’s disease (PD) is the second most common neurodegenerative disease with gradual loss of dopaminergic neurons. Despite extensive research in the past decades, the etiology of PD remains elusive. Nevertheless, multiple lines of evidence suggest that oxidative stress is one of the common causes in the pathogenesis of PD. It has also been suggested that heavy metal-associated oxidative stress may be implicated in the etiology and pathogenesis of PD. Here we review the roles of redox metals, including iron, copper and cobalt, in PD. Iron is a highly reactive element and deregulation of iron homeostasis is accompanied by concomitant oxidation processes in PD. Copper is a key metal in cell division process, and it has been shown to have an important role in neurodegenerative diseases such as PD. Cobalt induces the generation of reactive oxygen species (ROS) and DNA damage in brain tissues.     

Association of HFE common mutations with Parkinson's disease, Alzheimer's disease and mild cognitive impairment in a Portuguese cohort

Background  

Pathological brain iron deposition has been implicated as a source of neurotoxic reactive oxygen species in Alzheimer (AD) and Parkinson diseases (PD). Iron metabolism is associated with the gene hemochromatosis (HFE Human genome nomenclature committee ID:4886), and mutations in HFE are a cause of the iron mismetabolism disease, hemochromatosis. Several reports have tested the association of HFE variants with neurodegenerative diseases, such as AD and PD with conflicting results.     

A Computational Model of Liver Iron Metabolism

Iron is essential for all known life due to its redox properties; however, these same properties can also lead to its toxicity in overload through the production of reactive oxygen species. Robust systemic and cellular control are required to maintain safe levels of iron, and the liver seems to be where this regulation is mainly located. Iron misregulation is implicated in many diseases, and as our understanding of iron metabolism improves, the list of iron-related disorders grows. Recent developments have resulted in greater knowledge of the fate of iron in the body and have led to a detailed map of its metabolism; however, a quantitative understanding at the systems level of how its components interact to produce tight regulation remains elusive. A mechanistic computational model of human liver iron metabolism, which includes the core regulatory components, is presented here. It was constructed based on known mechanisms of regulation and on their kinetic properties, obtained from several publications. The model was then quantitatively validated by comparing its results with previously published physiological data, and it is able to reproduce multiple experimental findings. A time course simulation following an oral dose of iron was compared to a clinical time course study and the simulation was found to recreate the dynamics and time scale of the systems response to iron challenge. A disease state simulation of haemochromatosis was created by altering a single reaction parameter that mimics a human haemochromatosis gene (HFE) mutation. The simulation provides a quantitative understanding of the liver iron overload that arises in this disease. This model supports and supplements understanding of the role of the liver as an iron sensor and provides a framework for further modelling, including simulations to identify valuable drug targets and design of experiments to improve further our knowledge of this system.     

Iron regulatory protein 1 as a sensor of reactive oxygen species

Iron regulatory proteins (IRP1 and 2) function as translational regulators that coordinate the cellular iron metabolism of eukaryotes by binding to the mRNA of target genes such as the transferrin receptor or ferritin. In addition to IRP2, IRP1 serves as sensor of reactive oxygen species (ROS). As iron and oxygen are essential but potentially toxic constituents of most organisms, ROS-mediated modulation of IRP1 activity may be an important regulatory element in dissecting iron homeostasis and oxidative stress. The responses of IRP1 towards reactive oxygen species are compartment-specific and rather complex: H2O2 activates IRP1 via a signaling cascade that leads to upregulation of the transferrin receptor and cellular iron accumulation. Contrary, superoxide inactivates IRP1 by a direct chemical attack being limited to the intracellular compartment. In particular, activation of IRP1 by H2O2 has established a new regulatory link between inflammation and iron metabolism with new clinical implications. This mechanism seems to contribute to the anemia of chronic disease and inflammation-mediated iron accumulation in tissues. In addition, the cytotoxic side effects of redox-cycling anticancer drugs such as doxorubicin may involve H2O2-mediated IRP1 activation. These molecular insights open up new therapeutic strategies for the clinical management of chronic inflammation and drug-mediated cardiotoxicity.     

Iron-catalyzed reactions may be responsible for the biochemical and biological effects of asbestos

The most carcinogenic forms of asbestos contain iron to levels as high as 36% by weight and catalyze many of the same biochemical reactions that freshly prepared solutions of iron do, i.e. oxygen consumption, generation of reactive oxygen species, lipid peroxidation and DNA damage. The participation of iron from asbestos in these reactions has been demonstrated using the iron chelator desferrioxamine B which inhibits iron-catalyzed reactions. Iron appears to be redox active on the asbestos fiber, but chelation and subsequent iron mobilization from asbestos by a variety of chelators, e.g. citrate, EDTA or nitrilotriacetate, makes the iron more redox active resulting in greater oxygen consumption and production of oxygen radicals in the presence of reducing agents. Iron also appears to be important for some of the asbestos-dependent biological effects on tissues or cells in culture, such as phagocytosis, cytotoxicity, lipid peroxidation and DNA damage. Therefore, redox cycling of iron to generate oxygen radicals at the surface of the fiber and/or in solution, as mobilized, low molecular weight chelates, may be very important in eliciting some of the biological effects of asbestos in vivo.     

厌氧氨氧化细菌Candidatus Kuenenia stuttgartiensis铁的吸收利用研究进展

铁是影响微生物生长代谢的关键元素,它与蛋白质结合,起催化、氧化还原或调节作用。厌氧氨氧化(ANAMMOX)细菌的生长代谢严重依赖铁,尤其是含铁蛋白。ANAMMOX细菌的厌氧生活方式和厌氧氨氧化体的存在使其对铁代谢的模式不同于其他微生物。弄清ANAMMOX细菌的铁吸收代谢模式,可为获得其纯培养物奠定基础,有利于促进其在环境领域中的应用。在这里,我们将现有铁吸收、利用和代谢的观点、与ANAMMOX细菌的基因组信息和有限的生化生理数据结合起来,提出ANAMMOX细菌可能的铁利用途径,为后续的生理生化研究提供参考。     

Cellular metabolic and autophagic pathways: Traffic control by redox signaling

It has been established that the key metabolic pathways of glycolysis and oxidative phosphorylation are intimately related to redox biology through control of cell signaling. Under physiological conditions glucose metabolism is linked to control of the NADH/NAD redox couple, as well as providing the major reductant, NADPH, for thiol-dependent antioxidant defenses. Retrograde signaling from the mitochondrion to the nucleus or cytosol controls cell growth and differentiation. Under pathological conditions mitochondria are targets for reactive oxygen and nitrogen species and are critical in controlling apoptotic cell death. At the interface of these metabolic pathways, the autophagy–lysosomal pathway functions to maintain mitochondrial quality and generally serves an important cytoprotective function. In this review we will discuss the autophagic response to reactive oxygen and nitrogen species that are generated from perturbations of cellular glucose metabolism and bioenergetic function.     

Mitochondria: Biological roles in platelet physiology and pathology

Mitochondria are key regulators of cellular energy and redox metabolism, also playing a central role in cell signaling and death pathways. A number of processes occur within mitochondria, including redox-dependent ATP synthesis by oxidative phosphorylation and reactive oxygen species production. Mitochondrial permeability transition is a reversible process that may lead to cell death and is regulated by calcium and reactive oxygen species. Functional mitochondria are present in platelets, and evidence has demonstrated the direct involvement of these organelles in cellular ATP production, redox balance, as well as in platelet activation and apoptosis. Here, we review aspects of platelet physiology in which mitochondria are involved, as well as assess their function as new tools for studying a number of human diseases.     

Iron homeostasis and eye disease

Background

Iron is necessary for life, but excess iron can be toxic to tissues. Iron is thought to damage tissues primarily by generating oxygen free radicals through the Fenton reaction.

Methods

We present an overview of the evidence supporting iron's potential contribution to a broad range of eye disease using an anatomical approach.

Results

Iron can be visualized in the cornea as iron lines in the normal aging cornea as well as in diseases like keratoconus and pterygium. In the lens, we present the evidence for the role of oxidative damage in cataractogenesis. Also, we review the evidence that iron may play a role in the pathogenesis of the retinal disease age-related macular degeneration. Although currently there is no direct link between excess iron and development of optic neuropathies, ferrous iron's ability to form highly reactive oxygen species may play a role in optic nerve pathology. Lastly, we discuss recent advances in prevention and therapeutics for eye disease with antioxidants and iron chelators.

General significance

Iron homeostasis is important for ocular health.     

Disruption of iron homeostasis and lung disease

As a result of a direct exchange with the external environment, the lungs are exposed to both iron and agents with a capacity to disrupt the homeostasis of this metal (e.g. particles). An increased availability of catalytically reactive iron can result from these exposures and, by generating an oxidative stress, this metal can contribute to tissue injury. By importing this Fe³⁺ into cells for storage in a chemically less reactive form, the lower respiratory tract demonstrates an ability to mitigate both the oxidative stress presented by iron and its potential for tissue injury. This means that detoxification is accomplished by chemical reduction to Fe²⁺ (e.g. by duodenal cytochrome b and other ferrireductases), iron import (e.g. by divalent metal transporter 1 and other transporters), and storage in ferritin. The metal can subsequently be exported from the cell (e.g. by ferroportin 1) in a less reactive state relative to that initially imported. Iron is then transported out of the lung via the mucociliary pathway or blood and lymphatic pathways to the reticuloendothelial system for long term storage. This coordinated handling of iron in the lung appears to be disrupted in several acute diseases on the lung including infections, acute respiratory distress syndrome, transfusion-related acute lung injury, and ischemia–reperfusion. Exposures to bleomycin, dusts and fibers, and paraquat similarly alter iron homeostasis in the lung to affect an oxidative stress. Finally, iron homeostasis is disrupted in numerous chronic lung diseases including pulmonary alveolar proteinosis, transplantation, cigarette smoking, and cystic fibrosis.     

Pathogenesis of the systemic inflammatory syndrome and acute lung injury: role of iron mobilization and decompartmentalization

Changes in iron homeostatic responses routinely accompany infectious or proinflammatory insults. The systemic inflammatory response syndrome (SIRS) and the development of acute lung injury (ALI) feature pronounced systemic and lung-specific alterations in iron/heme mobilization and decompartmentalization; such responses may be of pathological significance for both the onset and progression of acute inflammation. The potential for excessive iron-catalyzed oxidative stress, altered proinflammatory redox signaling, and provision of iron as a microbial growth factor represent obvious adverse aspects of altered in vivo iron handling. The release of hemoglobin during hemolytic disease or surgical procedures such as those utilizing cardiopulmonary bypass procedures further impacts on iron mobilization, turnover, and storage with associated implications. Genetic predisposition may ultimately determine the extent to which SIRS and related syndromes develop in response to such changes. The design of specific therapeutic interventions based on endogenous stratagems to limit adverse aspects of altered iron handling may prove of therapeutic benefit for the treatment of SIRS and ALI.