Iron homeostasis and iron-regulated ROS in cell death,senescence and human diseases

BackgroundIron is essential for many types of biological processes. However, excessive iron can be cytotoxic and can lead to many diseases. Since ferroptosis, which is an iron-dependent regulated form of necrosis, was recently discovered, iron and iron-catalysed oxidative stress have attracted much interest because of their sophisticated mechanism of cellular signalling leading to cell death and associated with various diseases.Scope of reviewIn this review, we first focus on how iron catalyses reactive oxygen species (ROS). Next, we discuss the roles of iron in cell death and senescence and, in particular, the downstream signalling pathways of ROS. Finally, we discuss the potential regulation mechanism of iron as a therapeutic target for various iron-related diseases.Major conclusionsBoth labile iron released from organelles upon various stresses and iron incorporated in enzymes produce ROS, including lipid ROS. ROS produced by iron activates various signalling pathways, including mitogen-activated protein kinase (MAPK) signalling pathways such as the apoptosis signal-regulating kinase 1 (ASK1)-p38/JNK pathway. These ROS-activated signalling pathways regulate senescence or cell death and are linked to cancer, ischaemia-reperfusion injury during transplantation and ageing-related neurodegenerative diseases.General significanceIron overload damages cells and causes harmful effects on the body through oxidative stress. Thus, understanding the spatiotemporal availability of iron and the role of iron in generating ROS will provide clues for the suppression of ROS and cytotoxic redox-active iron. Moreover, elucidating the molecular mechanisms and signalling pathways of iron-dependent cytotoxicity will enable us to find novel therapeutic targets for various diseases.     

Mechanism of ROS scavenging and antioxidant signalling by redox metallic and fullerene nanomaterials: Potential implications in ROS associated degenerative disorders

BackgroundThe balance between oxidation and anti-oxidation is believed to be critical in maintaining healthy biological systems. However, our endogenous antioxidant defense systems are incomplete without exogenous antioxidants and, therefore, there is a continuous demand for exogenous antioxidants to prevent stress and ageing associated disorders. Nanotechnology has yielded enormous variety of nanomaterials (NMs) of which metallic and carbonic (mainly fullerenes) NMs, with redox property, have been found to be strong scavengers of ROS and antioxidants in preclinical in vitro and in vivo models.Scope of reviewRedox activity of metal based NMs and membrane translocation time of fullerene NMs seem to be the major determinants in ROS scavenging potential exhibited by these NMs. A comprehensive knowledge about the effects of ROS scavenging NMs in cellular antioxidant signalling is largely lacking. This review compiles the mechanisms of ROS scavenging as well as antioxidant signalling of the aforementioned metallic and fullerene NMs.Major conclusionsDirect interaction between NMs and proteins does greatly affect the corona/adsorption formation dynamics but such interaction does not provide the explanation behind diverse biological outcomes induced by NMs. Indirect interaction, however, that could occur via NMs uptake and dissolution, NMs ROS induction and ROS scavenging property, and NMs membrane translocation time seem to work as a central mode of interaction.General significanceThe usage of potential antioxidant NMs in biological systems would greatly impact the field of nanomedicine. ROS scavenging NMs hold great promise in the future treatment of ROS related degenerative disorders.     

Peroxisomes sense and respond to environmental cues by regulating ROS and RNS signalling networks

Background Peroxisomes are highly dynamic, metabolically active organelles that used to be regarded as a sink for H₂O₂ generated in different organelles. However, peroxisomes are now considered to have a more complex function, containing different metabolic pathways, and they are an important source of reactive oxygen species (ROS), nitric oxide (NO) and reactive nitrogen species (RNS). Over-accumulation of ROS and RNS can give rise oxidative and nitrosative stress, but when produced at low concentrations they can act as signalling molecules.Scope This review focuses on the production of ROS and RNS in peroxisomes and their regulation by antioxidants. ROS production is associated with metabolic pathways such as photorespiration and fatty acid β-oxidation, and disturbances in any of these processes can be perceived by the cell as an alarm that triggers defence responses. Genetic and pharmacological studies have shown that photorespiratory H₂O₂ can affect nuclear gene expression, regulating the response to pathogen infection and light intensity. Proteomic studies have shown that peroxisomal proteins are targets for oxidative modification, S-nitrosylation and nitration and have highlighted the importance of these modifications in regulating peroxisomal metabolism and signalling networks. The morphology, size, number and speed of movement of peroxisomes can also change in response to oxidative stress, meaning that an ROS/redox receptor is required. Information available on the production and detection of NO/RNS in peroxisomes is more limited. Peroxisomal homeostasis is critical for maintaining the cellular redox balance and is regulated by ROS, peroxisomal proteases and autophagic processes.Conclusions Peroxisomes play a key role in many aspects of plant development and acclimation to stress conditions. These organelles can sense ROS/redox changes in the cell and thus trigger rapid and specific responses to environmental cues involving changes in peroxisomal dynamics as well as ROS- and NO-dependent signalling networks, although the mechanisms involved have not yet been established. Peroxisomes can therefore be regarded as a highly important decision-making platform in the cell, where ROS and RNS play a determining role.     

植物过氧化物酶体在活性氧信号网络中的作用

过氧化物酶体是高度动态、代谢活跃的细胞器,主要参与脂肪酸等脂质的代谢及产生和清除不同的活性氧(reactive oxygen species, ROS)。ROS是细胞有氧代谢的副产物。当胁迫长期作用于植物,过量的ROS会引起氧胁迫,损害细胞结构和功能的完整性,导致细胞代谢减缓,活性降低,甚至死亡;但低浓度的ROS则作为分子信号,感应细胞ROS/氧化还原变化,从而触发由环境因素导致的过氧化物酶体动力学以及依赖ROS信号网络改变而产生快速、特异性的应答。ROS也可以通过直接或间接调节细胞生长来控制植物的发育,是植物发育的重要调节剂。此外,过氧化物酶体的动态平衡由ROS、过氧化物酶体蛋白酶及自噬过程调节,对于维持细胞的氧化还原平衡至关重要。本文就过氧化物酶体中ROS的产生和抗氧化剂的调控机制进行综述,以期为过氧化物酶体如何感知环境变化,以及在细胞应答中,ROS作为重要信号分子的研究提供参考。     

Life-history Constraints on the Mechanisms that Control the Rate of ROS Production

The quest to understand why and how we age has led to numerous lines of investigation that have gradually converged to consider mitochondrial metabolism as a major player. During mitochondrial respiration a small and variable amount of the consumed oxygen is converted to reactive species of oxygen (ROS). For many years, these ROS have been perceived as harmful by-products of respiration. However, evidence from recent years indicates that ROS fulfill important roles as cellular messengers. Results obtained using model organisms suggest that ROS-dependent signalling may even activate beneficial cellular stress responses, which eventually may lead to increased lifespan. Nevertheless, when an overload of ROS cannot be properly disposed of, its accumulation generates oxidative stress, which plays a major part in the ageing process. Comparative studies about the rates of ROS production and oxidative damage accumulation, have led to the idea that the lower rate of mitochondrial oxygen radical generation of long-lived animals with respect to that of their short-lived counterpart, could be a primary cause of their slow ageing rate. A hitherto largely under-appreciated alternative view is that such lower rate of ROS production, rather than a cause may be a consequence of the metabolic constraints imposed for the large body sizes that accompany high lifespans. To help understanding the logical underpinning of this rather heterodox view, herein I review the current literature regarding the mechanisms of ROS formation, with particular emphasis on evolutionary aspects.     

Hypoxia decreases ROS level in human fibroblasts

We have previously demonstrated that cells adapt to hypoxia using different metabolic reprogramming mechanisms depending on metabolism. We now investigate how the different adapting mechanisms affect reactive oxygen species (ROS) levels, and how ROS levels and cellular metabolism are linked. We show that when skin fibroblasts grew under short-term hypoxia (1% oxygen tension) ROS level markedly decreased (-50%) whatever substrate was available to the cells. Indeed, cellular ROS level linearly and directly decreased with oxygen tension. However, these relationships cannot explain the progressive ROS level decrease observed after prolonged cells hypoxia exposure. In glucose-enriched medium reduced mitochondrial mass and greater fragmentation are observed, both clear-cut indications of mitophagy suggesting that this is responsible for cellular ROS level decrease. Otherwise, in glucose-free medium exposure to prolonged hypoxia resulted in only minor mass reduction, but significantly enhanced expression of antioxidant enzymes. Interestingly, cellular ROS levels were lower in glucose-free compared to glucose-enriched medium under either normoxic or hypoxic conditions. Taken together, these findings reveal that in primary human fibroblasts hypoxia induces a decline in ROS and that different metabolism-dependent mechanisms contribute it, besides the major oxygen concentration decrease. In addition, the present data support the notion that metabolisms generating fewer ROS are associated with lower HIF-1α stabilization.     

ROS and redox signalling in the response of plants to abiotic stress

The redox state of the chloroplast and mitochondria, the two main powerhouses of photosynthesizing eukaryotes, is maintained by a delicate balance between energy production and consumption, and affected by the need to avoid increased production of reactive oxygen species (ROS). These demands are especially critical during exposure to extreme environmental conditions, such as high light (HL) intensity, heat, drought or a combination of different environmental stresses. Under these conditions, ROS and redox cues, generated in the chloroplast and mitochondria, are essential for maintaining normal energy and metabolic fluxes, optimizing different cell functions, activating acclimation responses through retrograde signalling, and controlling whole-plant systemic signalling pathways. Regulation of the multiple redox and ROS signals in plants requires a high degree of coordination and balance between signalling and metabolic pathways in different cellular compartments. In this review, we provide an update on ROS and redox signalling in the context of abiotic stress responses, while addressing their role in retrograde regulation, systemic acquired acclimation and cellular coordination in plants.     

Unravelling how plants benefit from ROS and NO reactions,while resisting oxidative stress

Background and Aims Reactive oxygen species (ROS) and reactive nitrogen species (RNS), such as nitric oxide (NO), play crucial roles in the signal transduction pathways that regulate plant growth, development and defence responses, providing a nexus of reduction/oxidation (redox) control that impacts on nearly every aspect of plant biology. Here we summarize current knowledge and concepts that lay the foundations of a new vision for ROS/RNS functions – particularly through signalling hubs – for the next decade.Scope Plants have mastered the art of redox control using ROS and RNS as secondary messengers to regulate a diverse range of protein functions through redox-based, post-translational modifications that act as regulators of molecular master-switches. Much current focus concerns the impact of this regulation on local and systemic signalling pathways, as well as understanding how such reactive molecules can be effectively used in the control of plant growth and stress responses.Conclusions The spectre of oxidative stress still overshadows much of our current philosophy and understanding of ROS and RNS functions. While many questions remain to be addressed – for example regarding inter-organellar regulation and communication, the control of hypoxia and how ROS/RNS signalling is used in plant cells, not only to trigger acclimation responses but also to create molecular memories of stress – it is clear that ROS and RNS function as vital signals of living cells.     

ROS directly activates transforming growth factor β type 1 receptor signalling in human vascular smooth muscle cells

BackgroundWidely used NAPDH oxidase (Nox) inhibitor, apocynin is a prodrug that needs to be converted to its pharmacologically active form by myeloperoxidase. In myeloperoxidase deficient non phagocytic cells such as vascular smooth muscle cells (VSMCs) apocynin stimulates the production of ROS. ROS is generated by the activation of many signalling pathways, thus we have used apocynin as a pharmacological tool to characterise the role of endogenous ROS in activating the transforming growth factor beta receptor (TGFBR1) without the activation of other pathways.MethodsThe in vitro study utilized human VSMCs. Western blotting and quantitative real time PCR were performed to assess signalling pathways and gene expression, respectively. Intracellular ROS levels was measured using fluorescence detection assay.ResultsTreatment with apocynin of human VSMCs stimulated ROS production and the phosphorylation of TGFBR1 and subsequent activation of TGFBR1 signalling leading to the formation of phosphorylated Smad2 which consequently upregulates the mRNA expression of glycosaminoglycan synthesizing enzyme.ConclusionsThese findings outline a specific involvement of ROS production in TGFBR1 activation. Furthermore, because apocynin stimulates Nox and ROS production, apocynin must be used with considerable care in vitro as its actions clearly extend beyond the stimulation of Nox enzymes and it has consequences for cellular signalling.General significanceApocynin can stimulate Nox leading to the production of ROS and the outcome is completely dependent upon the redox properties of the cell.     

Cellular localization of ROS and NO in olive reproductive tissues during flower development

Background  

Recent studies have shown that reactive oxygen species (ROS) and nitric oxide (NO) are involved in the signalling processes taking place during the interactions pollen-pistil in several plants. The olive tree (Olea europaea L.) is an important crop in Mediterranean countries. It is a dicotyledonous species, with a certain level of self-incompatibility, fertilisation preferentially allogamous, and with an incompatibility system of the gametophytic type not well determined yet. The purpose of the present study was to determine whether relevant ROS and NO are present in the stigmatic surface and other reproductive tissues in the olive over different key developmental stages of the reproductive process. This is a first approach to find out the putative function of these signalling molecules in the regulation of the interaction pollen-stigma.     

Regulation of plant reactive oxygen species (ROS) in stress responses: learning from AtRBOHD

Reactive oxygen species (ROS) are constantly produced in plants, as the metabolic by-products or as the signaling components in stress responses. High levels of ROS are harmful to plants. In contrast, ROS play important roles in plant physiology, including abiotic and biotic tolerance, development, and cellular signaling. Therefore, ROS production needs to be tightly regulated to balance their function. Respiratory burst oxidase homologue (RBOH) proteins, also known as plant nicotinamide adenine dinucleotide phosphate oxidases, are well studied enzymatic ROS-generating systems in plants. The regulatory mechanisms of RBOH-dependent ROS production in stress responses have been intensively studied. This has greatly advanced our knowledge of the mechanisms that regulate plant ROS production. This review attempts to integrate the regulatory mechanisms of RBOHD-dependent ROS production by discussing the recent advance. AtRBOHD-dependent ROS production could provide a valuable reference for studying ROS production in plant stress responses.     

Redox signalling: from nitric oxide to oxidized lipids

Cellular redox signalling is mediated by the post-translational modification of proteins in signal-transduction pathways by ROS/RNS (reactive oxygen species/reactive nitrogen species) or the products derived from their reactions. NO is perhaps the best understood in this regard with two important modifications of proteins known to induce conformational changes leading to modulation of function. The first is the addition of NO to haem groups as shown for soluble guanylate cyclase and the newly discovered NO/cytochrome c oxidase signalling pathway in mitochondria. The second mechanism is through the modification of thiols by NO to form an S-nitrosated species. Other ROS/RNS can also modify signalling proteins although the mechanisms are not as clearly defined. For example, electrophilic lipids, formed as the reaction products of oxidation reactions, orchestrate adaptive responses in the vasculature by reacting with nucleophilic cysteine residues. In modifying signalling proteins ROS/RNS appear to change the overall activity of signalling pathways in a process that we have termed 'redox tone'. In this review, we discuss these different mechanisms of redox cell signalling, and give specific examples of ROS/RNS participation in signal transduction.     

Reactive oxygen species (ROS) as defenses against a broad range of plant fungal infections and case study on ROS employed by crops against Verticillium dahliae wilts

Reactive oxygen species (ROS) are natural by products of cellular metabolism that were initially considered only deleterious towards the cellular macromolecules. Research advances have broadened the scope and now numerous studies are available rendering ROS molecules essential for plants to combat several biotic and abiotic stresses after being involved in essential defense mechanisms such as hypersensitivity reactions (HR) that lead to programmed cell death (PCD), cell wall reinforcement by cross-linking of cellular glycoproteins with other entities and salicylic acid mediated signal transduction pathways. During fungal attack, the fungal components like chitin and other elicitors activates the plant immune responses that employ ROS with other molecules like nitric oxide (NO), calcium ions to fight back the pathogen attack and restrict its spread to further plant parts. Here, several defense mechanisms mediated by ROS are discussed. Verticillium dahliae is one of the dreadful fungal pathogen to plants that cause wilts in many important plant species causing huge economic burden in food sector. The major constraint in its scenario being the deficit of field management systems based on chemicals or agronomics. It is evident by studying their interactions with the variety of hosts that in most cases, ROS mediated defenses play a key central role via cross-talk with other mechanisms making them a potential target for transgenics as well as resistant genotype selection.     

Role of ROS and auxin in plant response to metal-mediated stress

Being unable to move away from their places of germination, in order to avoid excess metal-induced damages, plants have to evolve different strategies and complex regulatory mechanisms to survive harsh conditions. While both ROS and auxin are documented to be important in plant response to metal stress, the mechanisms underlying the crosstalk between ROS and auxin in metal stress are poorly understood. In this review, we provide an update on the regulation of plant responses to metal-stress by ROS and auxin signaling pathways, primarily, with a focus on the copper, aluminum and cadmium stress. We aim at surveying the mechanisms underlying how metal stress modulates the changes in auxin distribution and the network of ROS and auxin in plant response to metal stress based on recent studies.     

Heme-induced ROS in Trypanosoma cruzi activates CaMKII-like that triggers epimastigote proliferation. One helpful effect of ROS

Heme is a ubiquitous molecule that has a number of physiological roles. The toxic effects of this molecule have been demonstrated in various models, based on both its pro-oxidant nature and through a detergent mechanism. It is estimated that about 10 mM of heme is released during blood digestion in the blood-sucking bug's midgut. The parasite Trypanosoma cruzi, the agent of Chagas' disease, proliferates in the midgut of the insect vector; however, heme metabolism in trypanosomatids remains to be elucidated. Here we provide a mechanistic explanation for the proliferative effects of heme on trypanosomatids. Heme, but not other porphyrins, induced T. cruzi proliferation, and this phenomenon was accompanied by a marked increase in reactive oxygen species (ROS) formation in epimastigotes when monitored by ROS-sensitive fluorescent probes. Heme-induced ROS production was time- and concentration-dependent. In addition, lipid peroxidation and the formation of 4-hydroxy-2-nonenal (4-HNE) adducts with parasite proteins were increased in epimastigotes in the presence of heme. Conversely, the antioxidants urate and GSH reversed the heme-induced ROS. Urate also decreased parasite proliferation. Among several protein kinase inhibitors tested only specific inhibitors of CaMKII, KN93 and Myr-AIP, were able to abolish heme-induced ROS formation in epimastigotes leading to parasite growth impairment. Taken together, these data provide new insight into T. cruzi- insect vector interactions: heme, a molecule from the blood digestion, triggers epimastigote proliferation through a redox-sensitive signalling mechanism.     

Mitochondrial ROS in myocardial ischemia reperfusion and remodeling

Despite major progress in interventional and medical treatments, myocardial infarction (MI) and subsequent development of heart failure (HF) are still associated with high mortality. Both during ischemia reperfusion (IR) in the acute setting of MI, as well as in the chronic remodeling process following MI, oxidative stress substantially contributes to cardiac damage. Reactive oxygen species (ROS) generated within mitochondria are particular drivers of mechanisms contributing to IR injury, including induction of mitochondrial permeability transition or oxidative damage of intramitochondrial structures and molecules. But even beyond the acute setting, mechanisms like inflammatory signaling, extracellular remodeling, or pro-apoptotic signaling that contribute to post-infarction remodeling are regulated by mitochondrial ROS. In the current review, we discuss both sources and consequences of mitochondrial ROS during IR and in the chronic setting following MI, thereby emphasizing the potential therapeutic value of attenuating mitochondrial ROS to improve outcome and prognosis for patients suffering MI.     

Direct oxidative modifications of signalling proteins in mammalian cells and their effects on apoptosis

The production of ROS is an inevitable consequence of metabolism. However, high levels of ROS within a cell can be lethal and so the cell has a number of defences against oxidative cell stress. Occasionally the cell's antioxidant mechanisms fail and oxidative stress occurs. High levels of ROS within a cell have a number of direct and indirect consequences on cell signalling pathways and may result in apoptosis or necrosis. Although some of the indirect effects of ROS are well known, limitations in technology mean that the direct effects of the cell's redox environment upon proteins are less understood. Recent work by a number of groups has demonstrated that ROS can directly modify signalling proteins through different modifications, for example by nitrosylation, carbonylation, di-sulphide bond formation and glutathionylation. These modifications modulate a protein's activity and several recent papers have demonstrated their importance in cell signalling events, especially those involved in cell death/survival. Redox modification of proteins allows for further regulation of cell signalling pathways in response to the cellular environment. Understanding them may be critical for us to modulate cell pathways for our own means, such as in cytotoxic drug treatments of cancer cells. Protein modifications mediated by oxidative stress can modulate apoptosis, either through specific protein modifications resulting in regulation of signalling pathways, or through a general increase in oxidised proteins resulting in reduced cellular function. This review discusses direct oxidative protein modifications and their effects on apoptosis.