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Iron is an essential trace metal for almost all organisms, including human; however, oxidative stress can easily be caused when iron is in excess, producing toxicity to the human body due to its capability to be both an electron donor and an electron acceptor. Although there is a strict regulation mechanism for iron homeostasis in the human body and brain, it is usually inevitably disturbed by genetic and environmental factors, or disordered with aging, which leads to iron metabolism diseases, including many neurodegenerative diseases such as Alzheimer’s disease (AD). AD is one of the most common degenerative diseases of the central nervous system (CNS) threatening human health. However, the precise pathogenesis of AD is still unclear, which seriously restricts the design of interventions and treatment drugs based on the pathogenesis of AD. Many studies have observed abnormal iron accumulation in different regions of the AD brain, resulting in cognitive, memory, motor and other nerve damages. Understanding the metabolic balance mechanism of iron in the brain is crucial for the treatment of AD, which would provide new cures for the disease. This paper reviews the recent progress in the relationship between iron and AD from the aspects of iron absorption in intestinal cells, storage and regulation of iron in cells and organs, especially for the regulation of iron homeostasis in the human brain and prospects the future directions for AD treatments.

Iron is an essential micronutrient for plants as it involves in several important physiological processes. Understanding iron homeostasis in plants is pivotal, not only for improving their growth and development but also for enhancing human nutrition as plants are the principal dietary source of iron. This calls for the need to enrich bioavailable iron in crops to resolve iron starvation issue especially in low income and rural populations who have limited access to food markets and proper health facilities. The uptake of iron from rhizosphere, its transporters and transcription factors that regulate iron acquisition are well characterized. Here, the present review emphasizes on the role of signalling molecules particularly phytohormones and nitric oxide and their interactive co-ordination in iron homeostasis in agriculturally important crops that grow at pH 6.0-7.5 and have limited access to Fe2+. The involvement of these signalling molecules in up-regulating iron acquisition genes (FRO2 and IRT1), iron translocation to the cellular compartments and accessibility of iron storage which are important for proper iron homeostasis hence can be considered as vital biofortification strategy for crop plants to address hidden hunger.

In this work, we present a novel modeling framework for understanding the dynamics of homeostatic regulation. Inspired by engineering control theory, this framework incorporates unique features of biological systems. First, biological variables often play physiological roles, and taking this functional context into consideration is essential to fully understand the goals and constraints of homeostatic regulation. Second, biological signals are not abstract variables, but rather material molecules that may undergo complex turnover processes of synthesis and degradation. We suggest that the particular nature of biological signals may condition the type of information they can convey, and their potential role in shaping the dynamics and the ultimate purpose of homeostatic systems. We show that the dynamic interplay between regulated variables and control signals is a key determinant of biological homeostasis, challenging the necessity and the convenience of strictly extrapolating concepts from engineering control theory in modeling the dynamics of homeostatic systems. This work provides a simple, unified framework for studying biological regulation and identifies general principles that transcend molecular details of particular homeostatic mechanisms. We show how this approach can be naturally applied to apparently different regulatory systems, contributing to a deeper understanding of homeostasis as a fundamental process in living systems.

BACKGROUND AND AIMS: Soil microbes have been demonstrated to play an important role in favouring plant iron (Fe) uptake under Fe-limiting conditions. However, the mechanisms involved are still unclear. This present study reported the effects of plant Fe status on the composition of siderophore-secreting microbes in the rhizosphere, and their potential function in improving plant Fe nutrition. METHODS: An Fe-efficient plant, red clover (Trifolium pratense 'Kenland') was cultured in a calcareous soil to obtain rhizosphere soils with (Fe-sufficient) or without (Fe-stressed) foliar FeEDTA spraying. The siderophore-producing ability of rhizospheric microbes was measured. The bioavailability of the siderophore-solubilized Fe from iron oxides/hydroxides was tested in hydroponic culture. KEY RESULTS: In rhizosphere soil, the number of microbes that secreted siderophores quickly was more in the Fe-stressed treatment than in the Fe-sufficient one, while the number of microbes that did not secret siderophores was the opposite. A significantly higher concentration of phenolics was detected in the rhizosphere soil of Fe-stressed plants. Moreover, after the soil was incubated with phenolic root exudates, the composition of the siderophore-secreting microbial community was similar with that of the rhizosphere of Fe-stressed plant. Additionally, the siderophores produced by a rhizospheric microbe isolated from the Fe-stressed treatment can well solubilize iron oxides/hydroxides, and the utilization of the siderophore-solubilized Fe by plant was even more efficient than EDTA-Fe. CONCLUSIONS: Iron-deficiency stress of red clover would alter the composition of siderophore-secreting microbes in the rhizosphere, which is probably due to the phenolics secretion of the root, and may in turn help to improve the solubility of Fe in soils and plant Fe nutrition via elevated microbial siderophore secretion.

Iron is essential for providing oxygen to working muscles during exercise, and iron deficiency leads to decreased exercise capacity during endurance events. However, the mechanism of iron deficiency among endurance athletes remains unclear. In this study, we compared iron status between two periods involving different training regimens. Sixteen female long-distance runners participated. Over a seven-month period, fasting blood samples were collected during their regular training period (LOW; middle of February) and during an intensified training period (INT; late of August) to determine blood hematological, iron, and inflammatory parameters. Three-day food diaries were also assessed. Body weight and lean body mass did not differ significantly between LOW and INT, while body fat and body fat percentage were significantly lower in INT (p < 0.05). Blood hemoglobin, serum ferritin, total protein, and iron levels, total iron-binding capacity, and transferrin saturation did not differ significantly between the two periods. Serum hepcidin levels were significantly higher during INT than LOW (p < 0.05). Carbohydrate and iron intakes from the daily diet were significantly higher during INT than LOW (p < 0.05). In conclusion, an elevated hepcidin level was observed during an intensified training period in long-distance runners, despite an apparently adequate daily intake of iron.

BACKGROUND: Iron is an essential element for both plant productivity and nutritional quality. Improving plant iron content was attempted through genetic engineering of plants overexpressing ferritins. However, both the roles of these proteins in plant physiology, and the mechanisms involved in the regulation of their expression are largely unknown. Although the structure of ferritins is highly conserved between plants and animals, their cellular localization differs. Furthermore, regulation of ferritin gene expression in response to iron excess occurs at the transcriptional level in plants, in contrast to animals which regulate ferritin expression at the translational level. SCOPE: In this review, an overview of our knowledge of bacterial and mammalian ferritin synthesis and functions is presented. Then the following will be reviewed: (a) the specific features of plant ferritins; (b) the regulation of their synthesis during development and in response to various environmental cues; and (c) their function in plant physiology, with special emphasis on the role that both bacterial and plant ferritins play during plant-bacteria interactions. Arabidopsis ferritins are encoded by a small nuclear gene family of four members which are differentially expressed. Recent results obtained by using this model plant enabled progress to be made in our understanding of the regulation of the synthesis and the in planta function of these various ferritins. CONCLUSIONS: Studies on plant ferritin functions and regulation of their synthesis revealed strong links between these proteins and protection against oxidative stress. In contrast, their putative iron-storage function to furnish iron during various development processes is unlikely to be essential. Ferritins, by buffering iron, exert a fine tuning of the quantity of metal required for metabolic purposes, and help plants to cope with adverse situations, the deleterious effects of which would be amplified if no system had evolved to take care of free reactive iron.

BACKGROUND AND AIMS: Iron (Fe) is necessary for plant growth and development. Although it is well known that Fe deficiency causes chlorosis in plants, it remains unclear how the Fe homeostasis is regulated in mesophyll cells. The aim of this work was to identify a gene related to Fe homeostasis in leaves. METHODS: A spontaneous mutant irm1, which revealed typical Fe-deficiency chlorosis, was found from Arabidopsis thaliana. Using map-based cloning, the gene responsible for the altered phenotype of irm1 was cloned. The expression of genes was analysed using northern blot hybridization and multiplex RT-PCR analysis. Further, GUS staining with transgenic promoter-GUS lines and transient expression of the fusion protein with GFP were used for detecting the expression pattern of the gene in different tissues and at different developmental stages, and for the subcelluar localization of the gene product. KEY RESULTS: A point mutation from G to A at nucleotide 2317 of ClpC1 on chromosome V of Arabidopsis is responsible for the irm1 phenotype. The leaf chlorosis of the mutant irm1 and clpc1 (a T-DNA-inserted null mutant of ClpC1) could be converted to green by watering the soil with Fe solution. The expression intensity of ferric reductase FRO8 in irm1 and clpc1 was disordered (significantly higher than that of wild type). CONCLUSIONS: The glycine residue at amino acid 773 of ClpC1 is essential for its functions. In addition to its known functions reported previously, ClpC1 is involved in leaf Fe homeostasis, presumably via chloroplast translocation of some nuclear-encoded proteins which function in Fe transport.

BACKGROUND: Nitric oxide (NO) is a signalling and physiologically active molecule in animals, plants and bacteria. The specificity of the molecular mechanism(s) involved in transducing the NO signal within and between cells and tissues is still poorly understood. NO has been shown to be an emerging and potent signal molecule in plant growth, development and stress physiology. The NO donor S-nitrosoglutathion (GSNO) was shown to be a biologically active compound in plants and a candidate for NO storage and/or mobilization between plant tissues and cells. NO has been implicated as a central component in maintaining iron bioavailavility in plants. SCOPE AND CONCLUSIONS: Iron is an essential nutrient for almost all organisms. This review presents an overview of the functions of NO in iron metabolism in animals and discusses how NO production constitutes a key response in plant iron sensing and availability. In plants, NO drives downstream responses to both iron deficiency and iron overload. NO-mediated improvement of iron nutrition in plants growing under iron-deficient conditions represents a powerful tool to cope with soils displaying low iron availability. An interconversion between different redox forms based on the iron and NO status of the plant cells might be the core of a metabolic process driving plant iron homeostasis. Frataxin, a recently identified protein in plants, plays an important role in mitochondria biogenesis and in maintaining mitochondrial iron homeostasis. Evidence regarding the interaction between frataxin, NO and iron from analysis of frataxin knock-down Arabidopsis thaliana mutants is reviewed and discussed.

Nuclear receptor coactivator 4 (NCOA4) is a selective cargo receptor that mediates the autophagic degradation of ferritin (“ferritinophagy”), the cytosolic iron storage complex. NCOA4-mediated ferritinophagy maintains intracellular iron homeostasis by facilitating ferritin iron storage or release according to demand. Ferritinophagy is involved in iron-dependent physiological processes such as erythropoiesis, where NCOA4 mediates ferritin iron release for mitochondrial heme synthesis. Recently, ferritinophagy has been shown to regulate ferroptosis, a newly described form of iron-dependent cell death mediated by excess lipid peroxidation. Dysregulation of iron metabolism and ferroptosis have been described in neurodegeneration, cancer, and infection, but little is known about the role of ferritinophagy in the pathogenesis of these diseases. Here, we will review the biochemical regulation of NCOA4, its contribution to physiological processes and its role in disease. Finally, we will discuss the potential of activating or inhibiting ferritinophagy and ferroptosis for therapeutic purposes.

Iron is an essential nutrient for plants, but excess iron is toxic due to its catalytic role in the formation of hydroxyl radicals. Thus, iron uptake is highly regulated and induced only under iron deficiency. The mechanisms of iron uptake in roots are well characterized, but less is known about how plants perceive iron deficiency. We show that a basic helix–loop–helix (bHLH) transcription factor Upstream Regulator of IRT1 (URI) acts as an essential part of the iron deficiency signaling pathway in Arabidopsis thaliana. The uri mutant is defective in inducing Iron-Regulated Transporter1 (IRT1) and Ferric Reduction Oxidase2 (FRO2) and their transcriptional regulators FER-like iron deficiency-induced transcription factor (FIT) and bHLH38/39/100/101 in response to iron deficiency. Chromatin immunoprecipitation followed by sequencing (ChIP-seq) reveals direct binding of URI to promoters of many iron-regulated genes, including bHLH38/39/100/101 but not FIT. While URI transcript and protein are expressed regardless of iron status, a phosphorylated form of URI only accumulates under iron deficiency. Phosphorylated URI is subject to proteasome-dependent degradation during iron resupply, and turnover of phosphorylated URI is dependent on the E3 ligase BTS. The subgroup IVc bHLH transcription factors, which have previously been shown to regulate bHLH38/39/100/101, coimmunoprecipitate with URI mainly under Fe-deficient conditions, suggesting that it is the phosphorylated form of URI that is capable of forming heterodimers in vivo. We propose that the phosphorylated form of URI accumulates under Fe deficiency, forms heterodimers with subgroup IVc proteins, and induces transcription of bHLH38/39/100/101. These transcription factors in turn heterodimerize with FIT and drive the transcription of IRT1 and FRO2 to increase Fe uptake.