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Sample records for iron metabolism limits

  1. Bypasses in intracellular glucose metabolism in iron-limited Pseudomonas putida.

    PubMed

    Sasnow, Samantha S; Wei, Hua; Aristilde, Ludmilla

    2016-02-01

    Decreased biomass growth in iron (Fe)-limited Pseudomonas is generally attributed to downregulated expression of Fe-requiring proteins accompanied by an increase in siderophore biosynthesis. Here, we applied a stable isotope-assisted metabolomics approach to explore the underlying carbon metabolism in glucose-grown Pseudomonas putida KT2440. Compared to Fe-replete cells, Fe-limited cells exhibited a sixfold reduction in growth rate but the glucose uptake rate was only halved, implying an imbalance between glucose uptake and biomass growth. This imbalance could not be explained by carbon loss via siderophore production, which accounted for only 10% of the carbon-equivalent glucose uptake. In lieu of the classic glycolytic pathway, the Entner-Doudoroff (ED) pathway in Pseudomonas is the principal route for glucose catabolism following glucose oxidation to gluconate. Remarkably, gluconate secretion represented 44% of the glucose uptake in Fe-limited cells but only 2% in Fe-replete cells. Metabolic (13) C flux analysis and intracellular metabolite levels under Fe limitation indicated a decrease in carbon fluxes through the ED pathway and through Fe-containing metabolic enzymes. The secreted siderophore was found to promote dissolution of Fe-bearing minerals to a greater extent than the high extracellular gluconate. In sum, bypasses in the Fe-limited glucose metabolism were achieved to promote Fe availability via siderophore secretion and to reroute excess carbon influx via enhanced gluconate secretion.

  2. METABOLISM OF IRON STORES

    PubMed Central

    SAITO, HIROSHI

    2014-01-01

    ABSTRACT Remarkable progress was recently achieved in the studies on molecular regulators of iron metabolism. Among the main regulators, storage iron, iron absorption, erythropoiesis and hepcidin interact in keeping iron homeostasis. Diseases with gene-mutations resulting in iron overload, iron deficiency, and local iron deposition have been introduced in relation to the regulators of storage iron metabolism. On the other hand, the research on storage iron metabolism has not advanced since the pioneering research by Shoden in 1953. However, we recently developed a new method for determining ferritin iron and hemosiderin iron by computer-assisted serum ferritin kinetics. Serum ferritin increase or decrease curves were measured in patients with normal storage iron levels (chronic hepatitis C and iron deficiency anemia treated by intravenous iron injection), and iron overload (hereditary hemochromatosis and transfusion dependent anemia). We thereby confirmed the existence of two iron pathways where iron flows followed the numbered order (1) labile iron, (2) ferritin and (3) hemosiderin in iron deposition and mobilization among many previously proposed but mostly unproven routes. We also demonstrated the increasing and decreasing phases of ferritin iron and hemosiderin iron in iron deposition and mobilization. The author first demonstrated here the change in proportion between pre-existing ferritin iron and new ferritin iron synthesized by removing iron from hemosiderin in the course of iron removal. In addition, the author disclosed the cause of underestimation of storage iron turnover rate which had been reported by previous investigators in estimating storage iron turnover rate of normal subjects. PMID:25741033

  3. Knockdown of proteins involved in iron metabolism limits tick reproduction and development

    PubMed Central

    Hajdusek, Ondrej; Sojka, Daniel; Kopacek, Petr; Buresova, Veronika; Franta, Zdenek; Sauman, Ivo; Winzerling, Joy; Grubhoffer, Libor

    2009-01-01

    Ticks are among the most important vectors of a wide range of human and animal diseases. During blood feeding, ticks are exposed to an enormous amount of free iron that must be appropriately used and detoxified. However, the mechanism of iron metabolism in ticks is poorly understood. Here, we show that ticks possess a complex system that efficiently utilizes, stores and transports non-heme iron within the tick body. We have characterized a new secreted ferritin (FER2) and an iron regulatory protein (IRP1) from the sheep tick, Ixodes ricinus, and have demonstrated their relationship to a previously described tick intracellular ferritin (FER1). By using RNA interference-mediated gene silencing in the tick, we show that synthesis of FER1, but not of FER2, is subject to IRP1-mediated translational control. Further, we find that depletion of FER2 from the tick plasma leads to a loss of FER1 expression in the salivary glands and ovaries that normally follows blood ingestion. We therefore suggest that secreted FER2 functions as the primary transporter of non-heme iron between the tick gut and the peripheral tissues. Silencing of the fer1, fer2, and irp1 genes by RNAi has an adverse impact on hatching rate and decreases postbloodmeal weight in tick females. Importantly, knockdown of fer2 dramatically impairs the ability of ticks to feed, thus making FER2 a promising candidate for development of an efficient anti-tick vaccine. PMID:19171899

  4. Physiology of Iron Metabolism

    PubMed Central

    Waldvogel-Abramowski, Sophie; Waeber, Gérard; Gassner, Christoph; Buser, Andreas; Frey, Beat M.; Favrat, Bernard; Tissot, Jean-Daniel

    2014-01-01

    Summary A revolution occurred during the last decade in the comprehension of the physiology as well as in the physiopathology of iron metabolism. The purpose of this review is to summarize the recent knowledge that has accumulated, allowing a better comprehension of the mechanisms implicated in iron homeostasis. Iron metabolism is very fine tuned. The free molecule is very toxic; therefore, complex regulatory mechanisms have been developed in mammalian to insure adequate intestinal absorption, transportation, utilization, and elimination. ‘Ironomics’ certainly will be the future of the understanding of genes as well as of the protein-protein interactions involved in iron metabolism. PMID:25053935

  5. Iron metabolism and toxicity

    SciTech Connect

    Papanikolaou, G.; Pantopoulos, K. . E-mail: kostas.pantopoulos@mcgill.ca

    2005-01-15

    Iron is an essential nutrient with limited bioavailability. When present in excess, iron poses a threat to cells and tissues, and therefore iron homeostasis has to be tightly controlled. Iron's toxicity is largely based on its ability to catalyze the generation of radicals, which attack and damage cellular macromolecules and promote cell death and tissue injury. This is lucidly illustrated in diseases of iron overload, such as hereditary hemochromatosis or transfusional siderosis, where excessive iron accumulation results in tissue damage and organ failure. Pathological iron accumulation in the liver has also been linked to the development of hepatocellular cancer. Here we provide a background on the biology and toxicity of iron and the basic concepts of iron homeostasis at the cellular and systemic level. In addition, we provide an overview of the various disorders of iron overload, which are directly linked to iron's toxicity. Finally, we discuss the potential role of iron in malignant transformation and cancer.

  6. Macrophages and iron metabolism

    PubMed Central

    Soares, Miguel P.; Hamza, Iqbal

    2016-01-01

    Iron is a transition metal that due to its inherent ability to exchange electrons with a variety of molecules is essential to support life. In mammals, iron exists mostly in the form of heme, enclosed within an organic protoporphyrin ring and functioning primarily as a prosthetic group in proteins. Paradoxically, free iron also has the potential to become cytotoxic when electron exchange with oxygen is unrestricted and catalyzes the production of reactive oxygen species. These biological properties demand that iron metabolism is tightly regulated such that iron is available for core biological functions whilst preventing its cytotoxic effects. Macrophages play a central role in establishing this delicate balance. Here, we review the impact of macrophages on heme-iron metabolism and, reciprocally, how heme-iron modulates macrophage function. PMID:26982356

  7. A Sinorhizobium meliloti RpoH-Regulated Gene Is Involved in Iron-Sulfur Protein Metabolism and Effective Plant Symbiosis under Intrinsic Iron Limitation.

    PubMed

    Sasaki, Shohei; Minamisawa, Kiwamu; Mitsui, Hisayuki

    2016-09-01

    In Sinorhizobium meliloti, RpoH-type sigma factors have a global impact on gene expression during heat shock and play an essential role in symbiosis with leguminous plants. Using mutational analysis of a set of genes showing highly RpoH-dependent expression during heat shock, we identified a gene indispensable for effective symbiosis. This gene, designated sufT, was located downstream of the sufBCDS homologs that specify the iron-sulfur (Fe/S) cluster assembly pathway. The identified transcription start site was preceded by an RpoH-dependent promoter consensus sequence. SufT was related to a conserved protein family of unknown molecular function, of which some members are involved in Fe/S cluster metabolism in diverse organisms. A sufT mutation decreased bacterial growth in both rich and minimal media, tolerance to stresses such as iron starvation, and activities of some Fe/S cluster-dependent enzymes. These results support the involvement of SufT in SUF (sulfur mobilization) system-mediated Fe/S protein metabolism. Furthermore, we isolated spontaneous pseudorevertants of the sufT mutant with partially recovered growth; each of them had a mutation in rirA This gene encodes a global iron regulator whose loss increases the intracellular iron content. Deletion of rirA in the original sufT mutant improved growth and restored Fe/S enzyme activities and effective symbiosis. These results suggest that enhanced iron availability compensates for the lack of SufT in the maintenance of Fe/S proteins. Although RpoH-type sigma factors of the RNA polymerase are present in diverse proteobacteria, their role as global regulators of protein homeostasis has been studied mainly in the enteric gammaproteobacterium Escherichia coli In the soil alphaproteobacterium Sinorhizobium meliloti, the rpoH mutations have a strong impact on symbiosis with leguminous plants. We found that sufT is a unique member of the S. meliloti RpoH regulon; sufT contributes to Fe/S protein metabolism and

  8. A Sinorhizobium meliloti RpoH-Regulated Gene Is Involved in Iron-Sulfur Protein Metabolism and Effective Plant Symbiosis under Intrinsic Iron Limitation

    PubMed Central

    Sasaki, Shohei; Minamisawa, Kiwamu

    2016-01-01

    /S protein metabolism and effective symbiosis under intrinsic iron limitation exerted by RirA, a global iron regulator. Our study provides insights into the RpoH regulon function in diverse proteobacteria adapted to particular ecological niches and into the mechanism of conserved Fe/S protein biogenesis. PMID:27297881

  9. Metabolic Remodeling in Iron-deficient Fungi

    PubMed Central

    Philpott, Caroline C.; Leidgens, Sebastien; Frey, Avery G.

    2012-01-01

    Eukaryotic cells contain dozens, perhaps hundreds, of iron-dependent proteins, which perform critical functions in nearly every major cellular process. Nutritional iron is frequently available to cells in only limited amounts; thus, unicellular and higher eukaryotes have evolved mechanisms to cope with iron scarcity. These mechanisms have been studied at the molecular level in the model eukaryotes Saccharomyces cerevisiae and Schizosaccharomyces pombe, as well as in some pathogenic fungi. Each of these fungal species exhibits metabolic adaptations to iron deficiency that serve to reduce the cell’s reliance on iron. However, the regulatory mechanisms that accomplish these adaptations differ greatly between fungal species. PMID:22306284

  10. Regulation of cellular iron metabolism

    PubMed Central

    Wang, Jian; Pantopoulos, Kostas

    2011-01-01

    Iron is an essential but potentially hazardous biometal. Mammalian cells require sufficient amounts of iron to satisfy metabolic needs or to accomplish specialized functions. Iron is delivered to tissues by circulating transferrin, a transporter that captures iron released into the plasma mainly from intestinal enterocytes or reticuloendothelial macrophages. The binding of iron-laden transferrin to the cell-surface transferrin receptor 1 results in endocytosis and uptake of the metal cargo. Internalized iron is transported to mitochondria for the synthesis of haem or iron–sulfur clusters, which are integral parts of several metalloproteins, and excess iron is stored and detoxified in cytosolic ferritin. Iron metabolism is controlled at different levels and by diverse mechanisms. The present review summarizes basic concepts of iron transport, use and storage and focuses on the IRE (iron-responsive element)/IRP (iron-regulatory protein) system, a well known post-transcriptional regulatory circuit that not only maintains iron homoeostasis in various cell types, but also contributes to systemic iron balance. PMID:21348856

  11. Iron metabolism in mammalian cells.

    PubMed

    Walker, B L; Tiong, J W; Jefferies, W A

    2001-01-01

    Most living things require iron to exist. Iron has many functions within cells but is rarely found unbound because of its propensity to catalyze the formation of toxic free radicals. Thus the regulation of iron requirements by cells and the acquisition and uptake of iron into tissues in multicellular organisms is tightly regulated. In humans, understanding iron transport and utility has recently been advanced by a "great conjunction" of molecular genetics in simple organisms, identifying genes involved in genetic diseases of metal metabolism and by the application of traditional cell physiology approaches. We are now able to approach a rudimentary understanding of the "iron cycle" within mammals. In the future, this information will be applied toward modulating the outcome of therapies designed to overcome diseases involving metals.

  12. Iron metabolism: current facts and future directions

    PubMed Central

    Tandara, Leida; Salamunic, Ilza

    2012-01-01

    Iron metabolism has been intensively examined over the last decade and there are many new players in this field which are worth to be introduced. Since its discovery many studies confirmed role of liver hormone hepcidin as key regulator of iron metabolism and pointed out liver as the central organ of system iron homeostasis. Liver cells receive multiple signals related to iron balance and respond by transcriptional regulation of hepcidin expression. This liver hormone is negative regulator of iron metabolism that represses iron efflux from macrophages, hepatocytes and enterocytes by its binding to iron export protein ferroportin. Ferroportin degradation leads to cellular iron retention and decreased iron availability. At level of a cell IRE/IRP (iron responsive elements/iron responsive proteins) system allows tight regulation of iron assimilation that prevents an excess of free intracellular iron which could lead to oxidative stress and damage of DNA, proteins and lipid membranes by ROS (reactive oxygen species). At the same time IRE/IRP system provides sufficient iron in order to meet the metabolic needs. Recently a significant progress in understanding of iron metabolism has been made and new molecular participants have been characterized. Article gives an overview of the current understanding of iron metabolism: absorption, distribution, cellular uptake, release, and storage. We also discuss mechanisms underlying systemic and cellular iron regulation with emphasis on central regulatory hormone hepcidin. PMID:23092063

  13. Iron metabolism: current facts and future directions.

    PubMed

    Tandara, Leida; Salamunic, Ilza

    2012-01-01

    Iron metabolism has been intensively examined over the last decade and there are many new players in this field which are worth to be introduced. Since its discovery many studies confirmed role of liver hormone hepcidin as key regulator of iron metabolism and pointed out liver as the central organ of system iron homeostasis. Liver cells receive multiple signals related to iron balance and respond by transcriptional regulation of hepcidin expression. This liver hormone is negative regulator of iron metabolism that represses iron efflux from macrophages, hepatocytes and enterocytes by its binding to iron export protein ferroportin. Ferroportin degradation leads to cellular iron retention and decreased iron availability. At level of a cell IRE/IRP (iron responsive elements/iron responsive proteins) system allows tight regulation of iron assimilation that prevents an excess of free intracellular iron which could lead to oxidative stress and damage of DNA, proteins and lipid membranes by ROS (reactive oxygen species). At the same time IRE/IRP system provides sufficient iron in order to meet the metabolic needs. Recently a significant progress in understanding of iron metabolism has been made and new molecular participants have been characterized. Article gives an overview of the current understanding of iron metabolism: absorption, distribution, cellular uptake, release, and storage. We also discuss mechanisms underlying systemic and cellular iron regulation with emphasis on central regulatory hormone hepcidin.

  14. Iron metabolism in burned children.

    PubMed

    Belmonte, J A; Ibáñez, L; Ras, M R; Aulesa, C; Vinzo, J; Iglesias, J; Carol, J

    1999-07-01

    The administration of iron supplementation in children with burns has been a subject of controversy. Recent studies argue against its use in the acute phase of stress. To assess whether iron metabolism parameters show significant differences in the acute phase and the recovery phase of burn, 21 patients (age range: 17 months to 13 years) with burns of more than 10% of body surface who had not received blood transfusions or iron supplementation were studied. Sideraemia, ferritin, transferrin, transferrin saturation index (TSI) and C-reactive protein (CRP) were assessed both in the acute and the recovery phase after burn. Sideraemia, transferrin, and TSI were significantly lower in the acute than in the recovery phase (17.3 +/- 3 vs 53.8 +/- 6.6 microg/dL, 190.5 +/- 15 vs 287.9 +/- 14.3 mg/dL and 7.7 +/- 1.3 vs 15.4 +/- 1.6%, P < 0.0001, P < 0.001 and P = 0.0006, respectively) while plasma ferritin and CRP were significantly higher (84.7 +/- 8.8 vs 43.1 +/- 8.5 ng/mL and 9.5 +/- 1.5 vs 0.7 +/- 0.2 mg/dL, P = 0.016 and P < 0.0001, respectively). When the above parameters were analysed based on age (< or = 2 years, > 2 years), the observed differences persisted. Hyposideraemia is a frequent finding in the acute phase of paediatric burns and is accompanied by increased ferritin levels and decreased transferrin concentrations. The low iron values tend to recover without the use of iron supplementation suggesting an endogenous block of iron release in the acute phase and indicates that iron therapy should be not recommended in the initial period of stress of the burned patient.

  15. Ferritin couples iron and fatty acid metabolism.

    PubMed

    Bu, Weiming; Liu, Renyu; Cheung-Lau, Jasmina C; Dmochowski, Ivan J; Loll, Patrick J; Eckenhoff, Roderic G

    2012-06-01

    A physiological relationship between iron, oxidative injury, and fatty acid metabolism exists, but transduction mechanisms are unclear. We propose that the iron storage protein ferritin contains fatty acid binding sites whose occupancy modulates iron uptake and release. Using isothermal microcalorimetry, we found that arachidonic acid binds ferritin specifically and with 60 μM affinity. Arachidonate binding by ferritin enhanced iron mineralization, decreased iron release, and protected the fatty acid from oxidation. Cocrystals of arachidonic acid and horse spleen apoferritin diffracted to 2.18 Å and revealed specific binding to the 2-fold intersubunit pocket. This pocket shields most of the fatty acid and its double bonds from solvent but allows the arachidonate tail to project well into the ferrihydrite mineralization site on the ferritin L-subunit, a structural feature that we implicate in the effects on mineralization by demonstrating that the much shorter saturated fatty acid, caprylate, has no significant effects on mineralization. These combined effects of arachidonate binding by ferritin are expected to lower both intracellular free iron and free arachidonate, thereby providing a previously unrecognized mechanism for limiting lipid peroxidation, free radical damage, and proinflammatory cascades during times of cellular stress.

  16. [Iron metabolism, overview and recent insights].

    PubMed

    Omar, S; Feki, M; Kaabachi, N

    2006-01-01

    The paper is an up to date overview of knowledge on iron metabolism that integrate recent findings in this field. Significant advances were made in understanding the implication of protein factors (transporters, enzymes and regulation factors) in iron metabolism, as well as related genetic abnormalities. The research highlighted the complexity of mechanisms in charge of maintaining equilibrium of Fe in the body. The iron is vital to the life of cells, but its presence in excess is rather toxic. Iron is mostly required for hemoglobin synthesis. It is recycled between reticulo-endothelial macrophages and bone marrow that is the main user of iron. Intestinal absorption is a key step in determining iron capital in the body. Its rate is tightly controlled by several factors that act under influence of signals of unknown nature, which indicate iron needs and storage. The IRP/IRE (iron regulatory protein/iron responsive element) system controls cellular uptake, stores and exportation of iron, and heme synthesis. Mitochondrion is a dynamo of iron metabolism, being vital for heme synthesis and iron sulphur cluster genesis. The recent discovery of several mitochondrial proteins involved in iron metabolism resulted in better understanding mitochondrial iron movement, storage and exchange. Nevertheless, much remains to be known on the role of some actors such as HFE protein, hepcidin, hemojuvelin and transferrin receptor 2, and to determine the nature and mechanisms of signals regulating iron level in the body.

  17. Iron metabolism in children: Confounding factors

    PubMed Central

    Brittenham, Gary M.

    2011-01-01

    Characterization of iron metabolism in infants and children may be confounded by the diverse effects of developmental, genetic, and acquired influences on iron metabolism and laboratory measurements of iron status, especially in areas with intense perennial transmission of Plasmodium falciparum malaria. In the Pemba iron and folic acid supplementation trial, the coadministration of folic acid with iron is a further confounding factor. Because the design of the Pemba iron and folic acid supplementation study did not include a group that received iron supplementation without folic acid, the observed increase in serious adverse events cannot be ascribed unequivocally to iron alone, to folic acid alone, or to the combination of the two. In interpreting the results from the Pemba iron and folic acid supplementation trial, additional analyses of existing data from the trial and from earlier studies in the area could help clarify the roles of iron and folic acid. PMID:18297889

  18. A Systems Biology Approach to Iron Metabolism

    PubMed Central

    Chifman, J.; Laubenbacher, R.; Torti, S.V.

    2015-01-01

    Iron is critical to the survival of almost all living organisms. However, inappropriately low or high levels of iron are detrimental and contribute to a wide range of diseases. Recent advances in the study of iron metabolism have revealed multiple intricate pathways that are essential to the maintenance of iron homeostasis. Further, iron regulation involves processes at several scales, ranging from the subcellular to the organismal. This complexity makes a systems biology approach crucial, with its enabling technology of computational models based on a mathematical description of regulatory systems. Systems biology may represent a new strategy for understanding imbalances in iron metabolism and their underlying causes. PMID:25480643

  19. In vivo iron metabolism by IRMS

    USDA-ARS?s Scientific Manuscript database

    Iron isotopes are used in both biological and geological investigations. Three low-abundance stable isotopes are available for human studies. They have been widely used to study iron metabolism. They have provided valuable insights into iron deficiency, one of the most common micronutrient deficienc...

  20. Mammalian iron metabolism and its control by iron regulatory proteins☆

    PubMed Central

    Anderson, Cole P.; Shen, Lacy; Eisenstein, Richard S.; Leibold, Elizabeth A.

    2013-01-01

    Cellular iron homeostasis is maintained by iron regulatory proteins 1 and 2 (IRP1 and IRP2). IRPs bind to iron-responsive elements (IREs) located in the untranslated regions of mRNAs encoding protein involved in iron uptake, storage, utilization and export. Over the past decade, significant progress has been made in understanding how IRPs are regulated by iron-dependent and iron-independent mechanisms and the pathological consequences of IRP2 deficiency in mice. The identification of novel IREs involved in diverse cellular pathways has revealed that the IRP–IRE network extends to processes other than iron homeostasis. A mechanistic understanding of IRP regulation will likely yield important insights into the basis of disorders of iron metabolism. This article is part of a Special Issue entitled: Cell Biology of Metals. PMID:22610083

  1. Iron metabolism: from health to disease.

    PubMed

    Oliveira, Fernando; Rocha, Sara; Fernandes, Rúben

    2014-05-01

    Iron is vital for almost all living organisms by participating in a wide range of metabolic processes. However, iron concentration in body tissues must be tightly regulated since excessive iron may lead to microbial infections or cause tissue damage. Disorders of iron metabolism are among the most common human diseases and cover several conditions with varied clinical manifestations. An extensive literature review on the basic aspects of iron metabolism was performed, and the most recent findings on this field were highlighted as well. New insights on iron metabolism have shed light into its real complexity, and its role in both healthy and pathological states has been recognized. Important discoveries about the iron regulatory machine and imbalances in its regulation have been made, which may lead in a near future to the development of new therapeutic strategies against iron disorders. Besides, the toxicity of free iron and its association with several pathologies has been addressed, although it requires further investigations. This review will provide students in the fields of biochemistry and health sciences a brief and clear overview of iron physiology and toxicity, as well as imbalances in the iron homeostasis and associated pathological conditions. © 2014 Wiley Periodicals, Inc.

  2. Brain Iron Metabolism Dysfunction in Parkinson's Disease.

    PubMed

    Jiang, Hong; Wang, Jun; Rogers, Jack; Xie, Junxia

    2017-05-01

    Dysfunction of iron metabolism, which includes its uptake, storage, and release, plays a key role in neurodegenerative disorders, including Parkinson's disease (PD), Alzheimer's disease, and Huntington's disease. Understanding how iron accumulates in the substantia nigra (SN) and why it specifically targets dopaminergic (DAergic) neurons is particularly warranted for PD, as this knowledge may provide new therapeutic avenues for a more targeted neurotherapeutic strategy for this disease. In this review, we begin with a brief introduction describing brain iron metabolism and its regulation. We then provide a detailed description of how iron accumulates specifically in the SN and why DAergic neurons are especially vulnerable to iron in PD. Furthermore, we focus on the possible mechanisms involved in iron-induced cell death of DAergic neurons in the SN. Finally, we present evidence in support that iron chelation represents a plausable therapeutic strategy for PD.

  3. Regulation of Iron Metabolism by Pyrococcus furiosus

    PubMed Central

    Zhu, Yixuan; Kumar, Sunil; Menon, Angeli L.; Scott, Robert A.

    2013-01-01

    Iron is an essential element for the hyperthermophilic archaeon Pyrococcus furiosus, and many of its iron-containing enzymes have been characterized. How iron assimilation is regulated, however, is unknown. The genome sequence contains genes encoding two putative iron-responsive transcription factors, DtxR and Fur. Global transcriptional profiles of the dtxR deletion mutant (ΔDTXR) and the parent strain under iron-sufficient and iron-limited conditions indicated that DtxR represses the expression of the genes encoding two putative iron transporters, Ftr1 and FeoAB, under iron-sufficient conditions. Under iron limitation, DtxR represses expression of the gene encoding the iron-containing enzyme aldehyde ferredoxin oxidoreductase and a putative ABC-type transporter. Analysis of the dtxR gene sequence indicated an incorrectly predicted translation start site, and the corrected full-length DtxR protein, in contrast to the truncated version, specifically bound to the promoters of ftr1 and feoAB, confirming its role as a transcription regulator. Expression of the gene encoding Ftr1 was dramatically upregulated by iron limitation, but no phenotype was observed for the ΔFTR1 deletion mutant under iron-limited conditions. The intracellular iron concentrations of ΔFTR1 and the parent strain were similar, suggesting that under the conditions tested, Ftr1 is not an essential iron transporter despite its response to iron. In contrast to DtxR, the Fur protein appears not to be a functional regulator in P. furiosus, since it did not bind to the promoters of any of the iron-regulated genes and the deletion mutant (ΔFUR) revealed no transcriptional responses to iron availability. DtxR is therefore the key iron-responsive transcriptional regulator in P. furiosus. PMID:23504018

  4. Iron regulatory proteins and their role in controlling iron metabolism.

    PubMed

    Kühn, Lukas C

    2015-02-01

    Cellular iron homeostasis is regulated by post-transcriptional feedback mechanisms, which control the expression of proteins involved in iron uptake, release and storage. Two cytoplasmic proteins with mRNA-binding properties, iron regulatory proteins 1 and 2 (IRP1 and IRP2) play a central role in this regulation. Foremost, IRPs regulate ferritin H and ferritin L translation and thus iron storage, as well as transferrin receptor 1 (TfR1) mRNA stability, thereby adjusting receptor expression and iron uptake via receptor-mediated endocytosis of iron-loaded transferrin. In addition splice variants of iron transporters for import and export at the plasma-membrane, divalent metal transporter 1 (DMT1) and ferroportin are regulated by IRPs. These mechanisms have probably evolved to maintain the cytoplasmic labile iron pool (LIP) at an appropriate level. In certain tissues, the regulation exerted by IRPs influences iron homeostasis and utilization of the entire organism. In intestine, the control of ferritin expression limits intestinal iron absorption and, thus, whole body iron levels. In bone marrow, erythroid heme biosynthesis is coordinated with iron availability through IRP-mediated translational control of erythroid 5-aminolevulinate synthase mRNA. Moreover, the translational control of HIF2α mRNA in kidney by IRP1 coordinates erythropoietin synthesis with iron and oxygen supply. Besides IRPs, body iron absorption is negatively regulated by hepcidin. This peptide hormone, synthesized and secreted by the liver in response to high serum iron, downregulates ferroportin at the protein level and thereby limits iron absorption from the diet. Hepcidin will not be discussed in further detail here.

  5. Genome and low-iron response of an oceanic diatom adapted to chronic iron limitation

    PubMed Central

    2012-01-01

    Background Biogeochemical elemental cycling is driven by primary production of biomass via phototrophic phytoplankton growth, with 40% of marine productivity being assigned to diatoms. Phytoplankton growth is widely limited by the availability of iron, an essential component of the photosynthetic apparatus. The oceanic diatom Thalassiosira oceanica shows a remarkable tolerance to low-iron conditions and was chosen as a model for deciphering the cellular response upon shortage of this essential micronutrient. Results The combined efforts in genomics, transcriptomics and proteomics reveal an unexpected metabolic flexibility in response to iron availability for T. oceanica CCMP1005. The complex response comprises cellular retrenchment as well as remodeling of bioenergetic pathways, where the abundance of iron-rich photosynthetic proteins is lowered, whereas iron-rich mitochondrial proteins are preserved. As a consequence of iron deprivation, the photosynthetic machinery undergoes a remodeling to adjust the light energy utilization with the overall decrease in photosynthetic electron transfer complexes. Conclusions Beneficial adaptations to low-iron environments include strategies to lower the cellular iron requirements and to enhance iron uptake. A novel contribution enhancing iron economy of phototrophic growth is observed with the iron-regulated substitution of three metal-containing fructose-bisphosphate aldolases involved in metabolic conversion of carbohydrates for enzymes that do not contain metals. Further, our data identify candidate components of a high-affinity iron-uptake system, with several of the involved genes and domains originating from duplication events. A high genomic plasticity, as seen from the fraction of genes acquired through horizontal gene transfer, provides the platform for these complex adaptations to a low-iron world. PMID:22835381

  6. Effects of alcohol consumption on iron metabolism.

    PubMed

    Lieb, M; Palm, U; Hock, B; Schwarz, M; Domke, I; Soyka, M

    2011-01-01

    Patients with alcohol abuse frequently suffer from malnutrition which may result in insufficient iron distribution and iron overload or deficiency. Iron metabolism can be described by a combination of biochemical soluble transferrin receptor, ferritin, C-reactive protein (CRP), and hematological parameters. Here, vitamin B12 and folic acid state were assessed. Results on iron metabolism in patients with alcohol dependence in comparison with social drinkers are presented. Samples from 101 patients with dependent alcohol consumption were included. The control group comprised 115 social drinkers. Inclusion criteria for patients with chronic regular drinking/social drinkers were positive/negative score of the Alcohol Use Disorders Identification Test (AUDIT), and positive/negative score for alcohol abuse/dependence (DSM-IV criteria). Absolute values for ferritin and sTfR are increased in patients with alcohol dependence with current consumption (ALC) compared with social drinkers. No major differences are observed in the ratio of sTfR/log ferritin in comparison with social drinkers. Hemoglobin concentrations correlated between the two groups. Mean corpuscular volume (MCV) was significantly increased in the ALC collective compared to social drinkers. Eighty patients of the alcohol-dependent group had sufficient iron repletion, 11 had iron overload, 6 are suspicious for functional iron deficiency, and 4 are suspicious for reduced iron supply. No vitamin B12/folate deficiencies are observed in alcohol-dependent patients. No major abnormalities of iron metabolism are seen in patients with chronic alcohol ingestion besides the well-known macrocytic anemia. Iron overload is relatively frequent and observed in 9% of cases. No differences in vitamin B12 and folate levels were found between individuals with alcohol dependence and social drinkers.

  7. Influence of iron-limited continuous culture on physiology and virulence of Legionella pneumophila.

    PubMed Central

    James, B W; Mauchline, W S; Fitzgeorge, R B; Dennis, P J; Keevil, C W

    1995-01-01

    A virulent strain of Legionella pneumophila serogroup 1, subgroup Pontiac, was grown in continuous culture at a constant growth rate under iron-replete and iron-limited conditions. Iron limitation was achieved by the removal of ferrous sulfate and hemin from the chemically defined medium. Residual contaminating iron, 0.45 microM, was sufficient to support iron-limited growth. Typical iron-replete cultures metabolized 3.3 microM iron. Serine provided the principal source of carbon and energy for both cultures, although iron-replete cultures also depleted a number of other amino acids. There was a 40% decrease in culture biomass under iron-restricted conditions. Iron limitation did not significantly affect carbohydrate metabolism, with the molar growth yield for carbon (Ycarbon) comparable for both cultures. However, under iron-limited conditions a sixfold increase in Yiron correlated with a significant decrease in the iron content of the biomass, as the culture utilized the available iron more efficiently. Highly pleomorphic iron-replete cultures became uniform cultures of short fine rods when adapted to iron-deficient conditions. In addition to the morphological and physiological changes, iron limitation had a critical effect on culture virulence. The virulence of this strain was significantly (P < 0.05) reduced when the culture was subjected to iron-limited conditions. This phenomenon was reversible, with a significant increase in culture virulence upon reversion to iron-replete conditions. When compared in an in vitro macrophage assay, the number of culturable avirulent iron-limited cells located intracellularly after infection was significantly lower than for the virulent replete and control cultures. These results further support the role of environmental parameters in regulating the virulence of L. pneumophila. PMID:7591051

  8. Iron metabolism: State of the art.

    PubMed

    Daher, R; Karim, Z

    2017-09-01

    Iron homeostasis relies on the amount of its absorption by the intestine and its release from storage sites, the macrophages. Iron homeostasis is also dependent on the amount of iron used for the erythropoiesis. Hepcidin, which is synthesized predominantly by the liver, is the main regulator of iron metabolism. Hepcidin reduces serum iron by inhibiting the iron exporter, ferroportin expressed both tissues, the intestine and the macrophages. In addition, in the enterocytes, hepcidin inhibits the iron influx by acting on the apical transporter, DMT1. A defect of hepcidin expression leading to the appearance of a parenchymal iron overload may be genetic or secondary to dyserythropoiesis. The exploration of genetic hemochromatosis has revealed the involvement of several genes, including the recently described BMP6. Non-transfusional secondary hemochromatosis is due to hepcidin repression by cytokines, in particular the erythroferone factor that is produced directly by the erythroid precursors. Iron overload is correlated with the appearance of a free form of iron called NTBI. The influx of NTBI seems to be mediated by ZIP14 transporter in the liver and by calcium channels in the cardiomyocytes. Beside the liver, hepcidin is expressed at lesser extent in several extrahepatic tissues where it plays its ancestral role of antimicrobial peptide. In the kidney, hepcidin modulates defense barriers against urinary tract infections. In the heart, hepcidin maintains tissue iron homeostasis by an autocrine regulation of ferroprotine expression on the surface of cardiomyocytes. In conclusion, hepcidin remains a promising therapeutic tool in various iron pathologies. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

  9. Proteomic analysis of iron acquisition, metabolic and regulatory responses of Yersinia pestis to iron starvation

    PubMed Central

    2010-01-01

    Background The Gram-negative bacterium Yersinia pestis is the causative agent of the bubonic plague. Efficient iron acquisition systems are critical to the ability of Y. pestis to infect, spread and grow in mammalian hosts, because iron is sequestered and is considered part of the innate host immune defence against invading pathogens. We used a proteomic approach to determine expression changes of iron uptake systems and intracellular consequences of iron deficiency in the Y. pestis strain KIM6+ at two physiologically relevant temperatures (26°C and 37°C). Results Differential protein display was performed for three Y. pestis subcellular fractions. Five characterized Y. pestis iron/siderophore acquisition systems (Ybt, Yfe, Yfu, Yiu and Hmu) and a putative iron/chelate outer membrane receptor (Y0850) were increased in abundance in iron-starved cells. The iron-sulfur (Fe-S) cluster assembly system Suf, adapted to oxidative stress and iron starvation in E. coli, was also more abundant, suggesting functional activity of Suf in Y. pestis under iron-limiting conditions. Metabolic and reactive oxygen-deactivating enzymes dependent on Fe-S clusters or other iron cofactors were decreased in abundance in iron-depleted cells. This data was consistent with lower activities of aconitase and catalase in iron-starved vs. iron-rich cells. In contrast, pyruvate oxidase B which metabolizes pyruvate via electron transfer to ubiquinone-8 for direct utilization in the respiratory chain was strongly increased in abundance and activity in iron-depleted cells. Conclusions Many protein abundance differences were indicative of the important regulatory role of the ferric uptake regulator Fur. Iron deficiency seems to result in a coordinated shift from iron-utilizing to iron-independent biochemical pathways in the cytoplasm of Y. pestis. With growth temperature as an additional variable in proteomic comparisons of the Y. pestis fractions (26°C and 37°C), there was little evidence for

  10. Diversity and Evolutionary History of Iron Metabolism Genes in Diatoms

    PubMed Central

    Groussman, Ryan D.; Parker, Micaela S.; Armbrust, E. Virginia

    2015-01-01

    Ferroproteins arose early in Earth’s history, prior to the emergence of oxygenic photosynthesis and the subsequent reduction of bioavailable iron. Today, iron availability limits primary productivity in about 30% of the world’s oceans. Diatoms, responsible for nearly half of oceanic primary production, have evolved molecular strategies for coping with variable iron concentrations. Our understanding of the evolutionary breadth of these strategies has been restricted by the limited number of species for which molecular sequence data is available. To uncover the diversity of strategies marine diatoms employ to meet cellular iron demands, we analyzed 367 newly released marine microbial eukaryotic transcriptomes, which include 47 diatom species. We focused on genes encoding proteins previously identified as having a role in iron management: iron uptake (high-affinity ferric reductase, multi-copper oxidase, and Fe(III) permease); iron storage (ferritin); iron-induced protein substitutions (flavodoxin/ferredoxin, and plastocyanin/cytochrome c6) and defense against reactive oxygen species (superoxide dismutases). Homologs encoding the high-affinity iron uptake system components were detected across the four diatom Classes suggesting an ancient origin for this pathway. Ferritin transcripts were also detected in all Classes, revealing a more widespread utilization of ferritin throughout diatoms than previously recognized. Flavodoxin and plastocyanin transcripts indicate possible alternative redox metal strategies. Predicted localization signals for ferredoxin identify multiple examples of gene transfer from the plastid to the nuclear genome. Transcripts encoding four superoxide dismutase metalloforms were detected, including a putative nickel-coordinating isozyme. Taken together, our results suggest that the majority of iron metabolism genes in diatoms appear to be vertically inherited with functional diversity achieved via possible neofunctionalization of paralogs. This

  11. Diversity and Evolutionary History of Iron Metabolism Genes in Diatoms.

    PubMed

    Groussman, Ryan D; Parker, Micaela S; Armbrust, E Virginia

    2015-01-01

    Ferroproteins arose early in Earth's history, prior to the emergence of oxygenic photosynthesis and the subsequent reduction of bioavailable iron. Today, iron availability limits primary productivity in about 30% of the world's oceans. Diatoms, responsible for nearly half of oceanic primary production, have evolved molecular strategies for coping with variable iron concentrations. Our understanding of the evolutionary breadth of these strategies has been restricted by the limited number of species for which molecular sequence data is available. To uncover the diversity of strategies marine diatoms employ to meet cellular iron demands, we analyzed 367 newly released marine microbial eukaryotic transcriptomes, which include 47 diatom species. We focused on genes encoding proteins previously identified as having a role in iron management: iron uptake (high-affinity ferric reductase, multi-copper oxidase, and Fe(III) permease); iron storage (ferritin); iron-induced protein substitutions (flavodoxin/ferredoxin, and plastocyanin/cytochrome c6) and defense against reactive oxygen species (superoxide dismutases). Homologs encoding the high-affinity iron uptake system components were detected across the four diatom Classes suggesting an ancient origin for this pathway. Ferritin transcripts were also detected in all Classes, revealing a more widespread utilization of ferritin throughout diatoms than previously recognized. Flavodoxin and plastocyanin transcripts indicate possible alternative redox metal strategies. Predicted localization signals for ferredoxin identify multiple examples of gene transfer from the plastid to the nuclear genome. Transcripts encoding four superoxide dismutase metalloforms were detected, including a putative nickel-coordinating isozyme. Taken together, our results suggest that the majority of iron metabolism genes in diatoms appear to be vertically inherited with functional diversity achieved via possible neofunctionalization of paralogs. This

  12. Co-regulation of Iron Metabolism and Virulence Associated Functions by Iron and XibR, a Novel Iron Binding Transcription Factor, in the Plant Pathogen Xanthomonas.

    PubMed

    Pandey, Sheo Shankar; Patnana, Pradeep Kumar; Lomada, Santosh Kumar; Tomar, Archana; Chatterjee, Subhadeep

    2016-11-01

    Abilities of bacterial pathogens to adapt to the iron limitation present in hosts is critical to their virulence. Bacterial pathogens have evolved diverse strategies to coordinately regulate iron metabolism and virulence associated functions to maintain iron homeostasis in response to changing iron availability in the environment. In many bacteria the ferric uptake regulator (Fur) functions as transcription factor that utilize ferrous form of iron as cofactor to regulate transcription of iron metabolism and many cellular functions. However, mechanisms of fine-tuning and coordinated regulation of virulence associated function beyond iron and Fur-Fe2+ remain undefined. In this study, we show that a novel transcriptional regulator XibR (named Xanthomonas iron binding regulator) of the NtrC family, is required for fine-tuning and co-coordinately regulating the expression of several iron regulated genes and virulence associated functions in phytopathogen Xanthomonas campestris pv. campestris (Xcc). Genome wide expression analysis of iron-starvation stimulon and XibR regulon, GUS assays, genetic and functional studies of xibR mutant revealed that XibR positively regulates functions involved in iron storage and uptake, chemotaxis, motility and negatively regulates siderophore production, in response to iron. Furthermore, chromatin immunoprecipitation followed by quantitative real-time PCR indicated that iron promoted binding of the XibR to the upstream regulatory sequence of operon's involved in chemotaxis and motility. Circular dichroism spectroscopy showed that purified XibR bound ferric form of iron. Electrophoretic mobility shift assay revealed that iron positively affected the binding of XibR to the upstream regulatory sequences of the target virulence genes, an effect that was reversed by ferric iron chelator deferoxamine. Taken together, these data revealed that how XibR coordinately regulates virulence associated and iron metabolism functions in Xanthomonads in

  13. Mitochondrial iron metabolism and sideroblastic anemia.

    PubMed

    Sheftel, Alex D; Richardson, Des R; Prchal, Josef; Ponka, Prem

    2009-01-01

    Sideroblastic anemias are a heterogeneous group of disorders, characterized by mitochondrial iron overload in developing red blood cells. The unifying characteristic of all sideroblastic anemias is the ring sideroblast, which is a pathological erythroid precursor containing excessive deposits of non-heme iron in mitochondria with perinuclear distribution creating a ring appearance. Sideroblastic anemias may be hereditary or acquired. Hereditary sideroblastic anemias are caused by defects in genes present on the X chromosome (mutations in the ALAS2, ABCB7, or GRLX5 gene), genes on autosomal chromosomes, or mitochondrial genes. Acquired sideroblastic anemias are either primary (refractory anemia with ring sideroblasts, RARS, representing one subtype of the myelodysplastic syndrome) or secondary due to some drugs, toxins, copper deficiency, or chronic neoplastic disease. The pathogenesis of mitochondrial iron loading in developing erythroblasts is diverse. Ring sideroblasts can develop as a result of a heme synthesis defect in erythroblasts (ALAS2 mutations), a defect in iron-sulfur cluster assembly, iron-sulfur protein precursor release from mitochondria (ABCB7 mutations), or by a defect in intracellular iron metabolism in erythroid cells (e.g. RARS).

  14. Recent advances in iron metabolism and related disorders.

    PubMed

    Camaschella, Clara; Strati, Paolo

    2010-10-01

    Iron is essential for life, because it is indispensable for several biological reactions such as oxygen transport, DNA synthesis and cell proliferation, but is toxic if present in excess since it causes cellular damage through free radical formation. Either cellular or systemic iron regulation can be disrupted in disorders of iron metabolism. In the past few years, our understanding of iron metabolism and its regulation has dramatically changed. New disorders of iron metabolism have emerged and the role of iron has started to be recognized as a cofactor of other disorders. The study of genetic conditions such as hemochromatosis and iron-refractory-iron-deficiency anemia (IRIDA) has provided crucial insights into the molecular mechanisms controlling iron homeostasis. In the future, these advances may be exploited for a more effective treatment of both genetic and acquired iron disorders.

  15. Metabolic Response to Iron Deficiency in Saccharomyces cerevisiae*

    PubMed Central

    Shakoury-Elizeh, Minoo; Protchenko, Olga; Berger, Alvin; Cox, James; Gable, Kenneth; Dunn, Teresa M.; Prinz, William A.; Bard, Martin; Philpott, Caroline C.

    2010-01-01

    Iron is an essential cofactor for enzymes involved in numerous cellular processes, yet little is known about the impact of iron deficiency on cellular metabolism or iron proteins. Previous studies have focused on changes in transcript and proteins levels in iron-deficient cells, yet these changes may not reflect changes in transport activity or flux through a metabolic pathway. We analyzed the metabolomes and transcriptomes of yeast grown in iron-rich and iron-poor media to determine which biosynthetic processes are altered when iron availability falls. Iron deficiency led to changes in glucose metabolism, amino acid biosynthesis, and lipid biosynthesis that were due to deficiencies in specific iron-dependent enzymes. Iron-sulfur proteins exhibited loss of iron cofactors, yet amino acid synthesis was maintained. Ergosterol and sphingolipid biosynthetic pathways had blocks at points where heme and diiron enzymes function, whereas Ole1, the essential fatty acid desaturase, was resistant to iron depletion. Iron-deficient cells exhibited depletion of most iron enzyme activities, but loss of activity during iron deficiency did not consistently disrupt metabolism. Amino acid homeostasis was robust, but iron deficiency impaired lipid synthesis, altering the properties and functions of cellular membranes. PMID:20231268

  16. Dietary iron controls circadian hepatic glucose metabolism through heme synthesis.

    PubMed

    Simcox, Judith A; Mitchell, Thomas Creighton; Gao, Yan; Just, Steven F; Cooksey, Robert; Cox, James; Ajioka, Richard; Jones, Deborah; Lee, Soh-Hyun; King, Daniel; Huang, Jingyu; McClain, Donald A

    2015-04-01

    The circadian rhythm of the liver maintains glucose homeostasis, and disruption of this rhythm is associated with type 2 diabetes. Feeding is one factor that sets the circadian clock in peripheral tissues, but relatively little is known about the role of specific dietary components in that regard. We assessed the effects of dietary iron on circadian gluconeogenesis. Dietary iron affects circadian glucose metabolism through heme-mediated regulation of the interaction of nuclear receptor subfamily 1 group d member 1 (Rev-Erbα) with its cosuppressor nuclear receptor corepressor 1 (NCOR). Loss of regulated heme synthesis was achieved by aminolevulinic acid (ALA) treatment of mice or cultured cells to bypass the rate-limiting enzyme in hepatic heme synthesis, ALA synthase 1 (ALAS1). ALA treatment abolishes differences in hepatic glucose production and in the expression of gluconeogenic enzymes seen with variation of dietary iron. The differences among diets are also lost with inhibition of heme synthesis with isonicotinylhydrazine. Dietary iron modulates levels of peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α), a transcriptional activator of ALAS1, to affect hepatic heme. Treatment of mice with the antioxidant N-acetylcysteine diminishes PGC-1α variation observed among the iron diets, suggesting that iron is acting through reactive oxygen species signaling. © 2015 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.

  17. Nitric oxide and changes of iron metabolism in exercise.

    PubMed

    Qian, Zhong Ming

    2002-11-01

    Accumulated data imply that exercise itself might not lead to a true iron deficiency or 'sport anaemia' in a healthy athlete who has adequate iron intake. The higher prevalence of iron deficiency anaemia in younger female athletes might be not due to exercise itself, but probably results from dietary choices, inadequate iron intake and menstruation. These factors can also induce iron deficiency or anaemia in the general population. However, exercise does affect iron metabolism, leading to low or sub-optimal iron status. The underlying mechanism is unknown. In this review, recent advances in the study of the effect of exercise on iron metabolism and nitric oxide, and the relationship between nitric oxide and iron status in exercise are discussed. A hypothesis that increased production of nitric oxide might contribute to sub-optimal iron status in exercise is proposed.

  18. Plastid proteomics for elucidating iron limited remodeling of plastid physiology in diatoms

    NASA Astrophysics Data System (ADS)

    Gomes, K. M.; Nunn, B. L.; Jenkins, B. D.

    2016-02-01

    Diatoms are important primary producers in the world's oceans and their growth is constrained in large regions by low iron availability. This low iron-induced limitation of primary production is due to the requirement for iron in components of essential metabolic pathways including key chloroplast functions such as photosynthesis and nitrate assimilation. Diatoms can bloom and accumulate high biomass during introduction of iron into low iron waters, indicating adaptations allowing for their survival in iron-limited waters and rapid growth when iron becomes more abundant. Prior studies have shown that under iron limited stress, diatoms alter plastid-specific processes including components of electron transport, size of light harvesting capacity and chlorophyll content, suggesting plastid-specific protein regulation. Due to their complex evolutionary history, resulting from a secondary endosymbiosis, knowledge regarding the complement of plastid localized proteins remains limited in comparison to other model photosynthetic organisms. While in-silico prediction of diatom protein localization provides putative candidates for plastid-localization, these analyses can be limited as most plastid prediction models were developed using plants, primary endosymbionts. In order to characterize proteins enriched in diatom chloroplast and to understand how the plastid proteome is remodeled in response to iron limitation, we used mass spectrometry based proteomics to compare plastid- enriched protein fractions from Thalassiosira pseudonana, grown in iron replete and limited conditions. These analyses show that iron stress alters regulation of major metabolic pathways in the plastid including the Calvin cycle and fatty acid synthesis. These components provide promising targets to further characterize the plastid specific response to iron limitation.

  19. Effects of Pregnancy and Lactation on Iron Metabolism in Rats

    PubMed Central

    Gao, Guofen; Liu, Shang-Yuan; Wang, Hui-Jie; Zhang, Tian-Wei; Yu, Peng; Duan, Xiang-Lin; Zhao, Shu-E; Chang, Yan-Zhong

    2015-01-01

    In female, inadequate iron supply is a highly prevalent problem that often leads to iron-deficiency anemia. This study aimed to understand the effects of pregnancy and lactation on iron metabolism. Rats with different days of gestation and lactation were used to determine the variations in iron stores and serum iron level and the changes in expression of iron metabolism-related proteins, including ferritin, ferroportin 1 (FPN1), ceruloplasmin (Cp), divalent metal transporter 1 (DMT1), transferrin receptor 1 (TfR1), and the major iron-regulatory molecule—hepcidin. We found that iron stores decline dramatically at late-pregnancy period, and the low iron store status persists throughout the lactation period. The significantly increased FPN1 level in small intestine facilitates digestive iron absorption, which maintains the serum iron concentration at a near-normal level to meet the increase of iron requirements. Moreover, a significant decrease of hepcidin expression is observed during late-pregnancy and early-lactation stages, suggesting the important regulatory role that hepcidin plays in iron metabolism during pregnancy and lactation. These results are fundamental to the understanding of iron homeostasis during pregnancy and lactation and may provide experimental bases for future studies to identify key molecules expressed during these special periods that regulate the expression of hepcidin, to eventually improve the iron-deficiency status. PMID:26788496

  20. Targeting iron metabolism in drug discovery and delivery

    PubMed Central

    Crielaard, Bart J.; Lammers, Twan; Rivella, Stefano

    2017-01-01

    Iron fulfils a central role in many essential biochemical processes in human physiology, which makes proper processing of iron crucial. Although iron metabolism is subject to relatively strict physiological control, in recent years numerous disorders, such as cancer and neurodegenerative diseases, have been linked to deregulated iron homeostasis. Because of its involvement in the pathogenesis of these diseases, iron metabolism constitutes a promising and largely unexploited therapeutic target for the development of new pharmacological treatments. Several iron metabolism-targeted therapies are already under clinical evaluation for haematological disorders, and these and newly developed therapeutic agents will likely have substantial benefit in the clinical management of iron metabolism-associated diseases, for which few efficacious treatments are often available. PMID:28154410

  1. A delicate balance: Iron metabolism and diseases of the brain

    PubMed Central

    Hare, Dominic; Ayton, Scott; Bush, Ashley; Lei, Peng

    2013-01-01

    Iron is the most abundant transition metal within the brain, and is vital for a number of cellular processes including neurotransmitter synthesis, myelination of neurons, and mitochondrial function. Redox cycling between ferrous and ferric iron is utilized in biology for various electron transfer reactions essential to life, yet this same chemistry mediates deleterious reactions with oxygen that induce oxidative stress. Consequently, there is a precise and tightly controlled mechanism to regulate iron in the brain. When iron is dysregulated, both conditions of iron overload and iron deficiencies are harmful to the brain. This review focuses on how iron metabolism is maintained in the brain, and how an alteration to iron and iron metabolism adversely affects neurological function. PMID:23874300

  2. Iron metabolism and ineffective erythropoiesis in β-thalassemia mouse models

    PubMed Central

    Ramos, Pedro; Melchiori, Luca; Gardenghi, Sara; Van-Roijen, Nico; Grady, Robert W.; Ginzburg, Yelena; Rivella, Stefano

    2013-01-01

    β-thalassemia is a disease associated with decreased β-globin production leading to anemia, ineffective erythropoiesis, and iron overload. New mechanisms associated with modulation of erythropoiesis and iron metabolism have recently been discovered in thalassemic mice, improving our understanding of the pathophysiology of this disease. These discoveries have the potential to be translated into clinically-relevant therapeutic options to reduce ineffective erythropoiesis and iron overload. A new generation of therapies based on limiting ineffective erythropoiesis, iron absorption, and the correction of iron maldistribution could be on the way, possibly complementing and improving the current standard of patient care. PMID:20712768

  3. METABOLIC CAPACITY REGULATES IRON HOMEOSTATIS IN ENDOTHELIAL CELLS

    EPA Science Inventory

    The sensitivity of endothelial cells to oxidative stress and the high concentrations of iron in mitochondria led us to test the hypotheses that (1) changes in respiratory capacity alter iron homeostasis, and (2) lack of aerobic metabolism decreases labile iron stores and attenuat...

  4. METABOLIC CAPACITY REGULATES IRON HOMEOSTATIS IN ENDOTHELIAL CELLS

    EPA Science Inventory

    The sensitivity of endothelial cells to oxidative stress and the high concentrations of iron in mitochondria led us to test the hypotheses that (1) changes in respiratory capacity alter iron homeostasis, and (2) lack of aerobic metabolism decreases labile iron stores and attenuat...

  5. Alginate-Iron Speciation and Its Effect on In Vitro Cellular Iron Metabolism

    PubMed Central

    Horniblow, Richard D.; Dowle, Miriam; Iqbal, Tariq H.; Latunde-Dada, Gladys O.; Palmer, Richard E.

    2015-01-01

    Alginates are a class of biopolymers with known iron binding properties which are routinely used in the fabrication of iron-oxide nanoparticles. In addition, alginates have been implicated in influencing human iron absorption. However, the synthesis of iron oxide nanoparticles employs non-physiological pH conditions and whether nanoparticle formation in vivo is responsible for influencing cellular iron metabolism is unclear. Thus the aims of this study were to determine how alginate and iron interact at gastric-comparable pH conditions and how this influences iron metabolism. Employing a range of spectroscopic techniques under physiological conditions alginate-iron complexation was confirmed and, in conjunction with aberration corrected scanning transmission electron microscopy, nanoparticles were observed. The results infer a nucleation-type model of iron binding whereby alginate is templating the condensation of iron-hydroxide complexes to form iron oxide centred nanoparticles. The interaction of alginate and iron at a cellular level was found to decrease cellular iron acquisition by 37% (p < 0.05) and in combination with confocal microscopy the alginate inhibits cellular iron transport through extracellular iron chelation with the resulting complexes not internalised. These results infer alginate as being useful in the chelation of excess iron, especially in the context of inflammatory bowel disease and colorectal cancer where excess unabsorbed luminal iron is thought to be a driver of disease. PMID:26378798

  6. Alginate-Iron Speciation and Its Effect on In Vitro Cellular Iron Metabolism.

    PubMed

    Horniblow, Richard D; Dowle, Miriam; Iqbal, Tariq H; Latunde-Dada, Gladys O; Palmer, Richard E; Pikramenou, Zoe; Tselepis, Chris

    2015-01-01

    Alginates are a class of biopolymers with known iron binding properties which are routinely used in the fabrication of iron-oxide nanoparticles. In addition, alginates have been implicated in influencing human iron absorption. However, the synthesis of iron oxide nanoparticles employs non-physiological pH conditions and whether nanoparticle formation in vivo is responsible for influencing cellular iron metabolism is unclear. Thus the aims of this study were to determine how alginate and iron interact at gastric-comparable pH conditions and how this influences iron metabolism. Employing a range of spectroscopic techniques under physiological conditions alginate-iron complexation was confirmed and, in conjunction with aberration corrected scanning transmission electron microscopy, nanoparticles were observed. The results infer a nucleation-type model of iron binding whereby alginate is templating the condensation of iron-hydroxide complexes to form iron oxide centred nanoparticles. The interaction of alginate and iron at a cellular level was found to decrease cellular iron acquisition by 37% (p < 0.05) and in combination with confocal microscopy the alginate inhibits cellular iron transport through extracellular iron chelation with the resulting complexes not internalised. These results infer alginate as being useful in the chelation of excess iron, especially in the context of inflammatory bowel disease and colorectal cancer where excess unabsorbed luminal iron is thought to be a driver of disease.

  7. Iron uptake and metabolism in the new millennium.

    PubMed

    Dunn, Louise L; Suryo Rahmanto, Yohan; Richardson, Des R

    2007-02-01

    Iron is an essential element for metabolic processes intrinsic to life, and yet the properties that make iron a necessity also make it potentially deleterious. To avoid harm, iron homeostasis is achieved through iron transport, storage and regulatory proteins. The functions of some of these molecules are well described, for example transferrin and transferrin receptor-1, whereas the roles of others, such as the transferrin homolog melanotransferrin, remain unclear. The past decade has seen the identification of new molecules involved in iron metabolism, such as divalent metal transporter-1, ferroportin-1, hepcidin, hemojuvelin and heme carrier protein-1. Here, we focus on these intriguing new molecules and the insights gained from them into cellular iron uptake and the regulation of iron metabolism.

  8. Oral iron treatment has a positive effect on iron metabolism in elite soccer players.

    PubMed

    Villanueva, Jesús; Soria, Marisol; González-Haro, Carlos; Ezquerra, Laura; Nieto, José L; Escanero, Jesús F

    2011-09-01

    The purpose of this study was to assess the effects of oral iron supplementation on hematological and iron metabolism in elite soccer players. Thirty-five members of the Real Zaragoza SAD soccer team took part in this study: group A (GA, n = 24; Spanish Premier League) took an oral iron supplement of 80 mg day(-1) for 3 weeks, and group B (GB, n = 11; Spanish Third Division League) did not receive any supplementation. In GA, the parameters were measured before and after giving the iron supplements, while in GB, measurements were only made at the time of collecting the second set of data from GA. After supplementation, GA showed an increase in serum iron (SI) (P < 0.05), serum ferritin (Ftn) (P < 0.01), and transferrin saturation (Sat) (P < 0.01) with respect to the basal values. In addition, GA showed higher values of hematocrit (P < 0.01), mean corpuscular volume (P < 0.01), Ftn (P < 0.01), and Sat (P < 0.01) than GB. No significant differences were found in any other parameters. More specifically, a higher percentage of players had Ftn levels above upper limits in GA vs. GB (P < 0.05), and GB had a higher incidence of Ftn below lower limits with respect to subjects in GA (P < 0.01). Further, after treatment, 58.3% of GA had >800 mg of SI, while all players in GB presented levels below the lower limits. In conclusion, iron supplementation with 80 mg·day(-1) for 3 weeks, before the start of the soccer season, can be recommended for elite soccer players.

  9. Ostreococcus tauri is a new model green alga for studying iron metabolism in eukaryotic phytoplankton.

    PubMed

    Lelandais, Gaëlle; Scheiber, Ivo; Paz-Yepes, Javier; Lozano, Jean-Claude; Botebol, Hugo; Pilátová, Jana; Žárský, Vojtěch; Léger, Thibaut; Blaiseau, Pierre-Louis; Bowler, Chris; Bouget, François-Yves; Camadro, Jean-Michel; Sutak, Robert; Lesuisse, Emmanuel

    2016-05-03

    Low iron bioavailability is a common feature of ocean surface water and therefore micro-algae developed original strategies to optimize iron uptake and metabolism. The marine picoeukaryotic green alga Ostreococcus tauri is a very good model for studying physiological and genetic aspects of the adaptation of the green algal lineage to the marine environment: it has a very compact genome, is easy to culture in laboratory conditions, and can be genetically manipulated by efficient homologous recombination. In this study, we aimed at characterizing the mechanisms of iron assimilation in O. tauri by combining genetics and physiological tools. Specifically, we wanted to identify and functionally characterize groups of genes displaying tightly orchestrated temporal expression patterns following the exposure of cells to iron deprivation and day/night cycles, and to highlight unique features of iron metabolism in O. tauri, as compared to the freshwater model alga Chalamydomonas reinhardtii. We used RNA sequencing to investigated the transcriptional responses to iron limitation in O. tauri and found that most of the genes involved in iron uptake and metabolism in O. tauri are regulated by day/night cycles, regardless of iron status. O. tauri lacks the classical components of a reductive iron uptake system, and has no obvious iron regulon. Iron uptake appears to be copper-independent, but is regulated by zinc. Conversely, iron deprivation resulted in the transcriptional activation of numerous genes encoding zinc-containing regulation factors. Iron uptake is likely mediated by a ZIP-family protein (Ot-Irt1) and by a new Fea1-related protein (Ot-Fea1) containing duplicated Fea1 domains. The adaptation of cells to iron limitation involved an iron-sparing response tightly coordinated with diurnal cycles to optimize cell functions and synchronize these functions with the day/night redistribution of iron orchestrated by ferritin, and a stress response based on the induction of

  10. Disorders of Iron Metabolism and Anemia in Chronic Kidney Disease.

    PubMed

    Panwar, Bhupesh; Gutiérrez, Orlando M

    2016-07-01

    Dysregulated iron homeostasis plays a central role in the development of anemia of chronic kidney disease (CKD) and is a major contributor toward resistance to treatment with erythropoiesis-stimulating agents. Understanding the underlying pathophysiology requires an in-depth understanding of normal iron physiology and regulation. Recent discoveries in the field of iron biology have greatly improved our understanding of the hormonal regulation of iron trafficking in human beings and how its alterations lead to the development of anemia of CKD. In addition, emerging evidence has suggested that iron homeostasis interacts with bone and mineral metabolism on multiple levels, opening up new avenues of investigation into the genesis of disordered iron metabolism in CKD. Building on recent advances in our understanding of normal iron physiology and abnormalities in iron homeostasis in CKD, this review characterizes how anemia related to disordered iron metabolism develops in the setting of CKD. In addition, this review explores our emerging recognition of the connections between iron homeostasis and mineral metabolism and their implications for the management of altered iron status and anemia of CKD. Copyright © 2016 Elsevier Inc. All rights reserved.

  11. Recent Advances in Iron Metabolism: Relevance for Health, Exercise, and Performance.

    PubMed

    Buratti, Paolo; Gammella, Elena; Rybinska, Ilona; Cairo, Gaetano; Recalcati, Stefania

    2015-08-01

    Iron is necessary for physiological processes essential for athletic performance, such as oxygen transport, energy production, and cell division. However, an excess of "free" iron is toxic because it produces reactive hydroxyl radicals that damage biological molecules, thus leading to cell and tissue injury. Therefore, iron homeostasis is strictly regulated; and in recent years, there have been important advancements in our knowledge of the underlying processes. Hepcidin is the central regulator of systemic iron homeostasis and exerts its function by controlling the presence of the iron exporter ferroportin on the cell membrane. Hepcidin binding induces ferroportin degradation, thus leading to cellular iron retention and decreased levels of circulating iron. As iron is required for hemoglobin synthesis, the tight link between erythropoiesis and iron metabolism is particularly relevant to sports physiology. The iron needed for hemoglobin synthesis is ensured by inhibiting hepcidin to increase ferroportin activity and iron availability and hence to make certain that efficient blood oxygen transport occurs for aerobic exercise. However, hepcidin expression is also affected by exercise-associated conditions, such as iron deficiency, anemia or hypoxia, and, particularly, inflammation, which can play a role in the pathogenesis of sports anemia. Here, we review recent advances showing the relevance of iron for physical exercise and athletic performance. Low body iron levels can cause anemia and thus limit the delivery of oxygen to exercising muscle, but tissue iron deficiency may also affect performance by, for example, hampering muscle oxidative metabolism. Accordingly, a hemoglobin-independent effect of iron on exercise capacity has been demonstrated in animal models and humans. Here, we review recent advances showing the relevance of iron for physical exercise and athletic performance.

  12. Co-regulation of Iron Metabolism and Virulence Associated Functions by Iron and XibR, a Novel Iron Binding Transcription Factor, in the Plant Pathogen Xanthomonas

    PubMed Central

    Pandey, Sheo Shankar; Patnana, Pradeep Kumar; Lomada, Santosh Kumar; Tomar, Archana; Chatterjee, Subhadeep

    2016-01-01

    Abilities of bacterial pathogens to adapt to the iron limitation present in hosts is critical to their virulence. Bacterial pathogens have evolved diverse strategies to coordinately regulate iron metabolism and virulence associated functions to maintain iron homeostasis in response to changing iron availability in the environment. In many bacteria the ferric uptake regulator (Fur) functions as transcription factor that utilize ferrous form of iron as cofactor to regulate transcription of iron metabolism and many cellular functions. However, mechanisms of fine-tuning and coordinated regulation of virulence associated function beyond iron and Fur-Fe2+ remain undefined. In this study, we show that a novel transcriptional regulator XibR (named Xanthomonas iron binding regulator) of the NtrC family, is required for fine-tuning and co-coordinately regulating the expression of several iron regulated genes and virulence associated functions in phytopathogen Xanthomonas campestris pv. campestris (Xcc). Genome wide expression analysis of iron-starvation stimulon and XibR regulon, GUS assays, genetic and functional studies of xibR mutant revealed that XibR positively regulates functions involved in iron storage and uptake, chemotaxis, motility and negatively regulates siderophore production, in response to iron. Furthermore, chromatin immunoprecipitation followed by quantitative real-time PCR indicated that iron promoted binding of the XibR to the upstream regulatory sequence of operon’s involved in chemotaxis and motility. Circular dichroism spectroscopy showed that purified XibR bound ferric form of iron. Electrophoretic mobility shift assay revealed that iron positively affected the binding of XibR to the upstream regulatory sequences of the target virulence genes, an effect that was reversed by ferric iron chelator deferoxamine. Taken together, these data revealed that how XibR coordinately regulates virulence associated and iron metabolism functions in Xanthomonads in

  13. Mitochondrial iron trafficking and the integration of iron metabolism between the mitochondrion and cytosol

    PubMed Central

    Richardson, Des R.; Lane, Darius J. R.; Becker, Erika M.; Huang, Michael L.-H.; Whitnall, Megan; Rahmanto, Yohan Suryo; Sheftel, Alex D.; Ponka, Prem

    2010-01-01

    The mitochondrion is well known for its key role in energy transduction. However, it is less well appreciated that it is also a focal point of iron metabolism. Iron is needed not only for heme and iron sulfur cluster (ISC)-containing proteins involved in electron transport and oxidative phosphorylation, but also for a wide variety of cytoplasmic and nuclear functions, including DNA synthesis. The mitochondrial pathways involved in the generation of both heme and ISCs have been characterized to some extent. However, little is known concerning the regulation of iron uptake by the mitochondrion and how this is coordinated with iron metabolism in the cytosol and other organelles (e.g., lysosomes). In this article, we discuss the burgeoning field of mitochondrial iron metabolism and trafficking that has recently been stimulated by the discovery of proteins involved in mitochondrial iron storage (mitochondrial ferritin) and transport (mitoferrin-1 and -2). In addition, recent work examining mitochondrial diseases (e.g., Friedreich's ataxia) has established that communication exists between iron metabolism in the mitochondrion and the cytosol. This finding has revealed the ability of the mitochondrion to modulate whole-cell iron-processing to satisfy its own requirements for the crucial processes of heme and ISC synthesis. Knowledge of mitochondrial iron-processing pathways and the interaction between organelles and the cytosol could revolutionize the investigation of iron metabolism. PMID:20495089

  14. Chronic Iron Limitation Confers Transient Resistance to Oxidative Stress in Marine Diatoms.

    PubMed

    Graff van Creveld, Shiri; Rosenwasser, Shilo; Levin, Yishai; Vardi, Assaf

    2016-10-01

    Diatoms are single-celled, photosynthetic, bloom-forming algae that are responsible for at least 20% of global primary production. Nevertheless, more than 30% of the oceans are considered "ocean deserts" due to iron limitation. We used the diatom Phaeodactylum tricornutum as a model system to explore diatom's response to iron limitation and its interplay with susceptibility to oxidative stress. By analyzing physiological parameters and proteome profiling, we defined two distinct phases: short-term (<3 d, phase I) and chronic (>5 d, phase II) iron limitation. While at phase I no significant changes in physiological parameters were observed, molecular markers for iron starvation, such as Iron Starvation Induced Protein and flavodoxin, were highly up-regulated. At phase II, down-regulation of numerous iron-containing proteins was detected in parallel to reduction in growth rate, chlorophyll content, photosynthetic activity, respiration rate, and antioxidant capacity. Intriguingly, while application of oxidative stress to phase I and II iron-limited cells similarly oxidized the reduced glutathione (GSH) pool, phase II iron limitation exhibited transient resistance to oxidative stress, despite the down regulation of many antioxidant proteins. By comparing proteomic profiles of P. tricornutum under iron limitation and metatranscriptomic data of an iron enrichment experiment conducted in the Pacific Ocean, we propose that iron-limited cells in the natural environment resemble the phase II metabolic state. These results provide insights into the trade-off between optimal growth rate and susceptibility to oxidative stress in the response of diatoms to iron quota in the marine environment. © 2016 American Society of Plant Biologists. All Rights Reserved.

  15. Hepcidin induction limits mobilisation of splenic iron in a mouse model of secondary iron overload.

    PubMed

    Camberlein, Emilie; Abgueguen, Emmanuelle; Fatih, Nadia; Canonne-Hergaux, François; Leroyer, Patricia; Turlin, Bruno; Ropert, Martine; Brissot, Pierre; Loréal, Olivier

    2010-03-01

    Venesection has been proposed as a treatment for hepatic iron overload in a number of chronic liver disorders that are not primarily linked to mutations in iron metabolism genes. Our aim was to analyse the impact of venesection on iron mobilisation in a mouse model of secondary iron overload. C57Bl/6 mice were given oral iron supplementation with or without phlebotomy between day 0 (D0) and D22, and the results were compared to controls without iron overload. We studied serum and tissue iron parameters, mRNA levels of hepcidin1, ferroportin, and transferrin receptor 1, and protein levels of ferroportin in the liver and spleen. On D0, animals with iron overload displayed elevations in iron parameters and hepatic hepcidin1 mRNA. By D22, in the absence of phlebotomies, splenic iron had increased, but transferrin saturation had decreased. This was associated with high hepatic hepcidin1 mRNA, suggesting that iron bioavailability decreased due to splenic iron sequestration through ferroportin protein downregulation. After 22days with phlebotomy treatments, control mice displayed splenic iron mobilisation that compensated for the iron lost due to phlebotomy. In contrast, phlebotomy treatments in mice with iron overload caused anaemia due to inadequate iron mobilisation. In conclusion, our model of secondary iron overload led to decreased plasma iron associated with an increase in hepcidin expression and subsequent restriction of iron export from the spleen. Our data support the importance of managing hepcidin levels before starting venesection therapy in patients with secondary iron overload that are eligible for phlebotomy.

  16. Effect of estrogen on iron metabolism in mammals.

    PubMed

    Yang, Xiao; Xu, Man-Man; Wang, Jun; Xie, Jun-Xia

    2016-10-25

    Estrogen is a steroid hormone produced mainly by the ovaries. It combines with the nuclear receptors to exert the biological effects influencing the metabolism of body. Elevated levels of estrogen are often associated with altered iron levels in mammals. Furthermore, the findings of estrogen response element (ERE) have demonstrated that estrogen affects iron metabolism directly in peripheral tissues. In this review, we will briefly summarize the effect of estrogen on iron metabolism in mammals, and discuss recent progress in the mechanisms of estrogen on some iron related proteins in order to provide guidance for clinical use of estrogen. Estrogen and iron metabolism are closely related, but the exact regulatory mechanisms still need further exploration.

  17. Role of alcohol in the regulation of iron metabolism

    PubMed Central

    Harrison-Findik, Duygu Dee

    2007-01-01

    Patients with alcoholic liver disease frequently exhibit increased body iron stores, as reflected by elevated serum iron indices (transferrin saturation, ferritin) and hepatic iron concentration. Even mild to moderate alcohol consumption has been shown to increase the prevalence of iron overload. Moreover, increased hepatic iron content is associated with greater mortality from alcoholic cirrhosis, suggesting a pathogenic role for iron in alcoholic liver disease. Alcohol increases the severity of disease in patients with genetic hemochromatosis, an iron overload disorder common in the Caucasian population. Both iron and alcohol individually cause oxidative stress and lipid peroxidation, which culminates in liver injury. Despite these observations, the underlying mechanisms of iron accumulation and the source of the excess iron observed in alcoholic liver disease remain unclear. Over the last decade, several novel iron-regulatory proteins have been identified and these have greatly enhanced our understanding of iron metabolism. For example, hepcidin, a circulatory antimicrobial peptide synthesized by the hepatocytes of the liver is now known to play a central role in the regulation of iron homeostasis. This review attempts to describe the interaction of alcohol and iron-regulatory molecules. Understanding these molecular mechanisms is of considerable clinical importance because both alcoholic liver disease and genetic hemochromatosis are common diseases, in which alcohol and iron appear to act synergistically to cause liver injury. PMID:17854133

  18. Iron metabolism in athletes--achieving a gold standard.

    PubMed

    Latunde-Dada, Gladys O

    2013-01-01

    Iron is an important mineral element required for diverse life processes. Its metabolism is almost synonymous to erythrocyte maintenance, erythropoiesis and erythrophagocytosis. Consequently, exercise exertion impacts significantly on red cell haematology. Here, the interactions between exercise and erythropoiesis are explored. Hepcidin, the peptide hormone that regulates systemic iron metabolism, decreases in response to erythropoiesis by facilitating increased iron efflux from ferroportin into circulation. However, during exercise, there is an alarming increase in the expression of hepcidin resulting in a negative iron balance in athletes. In this review, the confounding cause and effect scenarios of exercise, athlete training and haematology and hepcidin interactions are discussed.

  19. Disorders of iron metabolism. Part 1: molecular basis of iron homoeostasis.

    PubMed

    Muñoz, Manuel; García-Erce, José Antonio; Remacha, Angel Francisco

    2011-04-01

    IRON FUNCTIONS: Iron is an essential micronutrient, as it is required for satisfactory erythropoietic function, oxidative metabolism and cellular immune response. IRON PHYSIOLOGY: Absorption of dietary iron (1-2 mg/day) is tightly regulated and just balanced against iron loss because there are no active iron excretory mechanisms. Dietary iron is found in haem (10%) and non-haem (ionic, 90%) forms, and their absorption occurs at the apical surface of duodenal enterocytes via different mechanisms. Iron is exported by ferroportin 1 (the only putative iron exporter) across the basolateral membrane of the enterocyte into the circulation (absorbed iron), where it binds to transferrin and is transported to sites of use and storage. Transferrin-bound iron enters target cells-mainly erythroid cells, but also immune and hepatic cells-via receptor-mediated endocytosis. Senescent erythrocytes are phagocytosed by reticuloendothelial system macrophages, haem is metabolised by haem oxygenase, and the released iron is stored as ferritin. Iron will be later exported from macrophages to transferrin. This internal turnover of iron is essential to meet the requirements of erythropoiesis (20-30 mg/day). As transferrin becomes saturated in iron-overload states, excess iron is transported to the liver, the other main storage organ for iron, carrying the risk of free radical formation and tissue damage. REGULATION OF IRON HOMOEOSTASIS: Hepcidin, synthesised by hepatocytes in response to iron concentrations, inflammation, hypoxia and erythropoiesis, is the main iron-regulatory hormone. It binds ferroportin on enterocytes, macrophages and hepatocytes triggering its internalisation and lysosomal degradation. Inappropriate hepcidin secretion may lead to either iron deficiency or iron overload.

  20. Molecular and Cellular Bases of Iron Metabolism in Humans.

    PubMed

    Milto, I V; Suhodolo, I V; Prokopieva, V D; Klimenteva, T K

    2016-06-01

    Iron is a microelement with the most completely studied biological functions. Its wide dissemination in nature and involvement in key metabolic pathways determine the great importance of this metal for uni- and multicellular organisms. The biological role of iron is characterized by its indispensability in cell respiration and various biochemical processes providing normal functioning of cells and organs of the human body. Iron also plays an important role in the generation of free radicals, which under different conditions can be useful or damaging to biomolecules and cells. In the literature, there are many reviews devoted to iron metabolism and its regulation in pro- and eukaryotes. Significant progress has been achieved recently in understanding molecular bases of iron metabolism. The purpose of this review is to systematize available data on mechanisms of iron assimilation, distribution, and elimination from the human body, as well as on its biological importance and on the major iron-containing proteins. The review summarizes recent ideas about iron metabolism. Special attention is paid to mechanisms of iron absorption in the small intestine and to interrelationships of cellular and extracellular pools of this metal in the human body.

  1. Metabolic crossroads of iron and copper

    PubMed Central

    Collins, James F; Prohaska, Joseph R; Knutson, Mitchell D

    2013-01-01

    Interactions between the essential dietary metals, iron and copper, have been known for many years. This review highlights recent advances in iron-copper interactions with a focus on tissues and cell types important for regulating whole-body iron and copper homeostasis. Cells that mediate dietary assimilation (enterocytes) and storage and distribution (hepatocytes) of iron and copper are considered, along with the principal users (erythroid cells) and recyclers of red cell iron (reticuloendothelial macrophages). Interactions between iron and copper in the brain are also discussed. Many unanswered questions regarding the role of these metals and their interactions in health and disease emerge from this synopsis, highlighting extensive future research opportunities. PMID:20384844

  2. The Role of Hepcidin in Iron Metabolism

    PubMed Central

    Nemeth, Elizabeta; Ganz, Tomas

    2009-01-01

    Hepcidin is the central regulator of systemic iron homeostasis. Dysregulation of hepcidin production results in a variety of iron disorders. Hepcidin deficiency is the cause of iron overload in hereditary hemochromatosis, iron-loading anemias, and hepatitis C. Hepcidin excess is associated with anemia of inflammation, chronic kidney disease and iron-refractory iron deficiency anemia. Diagnostic and therapeutic applications of this new knowledge are beginning to emerge. Dr. Ernest Beutler played a significant role in advancing our understanding of the function of hepcidin. This review is dedicated to his memory. PMID:19907144

  3. Current status of iron metabolism: Clinical and therapeutic implications.

    PubMed

    Conde Diez, Susana; de Las Cuevas Allende, Ricardo; Conde García, Eulogio

    2017-03-03

    Hepcidin is the main regulator of iron metabolism and a pathogenic factor in iron disorders. Hepcidin deficiency causes iron overload, whereas hepcidin excess causes or contributes to the development of iron-restricted anaemia in chronic inflammatory diseases. We know the mechanisms involved in the synthesis of hepcidin and, under physiological conditions, there is a balance between activating signals and inhibitory signals that regulate its synthesis. The former include those related to plasmatic iron level and also those related to chronic inflammatory diseases. The most important inhibitory signals are related to active erythropoiesis and to matriptase-2. Knowing how hepcidin is synthesised has helped design new pharmacological treatments whose main target is the hepcidin. In the near future, there will be effective treatments aimed at correcting the defect of many of these iron metabolism disorders.

  4. Mitochondrial iron metabolism in the yeast Saccharomyces cerevisiae.

    PubMed

    Craig, E A; Voisine, C; Schilke, B

    1999-10-01

    Iron is fundamental to many biological processes, but is also detrimental as it fosters the synthesis of destructive oxygen radicals. Recent experiments have increased our knowledge of the critical process of regulation of mitochondrial iron metabolism. A number of genes directly involved in iron homeostasis in this organelle have been identified. Intriguingly, a minor Hsp70 molecular chaperone of the mitochondrial matrix has been implicated as a player in this process as well.

  5. Dissolved iron supply limits early growth of estuarine mangroves.

    PubMed

    Alongi, Daniel M

    2010-11-01

    Three mesocosm experiments were performed in an outdoor facility to quantify the responses of five mangrove species grown from seedling to sapling stage to increasing rates of dissolved iron supply. Stem extension and biomass of mangroves were measured in the first two experiments, and in the third experiment, rates of microbial iron reduction were measured in relation to stem extension of two mangrove species. In all experiments, mangrove growth was enhanced by increasing iron supply, although some species showed iron toxicity at the higher supply rates. In the first two experiments, stem extension rates of Rhizophora apiculata, Bruguiera gymnorrhiza, and Xylocarpus moluccensis best fit Gaussian curves with maximal growth at supply rates of 50-60 mmol Fe x m(-2) x d(-1), whereas growth of Avicennia marina and Ceriops tagal increased to the highest rate (100 mmol Fe x m(-2) x d(-1)) of iron supply. Changes in leaf chlorophyll concentrations and iron content of roots mirrored the growth responses. In the third experiment, rates of microbial iron reduction were greater with R. apiculata and A. marina than in controls without plants; for both species, there was a positive relationship between stem extension and iron reduction. The rates of iron reduction and rates of iron supplied to the plants were well within the range of interstitial iron concentrations and rates of iron reduction found in the natural mangrove soils from which the seedlings were obtained. The responses of these species show that mangroves growing from seedling to sapling stage have a strong nutritional requirement for iron, and that there is a close relationship between plant roots and the activities of iron-reducing bacteria. These results suggest that mangrove growth may be limited in some natural forests by the rate at which iron is solubilized by iron-reducing bacteria. Such biogeochemical conditions have significant implications for successful recruitment, establishment, and early growth of

  6. New developments and controversies in iron metabolism and iron chelation therapy

    PubMed Central

    Kontoghiorghe, Christina N; Kontoghiorghes, George J

    2016-01-01

    Iron is essential for all organisms including microbial, cancer and human cells. More than a quarter of the human population is affected by abnormalities of iron metabolism, mainly from iron deficiency and iron overload. Iron also plays an important role in free radical pathology and oxidative damage which is observed in almost all major diseases, cancer and ageing. New developments include the complete treatment of iron overload and reduction of morbidity and mortality in thalassaemia using deferiprone and selected deferiprone/deferoxamine combinations and also the use of the maltol iron complex in the treatment of iron deficiency anaemia. There is also a prospect of using deferiprone as a universal antioxidant in non iron overloaded diseases such as neurodegenerative, cardiovascular, renal, infectious diseases and cancer. New regulatory molecules of iron metabolism such as endogenous and dietary chelating molecules, hepcidin, mitochondrial ferritin and their role in health and disease is under evaluation. Similarly, new mechanisms of iron deposition, removal, distribution and toxicity have been identified using new techniques such as magnetic resonance imaging increasing our understanding of iron metabolic processes and the targeted treatment of related diseases. The uniform distribution of iron in iron overload between organs and within each organ is no longer valid. Several other controversies such as the toxicity impact of non transferrin bound iron vs injected iron, the excess levels of iron in tissues causing toxicity and the role of chelation on iron absorption need further investigation. Commercial interests of pharmaceutical companies and connections to leading journals are playing a crucial role in shaping worldwide medical opinion on drug sales and use but also patients’ therapeutic outcome and safety. Major controversies include the selection criteria and risk/benefit assessment in the use of deferasirox in thalassaemia and more so in idiopathic

  7. New developments and controversies in iron metabolism and iron chelation therapy.

    PubMed

    Kontoghiorghe, Christina N; Kontoghiorghes, George J

    2016-03-26

    Iron is essential for all organisms including microbial, cancer and human cells. More than a quarter of the human population is affected by abnormalities of iron metabolism, mainly from iron deficiency and iron overload. Iron also plays an important role in free radical pathology and oxidative damage which is observed in almost all major diseases, cancer and ageing. New developments include the complete treatment of iron overload and reduction of morbidity and mortality in thalassaemia using deferiprone and selected deferiprone/deferoxamine combinations and also the use of the maltol iron complex in the treatment of iron deficiency anaemia. There is also a prospect of using deferiprone as a universal antioxidant in non iron overloaded diseases such as neurodegenerative, cardiovascular, renal, infectious diseases and cancer. New regulatory molecules of iron metabolism such as endogenous and dietary chelating molecules, hepcidin, mitochondrial ferritin and their role in health and disease is under evaluation. Similarly, new mechanisms of iron deposition, removal, distribution and toxicity have been identified using new techniques such as magnetic resonance imaging increasing our understanding of iron metabolic processes and the targeted treatment of related diseases. The uniform distribution of iron in iron overload between organs and within each organ is no longer valid. Several other controversies such as the toxicity impact of non transferrin bound iron vs injected iron, the excess levels of iron in tissues causing toxicity and the role of chelation on iron absorption need further investigation. Commercial interests of pharmaceutical companies and connections to leading journals are playing a crucial role in shaping worldwide medical opinion on drug sales and use but also patients' therapeutic outcome and safety. Major controversies include the selection criteria and risk/benefit assessment in the use of deferasirox in thalassaemia and more so in idiopathic

  8. Growth of Aerobic Ripening Bacteria at the Cheese Surface Is Limited by the Availability of Iron

    PubMed Central

    Back, Alexandre; Irlinger, Françoise

    2012-01-01

    The microflora on the surface of smear-ripened cheeses is composed of various species of bacteria and yeasts that contribute to the production of the desired organoleptic properties. The objective of the present study was to show that iron availability is a limiting factor in the growth of typical aerobic ripening bacteria in cheese. For that purpose, we investigated the effect of iron or siderophore addition in model cheeses that were coinoculated with a yeast and a ripening bacterium. Both iron and the siderophore desferrioxamine B stimulated the growth of ripening bacteria belonging to the genera Arthrobacter, Corynebacterium, and Brevibacterium. The extent of stimulation was strain dependent, and generally, the effect of desferrioxamine B was greater than that of iron. Measurements of the expression of genes related to the metabolism of iron by Arthrobacter arilaitensis Re117 by real-time reverse transcription-PCR showed that these genes were transcribed during growth in cheese. The addition of desferrioxamine B increased the expression of two genes encoding iron-siderophore ABC transport binding proteins. The addition of iron decreased the expression of siderophore biosynthesis genes and of part of the genes encoding iron-siderophore ABC transport components. It was concluded that iron availability is a limiting factor in the growth of typical cheese surface bacteria. The selection of strains with efficient iron acquisition systems may be useful for the development of defined-strain surface cultures. Furthermore, the importance of iron metabolism in the microbial ecology of cheeses should be investigated since it may result in positive or negative microbial interactions. PMID:22367081

  9. Growth of aerobic ripening bacteria at the cheese surface is limited by the availability of iron.

    PubMed

    Monnet, Christophe; Back, Alexandre; Irlinger, Françoise

    2012-05-01

    The microflora on the surface of smear-ripened cheeses is composed of various species of bacteria and yeasts that contribute to the production of the desired organoleptic properties. The objective of the present study was to show that iron availability is a limiting factor in the growth of typical aerobic ripening bacteria in cheese. For that purpose, we investigated the effect of iron or siderophore addition in model cheeses that were coinoculated with a yeast and a ripening bacterium. Both iron and the siderophore desferrioxamine B stimulated the growth of ripening bacteria belonging to the genera Arthrobacter, Corynebacterium, and Brevibacterium. The extent of stimulation was strain dependent, and generally, the effect of desferrioxamine B was greater than that of iron. Measurements of the expression of genes related to the metabolism of iron by Arthrobacter arilaitensis Re117 by real-time reverse transcription-PCR showed that these genes were transcribed during growth in cheese. The addition of desferrioxamine B increased the expression of two genes encoding iron-siderophore ABC transport binding proteins. The addition of iron decreased the expression of siderophore biosynthesis genes and of part of the genes encoding iron-siderophore ABC transport components. It was concluded that iron availability is a limiting factor in the growth of typical cheese surface bacteria. The selection of strains with efficient iron acquisition systems may be useful for the development of defined-strain surface cultures. Furthermore, the importance of iron metabolism in the microbial ecology of cheeses should be investigated since it may result in positive or negative microbial interactions.

  10. Limited Role for Iron Regulation in Coxiella burnetii Pathogenesis▿ †

    PubMed Central

    Briggs, Heather L.; Pul, Nicolein; Seshadri, Rekha; Wilson, Mary J.; Tersteeg, Claudia; Russell-Lodrigue, Kasi E.; Andoh, Masako; Bäumler, Andreas J.; Samuel, James E.

    2008-01-01

    In gram-negative bacteria, iron acquisition proteins are commonly regulated by Fur (ferric uptake regulator), which binds iron-regulated promoters (the Fur box). We hypothesized that Coxiella burnetii requires iron and employs an iron-regulatory system and used various approaches to define a Fur regulon. Cloned C. burnetii fur complemented an Escherichia coli fur deletion mutant. A ferrous iron transporter gene (CBU1766), a putative iron binding protein-encoding gene (CBU0970), and a cation efflux pump gene (CBU1362) were identified by genome annotation and using a Fur titration assay. Bioinformatically predicted Fur box-containing promoters were tested for transcriptional control by iron. Five genes demonstrated at least a twofold induction with minimal iron. Putatively regulated genes were evaluated in a two-plasmid regulator/promoter heterologous expression system. These data suggested a very limited Fur-regulated system in C. burnetii. In an in vitro tissue culture model, a significant increase in bacterial growth was observed with infected cells treated with deferoxamine in comparison to growth under iron-replete conditions. In an iron-overloaded animal model in vivo, the level of bacterial growth detected in the iron-injected animals was significantly decreased in comparison to growth in control animals. In a low-iron-diet animal model, a significant increase in splenomegaly was observed, but no significant change in bacterial growth was identified. The small number of predicted iron acquisition systems, few Fur-regulated genes, and enhanced replication under a decreased iron level predict a requirement of a low level of iron for survival, perhaps to avoid creation of additional reactive oxygen radicals. PMID:18316381

  11. Limited role for iron regulation in Coxiella burnetii pathogenesis.

    PubMed

    Briggs, Heather L; Pul, Nicolein; Seshadri, Rekha; Wilson, Mary J; Tersteeg, Claudia; Russell-Lodrigue, Kasi E; Andoh, Masako; Bäumler, Andreas J; Samuel, James E

    2008-05-01

    In gram-negative bacteria, iron acquisition proteins are commonly regulated by Fur (ferric uptake regulator), which binds iron-regulated promoters (the Fur box). We hypothesized that Coxiella burnetii requires iron and employs an iron-regulatory system and used various approaches to define a Fur regulon. Cloned C. burnetii fur complemented an Escherichia coli fur deletion mutant. A ferrous iron transporter gene (CBU1766), a putative iron binding protein-encoding gene (CBU0970), and a cation efflux pump gene (CBU1362) were identified by genome annotation and using a Fur titration assay. Bioinformatically predicted Fur box-containing promoters were tested for transcriptional control by iron. Five genes demonstrated at least a twofold induction with minimal iron. Putatively regulated genes were evaluated in a two-plasmid regulator/promoter heterologous expression system. These data suggested a very limited Fur-regulated system in C. burnetii. In an in vitro tissue culture model, a significant increase in bacterial growth was observed with infected cells treated with deferoxamine in comparison to growth under iron-replete conditions. In an iron-overloaded animal model in vivo, the level of bacterial growth detected in the iron-injected animals was significantly decreased in comparison to growth in control animals. In a low-iron-diet animal model, a significant increase in splenomegaly was observed, but no significant change in bacterial growth was identified. The small number of predicted iron acquisition systems, few Fur-regulated genes, and enhanced replication under a decreased iron level predict a requirement of a low level of iron for survival, perhaps to avoid creation of additional reactive oxygen radicals.

  12. Oxidative Stress and the Homeodynamics of Iron Metabolism

    PubMed Central

    Bresgen, Nikolaus; Eckl, Peter M.

    2015-01-01

    Iron and oxygen share a delicate partnership since both are indispensable for survival, but if the partnership becomes inadequate, this may rapidly terminate life. Virtually all cell components are directly or indirectly affected by cellular iron metabolism, which represents a complex, redox-based machinery that is controlled by, and essential to, metabolic requirements. Under conditions of increased oxidative stress—i.e., enhanced formation of reactive oxygen species (ROS)—however, this machinery may turn into a potential threat, the continued requirement for iron promoting adverse reactions such as the iron/H2O2-based formation of hydroxyl radicals, which exacerbate the initial pro-oxidant condition. This review will discuss the multifaceted homeodynamics of cellular iron management under normal conditions as well as in the context of oxidative stress. PMID:25970586

  13. Microcytic anemia with iron malabsorption: an inherited disorder of iron metabolism.

    PubMed

    Hartman, K R; Barker, J A

    1996-04-01

    Two siblings were identified with severe hypoproliferative microcytic anemia and iron malabsorption, in the absence of any gastrointestinal disorder or blood loss. These children had severe microcytosis (MCV 48 fl, hemoglobin 7.5 g/dl) with decreased serum iron, elevated serum TIBC, and decreased serum ferritin, despite prolonged treatment with oral iron. An iron challenge study with an oral dose of 2 mg/kg elemental iron as ferrous sulfate documented iron malabsorption. After treatment with intravenous iron dextran, there was an absence of the expected reticulocytosis and only a partial correction of the hemoglobin, hematocrit, and microcytosis. The bone marrow was hypocellular with abnormal iron incorporation into erythroid precursor cells. This appears to be a rare form of inherited anemia characterized by iron malabsorption and disordered iron metabolism that only partially corrects after the administration of parenteral iron. These features resemble those found in the microcytic mouse (mk/mk), which also has severe microcytic anemia and iron malabsorption that partially responds to parenteral iron.

  14. Effect of Intravenous Iron on Aerobic Capacity and Iron Metabolism in Elite Athletes.

    PubMed

    Burden, Richard J; Pollock, Noel; Whyte, Gregory P; Richards, Toby; Moore, Brian; Busbridge, Mark; Srai, Surjit K; Otto, James; Pedlar, Charles R

    2015-07-01

    Iron-deficient athletes are often treated with long-term, low-dose iron therapy. Such treatments may be efficacious in correcting iron deficiency; however, the effect on acute and chronic iron metabolism and subsequent endurance capacity is less clear. Fifteen national and international standard runners were identified as iron deficient nonanemic (IDNA) and assigned to either an intravenous iron treatment group or placebo group. Participants completed three exercise tests to volitional exhaustion, as follows: before treatment, within 24 h, and 4 wk after treatment. Serum ferritin, serum iron, and transferrin saturation were significantly improved in the iron group after intervention and compared with those in placebo (P < 0.05). Hepcidin levels were significantly greater before and after exercise after the iron injection (P < 0.05), and this was independent of changes in interleukin-6. There were no differences between groups in red cell indices, total hemoglobin mass, V˙O2max, submaximal blood lactate, running economy, RPE, or time to exhaustion (P > 0.05). A single 500-mg intravenous iron injection is effective for improving iron status for at least 4 wk, but this does not lead to improved aerobic capacity. This investigation suggests that iron availability supersedes inflammation in the regulation of hepcidin in IDNA endurance athletes after acute intravascular iron injection treatment.

  15. Appraising the Role of Iron in Brain Aging and Cognition: Promises and Limitations of MRI Methods

    PubMed Central

    Daugherty, Ana M; Raz, Naftali

    2015-01-01

    Age-related increase in frailty is accompanied by a fundamental shift in cellular iron homeostasis. By promoting oxidative stress, the intracellular accumulation of non-heme iron outside of binding complexes contributes to chronic inflammation and interferes with normal brain metabolism. In the absence of direct non-invasive biomarkers of brain oxidative stress, iron accumulation estimated in vivo may serve as its proxy indicator. Hence, developing reliable in vivo measurements of brain iron content via magnetic resonance imaging (MRI) is of significant interest in human neuroscience. To date, by estimating brain iron content through various MRI methods, significant age differences and age-related increases in iron content of the basal ganglia have been revealed across multiple samples. Less consistent are the findings that pertain to the relationship between elevated brain iron content and systemic indices of vascular and metabolic dysfunction. Only a handful of cross-sectional investigations have linked high iron content in various brain regions and poor performance on assorted cognitive tests. The even fewer longitudinal studies indicate that iron accumulation may precede shrinkage of the basal ganglia and thus predict poor maintenance of cognitive functions. This rapidly developing field will benefit from introduction of higher-field MRI scanners, improvement in iron-sensitive and -specific acquisition sequences and post-processing analytic and computational methods, as well as accumulation of data from long-term longitudinal investigations. This review describes the potential advantages and promises of MRI-based assessment of brain iron, summarizes recent findings and highlights the limitations of the current methodology. PMID:26248580

  16. Ultrastructural aspects of iron storage, transport and metabolism.

    PubMed

    Iancu, Theodore C

    2011-03-01

    The iron storage proteins, ferritin and hemosiderin, enable electron microscopic visualization thanks to their electron-dense iron content, which is not present in other compounds involved in transport or metabolism of iron such as transferrin, lactoferrin, or hemoglobin. It is this electron density which contributed to the unraveling of stages in absorption, transport, deposition, storage, and release of iron. In recent years, additional methods of investigation have further supported the information achieved by the ultrastructural studies. Even while using new analytical methods, the seminal morphological observations remain valid for understanding the role of iron in health and disease. In this review, we will illustrate a few basic findings of electron microscopy in humans, experimental animals, and cell cultures. The importance of H chain ferritin as a transporter across the blood-brain barrier is just an example of a new role revealed for an "old" storage protein, explaining some controversial observations on the presence of iron in the brain.

  17. Physiological, biomass elemental composition and proteomic analyses of Escherichia coli ammonium-limited chemostat growth, and comparison with iron- and glucose-limited chemostat growth

    PubMed Central

    Folsom, James Patrick

    2015-01-01

    Escherichia coli physiological, biomass elemental composition and proteome acclimations to ammonium-limited chemostat growth were measured at four levels of nutrient scarcity controlled via chemostat dilution rate. These data were compared with published iron- and glucose-limited growth data collected from the same strain and at the same dilution rates to quantify general and nutrient-specific responses. Severe nutrient scarcity resulted in an overflow metabolism with differing organic byproduct profiles based on limiting nutrient and dilution rate. Ammonium-limited cultures secreted up to 35  % of the metabolized glucose carbon as organic byproducts with acetate representing the largest fraction; in comparison, iron-limited cultures secreted up to 70  % of the metabolized glucose carbon as lactate, and glucose-limited cultures secreted up to 4  % of the metabolized glucose carbon as formate. Biomass elemental composition differed with nutrient limitation; biomass from ammonium-limited cultures had a lower nitrogen content than biomass from either iron- or glucose-limited cultures. Proteomic analysis of central metabolism enzymes revealed that ammonium- and iron-limited cultures had a lower abundance of key tricarboxylic acid (TCA) cycle enzymes and higher abundance of key glycolysis enzymes compared with glucose-limited cultures. The overall results are largely consistent with cellular economics concepts, including metabolic tradeoff theory where the limiting nutrient is invested into essential pathways such as glycolysis instead of higher ATP-yielding, but non-essential, pathways such as the TCA cycle. The data provide a detailed insight into ecologically competitive metabolic strategies selected by evolution, templates for controlling metabolism for bioprocesses and a comprehensive dataset for validating in silico representations of metabolism. PMID:26018546

  18. Effects of iron replenishment on iron, calcium, phosphorus and magnesium metabolism in iron-deficient rats.

    PubMed

    Pallarés, I; López-Aliaga, I; Lisbona, F; Moratalla, A; Gómez-Ayala, A E; Barrionuevo, M; Hartiti, S; Alférez, M J; Campos, M S

    1996-01-01

    We investigated the effect of Fe deficiency on the nutritive utilization of Fe, Ca, P and Mg in rats. Aside from the well known depletion of Fe in liver, femur and sternum with low values of Hb, Fe deficiency impaired Ca, P and Mg metabolism at different degrees. Iron deficiency altered Mg absorption, lowered the concentration of Ca in the liver, femur and sternum, raised the concentration of P and Mg in the liver, and decreased P in the femur. The altered status was not completely rectified by iron supplementation as the animals were still slightly anemic at the end of the study. The second purpose of the study was to evaluate the ability of three iron compounds (ferric citrate, ferrous sulfate and ferrous ascorbate) to correct the undesirable effects of Fe deficiency. Ten days after treatment with these diets, Fe-deficient rats still had reduced Mg absorption, especially those fed ferric citrate. The concentrations of hemoglobin approached normal values in all groups; however, serum Fe remained low, indicating that Fe reserves were still depleted. Hepatic and femoral Fe concentrations were also lower in all Fe-deficient groups regardless of the diet given, compared with their respective controls, whereas Fe concentrations in the sternum increased significantly with all three diets, suggesting an increase in erythropoiesis. The concentration of Ca, P and Mg in liver approached normal values, and appeared to normalize in the femur, except that Ca and P concentrations remained low with the citrate diet. In the sternum, a site assumed to have higher requirements for these minerals, the concentrations of Ca, P and Mg also increased. These findings indicate that Fe is involved in the bone mineralization, and that in physiological terms, Fe interacts favorably with Ca, P and Mg metabolism, since Fe deficiency altered the status of these metals. These findings also suggest that ferrous ascorbate and ferrous sulfate were more effectively absorbed than was ferric citrate.

  19. Secreted Pyomelanin of Legionella pneumophila Promotes Bacterial Iron Uptake and Growth under Iron-Limiting Conditions

    PubMed Central

    Zheng, Huaixin; Chatfield, Christa H.; Liles, Mark R.

    2013-01-01

    Iron acquisition is critical to the growth and virulence of Legionella pneumophila. Previously, we found that L. pneumophila uses both a ferrisiderophore pathway and ferrous iron transport to obtain iron. We now report that two molecules secreted by L. pneumophila, homogentisic acid (HGA) and its polymerized variant (HGA-melanin, a pyomelanin), are able to directly mediate the reduction of various ferric iron salts. Furthermore, HGA, synthetic HGA-melanin, and HGA-melanin derived from bacterial supernatants enhanced the ability of L. pneumophila and other species of Legionella to take up radiolabeled iron. Enhanced iron uptake was not observed with a ferrous iron transport mutant. Thus, HGA and HGA-melanin mediate ferric iron reduction, with the resulting ferrous iron being available to the bacterium for uptake. Upon further testing of L. pneumophila culture supernatants, we found that significant amounts of ferric and ferrous iron were associated with secreted HGA-melanin. Importantly, a pyomelanin-containing fraction obtained from a wild-type culture supernatant was able to stimulate the growth of iron-starved legionellae. That the corresponding supernatant fraction obtained from a nonpigmented mutant culture did not stimulate growth demonstrated that HGA-melanin is able to both promote iron uptake and enhance growth under iron-limiting conditions. Indicative of a complementary role in iron acquisition, HGA-melanin levels were inversely related to the levels of siderophore activity. Compatible with a role in the ecology and pathogenesis of L. pneumophila, HGA and HGA-melanin were effective at reducing and releasing iron from both insoluble ferric hydroxide and the mammalian iron chelates ferritin and transferrin. PMID:23980114

  20. Vitamin A deficiency modulates iron metabolism via ineffective erythropoiesis.

    PubMed

    da Cunha, Marcela S B; Siqueira, Egle M A; Trindade, Luciano S; Arruda, Sandra F

    2014-10-01

    Vitamin A modulates inflammatory status, iron metabolism and erythropoiesis. Given that these factors modulate the expression of the hormone hepcidin (Hamp), we investigated the effect of vitamin A deficiency on molecular biomarkers of iron metabolism, the inflammatory response and the erythropoietic system. Five groups of male Wistar rats were treated: control (AIN-93G), the vitamin A-deficient (VAD) diet, the iron-deficient (FeD) diet, the vitamin A- and iron-deficient (VAFeD) diet or the diet with 12 mg atRA/kg diet replacing all-trans-retinyl palmitate by all-trans retinoic acid (atRA). Vitamin A deficiency reduced serum iron and transferrin saturation levels, increased spleen iron concentrations, reduced hepatic Hamp and kidney erythropoietin messenger RNA (mRNA) levels and up-regulated hepatic and spleen heme oxygenase-1 gene expression while reducing the liver HO-1 specific activity compared with the control. The FeD and VAFeD rats exhibited lower levels of serum iron and transferrin saturation, lower iron concentrations in tissues and lower hepatic Hamp mRNA levels compared with the control. The treatment with atRA resulted in lower serum iron and transferrin concentrations, an increased iron concentration in the liver, a decreased iron concentration in the spleen and in the gut, and decreased hepatic Hamp mRNA levels. In summary, these findings suggest that vitamin A deficiency leads to ineffective erythropoiesis by the down-regulation of renal erythropoietin expression in the kidney, resulting in erythrocyte malformation and the consequent accumulation of the heme group in the spleen. Vitamin A deficiency indirectly modulates systemic iron homeostasis by enhancing erythrophagocytosis of undifferentiated erythrocytes. Copyright © 2014 Elsevier Inc. All rights reserved.

  1. Phosphate Limitation Triggers the Dissolution of Precipitated Iron by the Marine Bacterium Pseudovibrio sp. FO-BEG1

    PubMed Central

    Romano, Stefano; Bondarev, Vladimir; Kölling, Martin; Dittmar, Thorsten; Schulz-Vogt, Heide N.

    2017-01-01

    Phosphorus is an essential nutrient for all living organisms. In bacteria, the preferential phosphorus source is phosphate, which is often a limiting macronutrient in many areas of the ocean. The geochemical cycle of phosphorus is strongly interconnected with the cycles of other elements and especially iron, because phosphate tends to adsorb onto iron minerals, such as iron oxide formed in oxic marine environments. Although the response to either iron or phosphate limitation has been investigated in several bacterial species, the metabolic interplay between these two nutrients has rarely been considered. In this study we evaluated the impact of phosphate limitation on the iron metabolism of the marine bacterium Pseudovibrio sp. FO-BEG1. We observed that phosphate limitation led to an initial decrease of soluble iron in the culture up to three times higher than under phosphate surplus conditions. Similarly, a decrease in soluble cobalt was more pronounced under phosphate limitation. These data point toward physiological changes induced by phosphate limitation that affect either the cellular surface and therefore the metal adsorption onto it or the cellular metal uptake. We discovered that under phosphate limitation strain FO-BEG1, as well as selected strains of the Roseobacter clade, secreted iron-chelating molecules. This leads to the hypothesis that these bacteria might release such molecules to dissolve iron minerals, such as iron-oxyhydroxide, in order to access the adsorbed phosphate. As the adsorption of phosphate onto iron minerals can significantly decrease phosphate concentrations in the environment, the observed release of iron-chelators might represent an as yet unrecognized link between the biogeochemical cycle of phosphorus and iron, and it suggests another biological function of iron-chelating molecules in addition to metal-scavenging. PMID:28352252

  2. Phosphate Limitation Triggers the Dissolution of Precipitated Iron by the Marine Bacterium Pseudovibrio sp. FO-BEG1.

    PubMed

    Romano, Stefano; Bondarev, Vladimir; Kölling, Martin; Dittmar, Thorsten; Schulz-Vogt, Heide N

    2017-01-01

    Phosphorus is an essential nutrient for all living organisms. In bacteria, the preferential phosphorus source is phosphate, which is often a limiting macronutrient in many areas of the ocean. The geochemical cycle of phosphorus is strongly interconnected with the cycles of other elements and especially iron, because phosphate tends to adsorb onto iron minerals, such as iron oxide formed in oxic marine environments. Although the response to either iron or phosphate limitation has been investigated in several bacterial species, the metabolic interplay between these two nutrients has rarely been considered. In this study we evaluated the impact of phosphate limitation on the iron metabolism of the marine bacterium Pseudovibrio sp. FO-BEG1. We observed that phosphate limitation led to an initial decrease of soluble iron in the culture up to three times higher than under phosphate surplus conditions. Similarly, a decrease in soluble cobalt was more pronounced under phosphate limitation. These data point toward physiological changes induced by phosphate limitation that affect either the cellular surface and therefore the metal adsorption onto it or the cellular metal uptake. We discovered that under phosphate limitation strain FO-BEG1, as well as selected strains of the Roseobacter clade, secreted iron-chelating molecules. This leads to the hypothesis that these bacteria might release such molecules to dissolve iron minerals, such as iron-oxyhydroxide, in order to access the adsorbed phosphate. As the adsorption of phosphate onto iron minerals can significantly decrease phosphate concentrations in the environment, the observed release of iron-chelators might represent an as yet unrecognized link between the biogeochemical cycle of phosphorus and iron, and it suggests another biological function of iron-chelating molecules in addition to metal-scavenging.

  3. Silica burial enhanced by iron limitation in oceanic upwelling margins

    NASA Astrophysics Data System (ADS)

    Pichevin, L. E.; Ganeshram, R. S.; Geibert, W.; Thunell, R.; Hinton, R.

    2014-07-01

    In large swaths of the ocean, primary production by diatoms may be limited by the availability of silica, which in turn limits the biological uptake of carbon dioxide. The burial of biogenic silica in the form of opal is the main sink of marine silicon. Opal burial occurs in equal parts in iron-limited open-ocean provinces and upwelling margins, especially the eastern Pacific upwelling zone. However, it is unclear why opal burial is so efficient in this margin. Here we measure fluxes of biogenic material, concentrations of diatom-bound iron and silicon isotope ratios using sediment traps and a sediment core from the Gulf of California upwelling margin. In the sediment trap material, we find that periods of intense upwelling are associated with transient iron limitation that results in a high export of silica relative to organic carbon. A similar correlation between enhanced silica burial and iron limitation is evident in the sediment core, which spans the past 26,000 years. A global compilation also indicates that hotspots of silicon burial in the ocean are all characterized by high silica to organic carbon export ratios, a diagnostic trait for diatoms growing under iron stress. We therefore propose that prevailing conditions of silica limitation in the ocean are largely caused by iron deficiency imposing an indirect constraint on oceanic carbon uptake.

  4. Hephaestin and ceruloplasmin facilitate iron metabolism in the mouse kidney

    PubMed Central

    Jiang, Bo; Liu, Guohao; Zheng, Jiashuo; Chen, Mengxia; Maimaitiming, Zaitunamu; Chen, Min; Liu, Shunli; Jiang, Ruiwei; Fuqua, Brie K.; Dunaief, Joshua L.; Vulpe, Chris D.; Anderson, Gregory J.; Wang, Hongwei; Chen, Huijun

    2016-01-01

    Multicopper ferroxidases (MCFs) play an important role in cellular iron homeostasis. However, the role of MCFs in renal metabolism remains unclear. We used Hephaestin (Heph) and Ceruloplasmin (Cp) single or double (Heph/Cp) knockout (KO) mice to study the roles of MCFs in the kidney. Renal iron levels and the expression of iron metabolism genes were examined. The non-heme iron content both in the renal cortex and medulla of Heph/Cp KO mice was significantly increased. Perls’ Prussian blue staining showed iron accumulation on the apical side of renal tubular cells in Heph/Cp KO mice. A significant increase in ferritin protein expression was also observed in the renal medulla and cortex of Heph/Cp KO mice. Both DMT1 and TfR1 protein expression were significantly decreased in the renal medulla of Heph/Cp KO mice, while the expression of DMT1 protein was significantly increased in the renal cortex of these animals. Significant increase in proteinuria and total urinary iron was observed in the double knockout mice, and this was associated with compromised structural integrity. These results suggest that KO of both the HEPH and CP genes leads to kidney iron deposition and toxicity, MCFs could protect kidney against a damage from iron excess. PMID:27991585

  5. Effect of diquat-induced oxidative stress on iron metabolism in male Fischer-344 rats.

    PubMed

    Higuchi, Masashi; Yoshikawa, Yasunaga; Orino, Koichi; Watanabe, Kiyotaka

    2011-12-01

    Diquat toxicity causes iron-mediated oxidative stress; however, it remains unclear how diquat affects iron metabolism. Here, we examined the effect of diquat-induced oxidative stress on iron metabolism in male Fischer-344 rats, with particular focus on gene expression. Hepatic nonheme iron content was unchanged until 20 h after diquat treatment. Hepatic free iron levels increased markedly in the early stages following treatment and remained elevated for at least 6 h, resulting in severe hepatotoxicity, until returning to control levels at 20 h. The level of hepatic ferritin, especially the H-subunit, increased 20 h after diquat treatment due to elevated hepatic ferritin-H mRNA expression. These results indicate that early elevated levels of free iron in the liver of diquat-treated rats cause hepatotoxicity, and that this free iron is subsequently sequestered by ferritin synthesized under conditions of oxidative stress, thus limiting the pro-oxidant challenge of iron. The plasma iron concentration decreased at 6 and 20 h after diquat treatment, whereas the level of plasma interleukin-6 increased markedly at 3 h and remained high until 20 h. In the liver of diquat-treated rats, expression of hepcidin mRNA was markedly upregulated at 3 and 6 h, whereas ferroportin mRNA expression was downregulated slightly at 20 h. Transferrin receptor 1 mRNA expression was significantly upregulated at 3, 6, and 20 h. These results indicate that inhibition of iron release from iron-storage tissues, through stimulation of the interleukin-6-hepcidin-ferroportin axis, and enhanced iron uptake into hepatocytes, mediated by transferrin receptor 1, cause hypoferremia.

  6. Identifying the Genes Responsible for Iron-Limited Condition in Riemerella anatipestifer CH-1 through RNA-Seq-Based Analysis

    PubMed Central

    Huang, Mi; Zhu, DeKang; Wang, MingShu; Jia, RenYong; Chen, Shun; Sun, KunFeng; Yang, Qiao; Wu, Ying; Biville, Francis

    2017-01-01

    One of the important elements for most bacterial growth is iron, the bioavailability of which is limited in hosts. Riemerella anatipestifer (R. anatipestifer, RA), an important duck pathogen, requires iron to live. However, the genes involved in iron metabolism and the mechanisms of iron transport are largely unknown. Here, we investigated the transcriptomic effects of iron limitation condition on R. anatipestifer CH-1 using the RNA-Seq and RNA-Seq-based analysis. Data analysis revealed genes encoding functions related to iron homeostasis, including a number of putative TonB-dependent receptor systems, a HmuY-like protein-dependent hemin (an iron-containing porphyrin) uptake system, a Feo system, a gene cluster related to starch utilization, and genes encoding hypothetical proteins that were significantly upregulated in response to iron limitation. Compared to the number of upregulated genes, more genes were significantly downregulated in response to iron limitation. The downregulated genes mainly encoded a number of outer membrane receptors, DNA-binding proteins, phage-related proteins, and many hypothetical proteins. This information suggested that RNA-Seq-based analysis in iron-limited medium is an effective and fast method for identifying genes involved in iron uptake in R. anatipestifer CH-1. PMID:28540303

  7. Nitrate-dependent iron oxidation limits iron transport in anoxic ocean regions

    NASA Astrophysics Data System (ADS)

    Scholz, Florian; Löscher, Carolin R.; Fiskal, Annika; Sommer, Stefan; Hensen, Christian; Lomnitz, Ulrike; Wuttig, Kathrin; Göttlicher, Jörg; Kossel, Elke; Steininger, Ralph; Canfield, Donald E.

    2016-11-01

    Iron is an essential element for life on Earth and limits primary production in large parts of the ocean. Oxygen-free continental margin sediments represent an important source of bioavailable iron to the ocean, yet little of the iron released from the seabed reaches the productive sea surface. Even in the anoxic water of oxygen minimum zones, where iron solubility should be enhanced, most of the iron is rapidly re-precipitated. To constrain the mechanism(s) of iron removal in anoxic ocean regions we explored the sediment and water in the oxygen minimum zone off Peru. During our sampling campaign the water column featured two distinct redox boundaries separating oxic from nitrate-reducing (i.e., nitrogenous) water and nitrogenous from weakly sulfidic water. The sulfidic water mass in contact with the shelf sediment contained elevated iron concentrations >300 nM. At the boundary between sulfidic and nitrogenous conditions, iron concentrations dropped sharply to <20 nM coincident with a maximum in particulate iron concentration. Within the iron gradient, we found an increased expression of the key functional marker gene for nitrate reduction (narG). Part of this upregulation was related to the activity of known iron-oxidizing bacteria. Collectively, our data suggest that iron oxidation and removal is induced by nitrate-reducing microbes, either enzymatically through anaerobic iron oxidation or by providing nitrite for an abiotic reaction. Given the important role that iron plays in nitrogen fixation, photosynthesis and respiration, nitrate-dependent iron oxidation likely represents a key-link between the marine biogeochemical cycles of nitrogen, oxygen and carbon.

  8. The Interface Between Iron Metabolism and Gene-Based Iron Contrast for MRI.

    PubMed

    Goldhawk, Donna E; Gelman, Neil; Sengupta, Anindita; Prato, Frank S

    2015-01-01

    Using a gene-based approach to track cellular and molecular activity with magnetic resonance imaging (MRI) has many advantages. The strong correlation between transverse relaxation rates and total cellular iron content provides a basis for developing sensitive and quantitative detection of MRI reporter gene expression. In addition to biophysical concepts, general features of mammalian iron regulation add valuable context for interpreting molecular MRI predicated on gene-based iron labeling. With particular reference to the potential of magnetotactic bacterial gene expression as a magnetic resonance (MR) contrast agent for mammalian cell tracking, studies in different cell culture models highlight the influence of intrinsic iron regulation on the MRI signal. The interplay between dynamic regulation of mammalian iron metabolism and expression systems designed to sequester iron biominerals for MRI is presented from the perspective of their potential influence on MR image interpretation.

  9. The Interface Between Iron Metabolism and Gene-Based Iron Contrast for MRI

    PubMed Central

    Goldhawk, Donna E.; Gelman, Neil; Sengupta, Anindita; Prato, Frank S.

    2015-01-01

    Using a gene-based approach to track cellular and molecular activity with magnetic resonance imaging (MRI) has many advantages. The strong correlation between transverse relaxation rates and total cellular iron content provides a basis for developing sensitive and quantitative detection of MRI reporter gene expression. In addition to biophysical concepts, general features of mammalian iron regulation add valuable context for interpreting molecular MRI predicated on gene-based iron labeling. With particular reference to the potential of magnetotactic bacterial gene expression as a magnetic resonance (MR) contrast agent for mammalian cell tracking, studies in different cell culture models highlight the influence of intrinsic iron regulation on the MRI signal. The interplay between dynamic regulation of mammalian iron metabolism and expression systems designed to sequester iron biominerals for MRI is presented from the perspective of their potential influence on MR image interpretation. PMID:26483608

  10. Hepcidin: Homeostasis and Diseases Related to Iron Metabolism.

    PubMed

    Reichert, Cadiele Oliana; da Cunha, Joel; Levy, Débora; Maselli, Luciana Morganti Ferreira; Bydlowski, Sérgio Paulo; Spada, Celso

    2017-01-01

    Iron is an essential metal for cell survival that is regulated by the peptide hormone hepcidin. However, its influence on certain diseases is directly related to iron metabolism or secondary to underlying diseases. Genetic alterations influence the serum hepcidin concentration, which can lead to an iron overload in tissues, as observed in haemochromatosis, in which serum hepcidin or defective hepcidin synthesis is observed. Another genetic imbalance of iron is iron-refractory anaemia, in which serum concentrations of hepcidin are increased, precluding the flow and efflux of extra- and intracellular iron. During the pathogenesis of certain diseases, the resulting oxidative stress, as well as the increase in inflammatory cytokines, influences the transcription of the HAMP gene to generate a secondary anaemia due to the increase in the serum concentration of hepcidin. To date, there is no available drug to inhibit or enhance hepcidin transcription, mostly due to the cytotoxicity described in the in vitro models. The proposed therapeutic targets are still in the early stages of clinical trials. Some candidates are promising, such as heparin derivatives and minihepcidins. This review describes the main pathways of systemic and genetic regulation of hepcidin, as well as its influence on the disorders related to iron metabolism. © 2017 S. Karger AG, Basel.

  11. Iron-dependent remodeling of fungal metabolic pathways associated with ferrichrome biosynthesis.

    PubMed

    Mercier, Alexandre; Labbé, Simon

    2010-06-01

    The fission yeast Schizosaccharomyces pombe excretes and accumulates the hydroxamate-type siderophore ferrichrome. The sib1(+) and sib2(+) genes encode, respectively, a siderophore synthetase and an l-ornithine N(5)-oxygenase that participate in ferrichrome biosynthesis. In the present report, we demonstrate that sib1(+) and sib2(+) are repressed by the GATA-type transcriptional repressor Fep1 in response to high levels of iron. We further found that the loss of Fep1 results in increased ferrichrome production. We showed that a sib1Delta sib2Delta mutant strain exhibits a severe growth defect on iron-poor media. We determined that two metabolic pathways are involved in biosynthesis of ornithine, an obligatory precursor of ferrichrome. Ornithine is produced by hydrolysis of arginine by the Car1 and Car3 proteins. Although car3(+) was constitutively expressed, car1(+) transcription levels were repressed upon exposure to iron, with a concomitant decrease of Car1 arginase activity. Ornithine is also generated by transformation of glutamate, which itself is produced by two separate biosynthetic pathways which are transcriptionally regulated by iron in an opposite fashion. In one pathway, the glutamate dehydrogenase Gdh1, which produces glutamate from 2-ketoglutarate, was repressed under iron-replete conditions in a Fep1-dependent manner. The other pathway involves two coupled enzymes, glutamine synthetase Gln1 and Fe-S cluster-containing glutamate synthase Glt1, which were both repressed under iron-limiting conditions but were expressed under iron-replete conditions. Collectively, these results indicate that under conditions of iron deprivation, yeast remodels metabolic pathways linked to ferrichrome synthesis in order to limit iron utilization without compromising siderophore production and its ability to sequester iron from the environment.

  12. Metabolic syndrome: its history, mechanisms, and limitations.

    PubMed

    Oda, Eiji

    2012-04-01

    In late twentieth century, Ruderman and Reaven showed that insulin resistance might be fundamental to metabolic syndrome (MetS) which means a constellation of obesity-related metabolic derangements predisposing to type 2 diabetes and cardiovascular disease. In 2001, user-friendly National Cholesterol Education Program (NCEP) criteria of MetS were proposed. In 2005, the International Diabetes Federation (IDF) and the Examination Committee for Criteria of Metabolic Syndrome in Japan issued different criteria of MetS where abdominal obesity is a necessary component. In 2009, IDF, National Heart, Lung, and Blood Institute, American Heart Association, World Heart Federation, International Atherosclerosis Society, and International Association for the Study of Obesity jointly adopted the revised NCEP criteria, where abdominal obesity is not a necessary component, as worldwide criteria of MetS. In 2010, WHO Expert Consultation warned that MetS is a concept that focuses attention on complex multifactorial health problems but has limited practical utility as a management tool. In animal studies, adipose tissue inflammation characterized by an increased number of crown-like structures in adipose tissue, rather than obesity per se, was shown to be a fundamental mechanism of metabolic derangements.

  13. Dysregulation of cellular iron metabolism in Friedreich ataxia: from primary iron-sulfur cluster deficit to mitochondrial iron accumulation

    PubMed Central

    Martelli, Alain; Puccio, Hélène

    2014-01-01

    Friedreich ataxia (FRDA) is the most common recessive ataxia in the Caucasian population and is characterized by a mixed spinocerebellar and sensory ataxia frequently associating cardiomyopathy. The disease results from decreased expression of the FXN gene coding for the mitochondrial protein frataxin. Early histological and biochemical study of the pathophysiology in patient's samples revealed that dysregulation of iron metabolism is a key feature of the disease, mainly characterized by mitochondrial iron accumulation and by decreased activity of iron-sulfur cluster enzymes. In the recent past years, considerable progress in understanding the function of frataxin has been provided through cellular and biochemical approaches, pointing to the primary role of frataxin in iron-sulfur cluster biogenesis. However, why and how the impact of frataxin deficiency on this essential biosynthetic pathway leads to mitochondrial iron accumulation is still poorly understood. Herein, we review data on both the primary function of frataxin and the nature of the iron metabolism dysregulation in FRDA. To date, the pathophysiological implication of the mitochondrial iron overload in FRDA remains to be clarified. PMID:24917819

  14. The effect of BCG on iron metabolism in the early neonatal period: A controlled trial in Gambian neonates.

    PubMed

    Prentice, Sarah; Jallow, Momodou W; Prentice, Andrew M

    2015-06-12

    Bacillus Calmette-Guerin (BCG) vaccination has been reported to protect neonates from non-tuberculous pathogens, but no biological mechanism to explain such effects is known. We hypothesised that BCG produces broad-spectrum anti-microbial protection via a hepcidin-mediated hypoferraemia, limiting iron availability for pathogens. To test this we conducted a trial in 120 Gambian neonates comparing iron status in the first 5-days of life after allocation to: (1) All routine vaccinations at birth (BCG/Oral Polio Vaccine (OPV)/Hepatitis B Vaccine (HBV)); (2) BCG delayed until after the study period (at day 5); and (3) All routine vaccinations delayed until after the study period. Vaccine regime at birth did not significantly impact on any measured parameter of iron metabolism. However, the ability to detect an effect of BCG on iron metabolism may have been limited by short follow-up time and high activation of the inflammatory-iron axis in the study population.

  15. Proteomic Analysis Reveals That Iron Availability Alters the Metabolic Status of the Pathogenic Fungus Paracoccidioides brasiliensis

    PubMed Central

    Parente, Ana F. A.; Bailão, Alexandre M.; Borges, Clayton L.; Parente, Juliana A.; Magalhães, Adriana D.; Ricart, Carlos A. O.; Soares, Célia M. A.

    2011-01-01

    Paracoccidioides brasiliensis is a thermodimorphic fungus and the causative agent of paracoccidioidomycosis (PCM). The ability of P. brasiliensis to uptake nutrients is fundamental for growth, but a reduction in the availability of iron and other nutrients is a host defense mechanism many pathogenic fungi must overcome. Thus, fungal mechanisms that scavenge iron from host may contribute to P. brasiliensis virulence. In order to better understand how P. brasiliensis adapts to iron starvation in the host we compared the two-dimensional (2D) gel protein profile of yeast cells during iron starvation to that of iron rich condition. Protein spots were selected for comparative analysis based on the protein staining intensity as determined by image analysis. A total of 1752 protein spots were selected for comparison, and a total of 274 out of the 1752 protein spots were determined to have changed significantly in abundance due to iron depletion. Ninety six of the 274 proteins were grouped into the following functional categories; energy, metabolism, cell rescue, virulence, cell cycle, protein synthesis, protein fate, transcription, cellular communication, and cell fate. A correlation between protein and transcript levels was also discovered using quantitative RT-PCR analysis from RNA obtained from P. brasiliensis under iron restricting conditions and from yeast cells isolated from infected mouse spleens. In addition, western blot analysis and enzyme activity assays validated the differential regulation of proteins identified by 2-D gel analysis. We observed an increase in glycolytic pathway protein regulation while tricarboxylic acid cycle, glyoxylate and methylcitrate cycles, and electron transport chain proteins decreased in abundance under iron limiting conditions. These data suggest a remodeling of P. brasiliensis metabolism by prioritizing iron independent pathways. PMID:21829521

  16. Metabolism of manganese, iron, copper, and selenium in calves

    SciTech Connect

    Ho, S.Y.

    1981-01-01

    Sixteen male Holstein calves were used to study manganese and iron metabolism. The calves were fed one of the following diets for 18 days: control, control + iron, control + manganese, and control + iron and manganese. All calves were dosed orally with manganese-54. Tissue concentrations of manganese, iron and manganese-54 were determined. Small intestinal iron was lower in calves fed the high manganese diet than in controls. Tissue manganese-54 was lower in calves fed a high manganese diet. Fecal manganese content increased in calves fed both high manganese and high manganese-high iron diets. Serum total iron was not affected by the dietary treatments. To study the effects of high dietary levels of copper and selenium on the intracellular distributions of these two elements in liver and kidney cytosol, calves were fed one of four diets for 15 days. These were 0 and 100 ppM supplemental copper and 0 and 1 ppM added selenium. The control diet containing 0.1 ppM of selenium and 15 ppM of copper. All calves were orally dosed 48 hrs prior to sacrifice with selenium-75. A high copper diet increased copper concentrations in all intracellular liver fractions and most kidney fractions. Only the effects in the liver were significant. Less copper was found in the mitochondria fractions in liver and kidney of calves fed a high selenium diet. Three major copper-binding protein peaks were separated from the soluble fractions of calf liver and kidney. Peak 1 appeared to be the major copper-binding protein in liver and kidney cytosol of copper-loaded animals. Added selenium alone or in combination with copper accentuated the copper accumulation in this peak. Most of selenium-75 was recovered in the same peak as the copper. The results of this experiment indicated that the large molecular proteins in liver and kidney cytosol of calves play an important role in copper and selenium-75 metabolism. (ERB)

  17. [Iron metabolism in breast cancer: knowledge and future].

    PubMed

    Durigova, Anna; Jacot, William; Pouderoux, Stéphane; Roques, Sylvie; Montels, Frédéric; Lamy, Pierre-Jean

    2012-01-01

    Iron plays a fundamental role in biology and its concentration in living organisms is regulated very precisely. Many molecules of storage and transportation are used to maintain the intracellular homeostasis. Cancer cells have alterations in this balance. Recent studies have shown that breast cancer cells present abnormal expression of several proteins such as hepcidin and ferroportin. A prognostic impact of these alterations has been reported in patients with breast cancer. Regulatory molecules of iron metabolism could become therapeutic targets. This is an innovative approach that has emerged for treating a cancer which, despite advances in treatment and the emergence of targeted therapies, remains the leading cause of cancer death in women.

  18. Metabolic adaptation to tissue iron overload confers tolerance to malaria.

    PubMed

    Gozzelino, Raffaella; Andrade, Bruno Bezerril; Larsen, Rasmus; Luz, Nivea F; Vanoaica, Liviu; Seixas, Elsa; Coutinho, Antonio; Cardoso, Sílvia; Rebelo, Sofia; Poli, Maura; Barral-Netto, Manoel; Darshan, Deepak; Kühn, Lukas C; Soares, Miguel P

    2012-11-15

    Disease tolerance is a defense strategy that limits the fitness costs of infection irrespectively of pathogen burden. While restricting iron (Fe) availability to pathogens is perceived as a host defense strategy, the resulting tissue Fe overload can be cytotoxic and promote tissue damage to exacerbate disease severity. Examining this interplay during malaria, the disease caused by Plasmodium infection, we find that expression of the Fe sequestering protein ferritin H chain (FtH) in mice, and ferritin in humans, is associated with reduced tissue damage irrespectively of pathogen burden. FtH protection relies on its ferroxidase activity, which prevents labile Fe from sustaining proapoptotic c-Jun N-terminal kinase (JNK) activation. FtH expression is inhibited by JNK activation, promoting tissue Fe overload, tissue damage, and malaria severity. Mimicking FtH's antioxidant effect or inhibiting JNK activation pharmacologically confers therapeutic tolerance to malaria in mice. Thus, FtH provides metabolic adaptation to tissue Fe overload, conferring tolerance to malaria.

  19. Iron retention in preterm infants fed low iron intakes: a metabolic balance study.

    PubMed

    Griffin, Ian; Cooke, Richard J

    2010-07-01

    There is little data on iron retention in healthy preterm infants. Twenty-four metabolic balance studies were carried out in 13 preterm infants between 17 and 63 days of age, in 11 cases 2 balance were carried out 7d apart. Iron intake was 1.11 mg/kg/day (SD 0.06), less than the 2 mg/kg/d typically recommended for preterm infants. Iron retention was positive in the majority (3/13) of the first balances, and in all 11 of the second balances. Iron retention increased significantly between the two balances (from 0.095 mg/kg/d (SD 0.178) to 0.270 (SD 0.209)). Iron retention was significantly related to the time that the infant had been on enteral feeds at the time the balance was carried out. Iron retention was significantly greater than the requirement estimated to be needed to meet the needs for growth and expansion of the circulating red cell mass. Iron intakes of about 1mg/kg/d seem to be adequate to support the requirements for growth in preterm infants during this time period, but are significantly less than the estimated in utero accretion rate of the fetus.

  20. Uptake and metabolism of iron oxide nanoparticles in brain cells.

    PubMed

    Petters, Charlotte; Irrsack, Ellen; Koch, Michael; Dringen, Ralf

    2014-09-01

    Magnetic iron oxide nanoparticles (IONPs) are used for various applications in biomedicine, for example as contrast agents in magnetic resonance imaging, for cell tracking and for anti-tumor treatment. However, IONPs are also known for their toxic effects on cells and tissues which are at least in part caused by iron-mediated radical formation and oxidative stress. The potential toxicity of IONPs is especially important concerning the use of IONPs for neurobiological applications as alterations in brain iron homeostasis are strongly connected with human neurodegenerative diseases. Since IONPs are able to enter the brain, potential adverse consequences of an exposure of brain cells to IONPs have to be considered. This article describes the pathways that allow IONPs to enter the brain and summarizes the current knowledge on the uptake, the metabolism and the toxicity of IONPs for the different types of brain cells in vitro and in vivo.

  1. Mutational Analysis of a Role for Salicylic Acid in Iron Metabolism of Mycobacterium smegmatis

    PubMed Central

    Adilakshmi, Tadepalli; Ayling, Peter D.; Ratledge, Colin

    2000-01-01

    The role of salicylic acid in iron metabolism was examined in two wild-type strains (mc2155 and NCIMB 8548) and three mutant strains (mc21292 [lacking exochelin], SM3 [lacking iron-dependent repressor protein IdeR] and S99 [a salicylate-requiring auxotroph derived in this study]) of Mycobacterium smegmatis. Synthesis of salicylate in SM3 was derepressed even in the presence of iron, as was synthesis of the siderophores exochelin, mycobactin, and carboxymycobactin. S99 was dependent on salicylate for growth and failed to grow with the three ferrisiderophores, suggesting that salicylate fulfills an additional function(s) other than being a precursor of mycobactin and carboxymycobactin. Salicylic acid at 100 μg/ml repressed the formation of a 29-kDa cell envelope protein (putative exochelin receptor protein) in S99 grown both iron deficiently and iron sufficiently. In contrast, synthesis of this protein was affected only under iron-limited conditions in the parent strain, mc2155, and remained unaltered in SM3, suggesting an interaction between the IdeR protein and salicylate. Thus, salicylate may also function as a signal molecule for recognition of cellular iron status. Growth of all strains and mutants with p-aminosalicylate (PAS) at 100 μg/ml increased salicylate accumulation between three- and eightfold under both iron-limited and iron-sufficient growth conditions and decreased mycobactin accumulation by 40 to 80% but increased carboxymycobactin accumulation by 50 to 55%. Thus, although PAS inhibited salicylate conversion to mycobactin, presumptively by blocking salicylate AMP kinase, PAS also interferes with the additional functions of salicylate, as its effect was heightened in S99 when the salicylate concentration was minimal. PMID:10629169

  2. Human macrophage hemoglobin-iron metabolism in vitro

    SciTech Connect

    Custer, G.; Balcerzak, S.; Rinehart, J.

    1982-01-01

    An entirely in vitro technique was employed to characterize hemoglobin-iron metabolism by human macrophages obtained by culture of blood monocytes and pulmonary alveolar macrophages. Macrophages phagocytized about three times as many erythrocytes as monocytes and six times as many erythrocytes as pulmonary alveolar macrophages. The rate of subsequent release of /sup 59/Fe to the extracellular transferrin pool was two- to fourfold greater for macrophages as compared to the other two cell types. The kinetics of /sup 59/Fe-transferrin release were characterized by a relatively rapid early phase (hours 1-4) followed by a slow phase (hours 4-72) for all three cell types. Intracellular movement of iron was characterized by a rapid shift from hemoglobin to ferritin that was complete with the onset of the slow phase of extracellular release. A transient increase in /sup 59/Fe associated with an intracellular protein eluting with transferrin was also observed within 1 hour after phagocytosis. The process of hemoglobin-iron release to extracellular transferrin was inhibited at 4 degrees C but was unaffected by inhibitory of protein synthesis, glycolysis, microtubule function, and microfilament function. These data emphasize the rapidity of macrophage hemoglobin iron metabolism, provide a model for characterization of this process in vitro, and in general confirm data obtained utilizing in vivo animal models.

  3. Altered erythropoiesis and iron metabolism in carriers of thalassemia

    PubMed Central

    Guimarães, Jacqueline S.; Cominal, Juçara G.; Silva-Pinto, Ana Cristina; Olbina, Gordana; Ginzburg, Yelena Z.; Nandi, Vijay; Westerman, Mark; Rivella, Stefano; de Souza, Ana Maria

    2014-01-01

    The thalassemia syndromes (α- and β-thalassemia) are the most common and frequent disorders associated with ineffective erythropoiesis. Imbalance of α- or β-globin chain production results in impaired red blood cell synthesis, anemia and more erythroid progenitors in the blood stream. While patients affected by these disorders show definitive altered parameters related to erythropoiesis, the relationship between the degree of anemia, altered erythropoiesis and dysfunctional iron metabolism have not been investigated in both α-thalassemia carriers (ATC) and β-thalassemia carriers (BTC). Here we demonstrate that ATC have a significantly reduced hepcidin and increased soluble transferrin receptor levels but relatively normal hematological findings. In contrast, BTC have several hematological parameters significantly different from controls, including increased soluble transferrin receptor and erythropoietin levels. These changings in both groups suggest an altered balance between erythropoiesis and iron metabolism. The index sTfR/log ferrin and (hepcidin/ferritin)/sTfR are respectively increased and reduced relative to controls, proportional to the severity of each thalassemia group. In conclusion, we showed in this study, for the first time in the literature, that thalassemia carriers have altered iron metabolism and erythropoiesis. PMID:25307880

  4. Altered erythropoiesis and iron metabolism in carriers of thalassemia.

    PubMed

    Guimarães, Jacqueline S; Cominal, Juçara G; Silva-Pinto, Ana Cristina; Olbina, Gordana; Ginzburg, Yelena Z; Nandi, Vijay; Westerman, Mark; Rivella, Stefano; de Souza, Ana Maria

    2015-06-01

    The thalassemia syndromes (α- and β-thalassemia) are the most common and frequent disorders associated with ineffective erythropoiesis. Imbalance of α- or β-globin chain production results in impaired red blood cell synthesis, anemia, and more erythroid progenitors in the blood stream. While patients affected by these disorders show definitive altered parameters related to erythropoiesis, the relationship between the degree of anemia, altered erythropoiesis, and dysfunctional iron metabolism has not been investigated in both α-thalassemia carriers (ATC) and β-thalassemia carriers (BTC). Here, we demonstrate that ATC have a significantly reduced hepcidin and increased soluble transferrin receptor levels but relatively normal hematological findings. In contrast, BTC have several hematological parameters significantly different from controls, including increased soluble transferrin receptor and erythropoietin levels. These changes in both groups suggest an altered balance between erythropoiesis and iron metabolism. The index sTfR/log ferritin and (hepcidin/ferritin)/sTfR are, respectively, increased and reduced relative to controls, proportional to the severity of each thalassemia group. In conclusion, we showed in this study, for the first time in the literature, that thalassemia carriers have altered iron metabolism and erythropoiesis. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  5. Copper's influence on iron metabolism in K562 cells

    SciTech Connect

    Percival, S.S.; Armstrong, E. )

    1991-03-15

    Copper deficiency is associated with a cellular defect in iron metabolism that results in poor hemoglobin synthesis. In order to determine this mechanisms, K562 cells, a human erythroleukemic cell line, were incubated with 1 mM bethocuproine disulfonic acid (BCS) to produce a copper deficiency or were supplemented with 8 {mu}M copper. Hemoglobin was simultaneously induced in some cells by the addition of 25 {mu}M hemin to the culture medium. Incubation with BCS resulted in a 30 to 40% reduction in intracellular Cu/Zn superoxide dismutase activity while supplementation resulted in a 20 to 50% increase in activity. The authors then examined the effect of these copper manipulations on {sup 59}Fe uptake from transferrin, on ferritin levels and on hemoglobin levels. Hemoglobin was only slightly affected by the copper treatments. In both noninduced cells and induced cells, copper supplementation resulted in a greater level of intracellular iron, a greater level of immunoreactive ferritin, and an enhanced uptake of {sup 59}Fe from transferrin. In BCS-incubated cells, intracellular iron, ferritin and {sup 59}Fe uptake from transferrin were reduced by at least 50%. Because the ferritin levels were reduced, intracellular iron mobilization did not appear to be impaired in copper deficiency. The results suggest that copper deficiency impairs the transport of iron by transferrin into the cell.

  6. Iron limitation of phytoplankton photosynthesis in the equatorial Pacific Ocean

    NASA Astrophysics Data System (ADS)

    Kolber, Zbigniew S.; Barber, Richard T.; Coale, Kenneth H.; Fitzwateri, Steve E.; Greene, Richard M.; Johnson, Kenneth S.; Lindley, Steven; Falkowski, Paul G.

    1994-09-01

    THE surface waters of the equatorial Pacific have unusually high nitrate and phosphate concentrations, but relatively low phyto-plankton biomass1-3. This 'high nitrate, low chlorophyll' (HNLC)4 phenomenon has been ascribed to 'top-down' grazing pressure by herbivores, which prevent the phytoplankton from fully utilizing the available nutrients5. In the late 1980s, however, Martin and co-workers proposed that iron, which is delivered to the remote open ocean in aeolean dust6, is the key factor limiting the standing crop of phytoplankton in HNLC areas7,8. Using a sensitive fluor-escence method9, we have followed changes in photochemical energy conversion efficiency9-10 of the natural phytoplankton com-munity both before and after artificial enrichment with iron of a small area (7.5 x 7.5 km) of the equatorial Pacific Ocean11. Our results show that iron limits phytoplankton photosynthesis in all size classes in this region by impairing intrinsic photochemical energy conversion, thereby supporting the hypothesis of physiologi-cal ('bottom up') limitation by this element.

  7. Hepcidin as a therapeutic tool to limit iron overload and improve anemia in β-thalassemic mice

    PubMed Central

    Gardenghi, Sara; Ramos, Pedro; Marongiu, Maria Franca; Melchiori, Luca; Breda, Laura; Guy, Ella; Muirhead, Kristen; Rao, Niva; Roy, Cindy N.; Andrews, Nancy C.; Nemeth, Elizabeta; Follenzi, Antonia; An, Xiuli; Mohandas, Narla; Ginzburg, Yelena; Rachmilewitz, Eliezer A.; Giardina, Patricia J.; Grady, Robert W.; Rivella, Stefano

    2010-01-01

    Excessive iron absorption is one of the main features of β-thalassemia and can lead to severe morbidity and mortality. Serial analyses of β-thalassemic mice indicate that while hemoglobin levels decrease over time, the concentration of iron in the liver, spleen, and kidneys markedly increases. Iron overload is associated with low levels of hepcidin, a peptide that regulates iron metabolism by triggering degradation of ferroportin, an iron-transport protein localized on absorptive enterocytes as well as hepatocytes and macrophages. Patients with β-thalassemia also have low hepcidin levels. These observations led us to hypothesize that more iron is absorbed in β-thalassemia than is required for erythropoiesis and that increasing the concentration of hepcidin in the body of such patients might be therapeutic, limiting iron overload. Here we demonstrate that a moderate increase in expression of hepcidin in β-thalassemic mice limits iron overload, decreases formation of insoluble membrane-bound globins and reactive oxygen species, and improves anemia. Mice with increased hepcidin expression also demonstrated an increase in the lifespan of their red cells, reversal of ineffective erythropoiesis and splenomegaly, and an increase in total hemoglobin levels. These data led us to suggest that therapeutics that could increase hepcidin levels or act as hepcidin agonists might help treat the abnormal iron absorption in individuals with β-thalassemia and related disorders. PMID:21099112

  8. Regulators of Iron Homeostasis: New Players in Metabolism, Cell Death, and Disease.

    PubMed

    Bogdan, Alexander R; Miyazawa, Masaki; Hashimoto, Kazunori; Tsuji, Yoshiaki

    2016-03-01

    Iron is necessary for life, but can also cause cell death. Accordingly, cells evolved a robust, tightly regulated suite of genes for maintaining iron homeostasis. Previous mechanistic studies on iron homeostasis have granted insight into the role of iron in human health and disease. We highlight new regulators of iron metabolism, including iron-trafficking proteins [solute carrier family 39, SLC39, also known as ZRT/IRT-like protein, ZIP; and poly-(rC)-binding protein, PCBP] and a cargo receptor (NCOA4) that is crucial for release of ferritin-bound iron. We also discuss emerging roles of iron in apoptosis and a novel iron-dependent cell death pathway termed 'ferroptosis', the dysregulation of iron metabolism in human pathologies, and the use of iron chelators in cancer therapy.

  9. Regulators of Iron Homeostasis: New Players in Metabolism, Cell Death, and Disease

    PubMed Central

    Bogdan, Alexander R.; Miyazawa, Masaki; Hashimoto, Kazunori; Tsuji, Yoshiaki

    2015-01-01

    Iron is necessary for life, but can also cause cell death. Accordingly, cells evolved a robust, tightly regulated suite of genes for maintaining iron homeostasis. Previous mechanistic studies on iron homeostasis have granted insight into the role of iron in human health and disease. We highlight new regulators of iron metabolism, including iron-trafficking proteins [solute carrier family 39, SLC39, also known as ZRT/IRT-like protein, ZIP; and poly-(rC)-binding protein, PCBP] and a cargo receptor (NCOA4) that is crucial for release of ferritin-bound iron. We also discuss emerging roles of iron in apoptosis and a novel iron-dependent cell death pathway termed ‘ferroptosis’, the dysregulation of iron metabolism in human pathologies, and the use of iron chelators in cancer therapy. PMID:26725301

  10. Effects of iron and nitrogen limitation on sulfur isotope fractionation during microbial sulfate reduction.

    PubMed

    Sim, Min Sub; Ono, Shuhei; Bosak, Tanja

    2012-12-01

    Sulfate-reducing microbes utilize sulfate as an electron acceptor and produce sulfide that is depleted in heavy isotopes of sulfur relative to sulfate. Thus, the distribution of sulfur isotopes in sediments can trace microbial sulfate reduction (MSR), and it also has the potential to reflect the physiology of sulfate-reducing microbes. This study investigates the relationship between the availability of iron and reduced nitrogen and the magnitude of S-isotope fractionation during MSR by a marine sulfate-reducing bacterium, DMSS-1, a Desulfovibrio species, isolated from salt marsh in Cape Cod, MA. Submicromolar levels of iron increase sulfur isotope fractionation by about 50% relative to iron-replete cultures of DMSS-1. Iron-limited cultures also exhibit decreased cytochrome c-to-total protein ratios and cell-specific sulfate reduction rates (csSRR), implying changes in the electron transport chain that couples carbon and sulfur metabolisms. When DMSS-1 fixes nitrogen in ammonium-deficient medium, it also produces larger fractionation, but it occurs at faster csSRRs than in the ammonium-replete control cultures. The energy and reducing power required for nitrogen fixation may be responsible for the reverse trend between S-isotope fractionation and csSRR in this case. Iron deficiency and nitrogen fixation by sulfate-reducing microbes may lead to the large observed S-isotope effects in some euxinic basins and various anoxic sediments.

  11. Effects of Iron and Nitrogen Limitation on Sulfur Isotope Fractionation during Microbial Sulfate Reduction

    PubMed Central

    Ono, Shuhei; Bosak, Tanja

    2012-01-01

    Sulfate-reducing microbes utilize sulfate as an electron acceptor and produce sulfide that is depleted in heavy isotopes of sulfur relative to sulfate. Thus, the distribution of sulfur isotopes in sediments can trace microbial sulfate reduction (MSR), and it also has the potential to reflect the physiology of sulfate-reducing microbes. This study investigates the relationship between the availability of iron and reduced nitrogen and the magnitude of S-isotope fractionation during MSR by a marine sulfate-reducing bacterium, DMSS-1, a Desulfovibrio species, isolated from salt marsh in Cape Cod, MA. Submicromolar levels of iron increase sulfur isotope fractionation by about 50% relative to iron-replete cultures of DMSS-1. Iron-limited cultures also exhibit decreased cytochrome c-to-total protein ratios and cell-specific sulfate reduction rates (csSRR), implying changes in the electron transport chain that couples carbon and sulfur metabolisms. When DMSS-1 fixes nitrogen in ammonium-deficient medium, it also produces larger fractionation, but it occurs at faster csSRRs than in the ammonium-replete control cultures. The energy and reducing power required for nitrogen fixation may be responsible for the reverse trend between S-isotope fractionation and csSRR in this case. Iron deficiency and nitrogen fixation by sulfate-reducing microbes may lead to the large observed S-isotope effects in some euxinic basins and various anoxic sediments. PMID:23001667

  12. Different iron sources to study the physiology and biochemistry of iron metabolism in marine micro-algae.

    PubMed

    Botebol, Hugo; Sutak, Robert; Scheiber, Ivo F; Blaiseau, Pierre-Louis; Bouget, François-Yves; Camadro, Jean-Michel; Lesuisse, Emmanuel

    2014-02-01

    We compared ferric EDTA, ferric citrate and ferrous ascorbate as iron sources to study iron metabolism in Ostreococcus tauri, Phaeodactlylum tricornutum and Emiliania huxleyi. Ferric EDTA was a better iron source than ferric citrate for growth and chlorophyll levels. Direct and indirect experiments showed that iron was much more available to the cells when provided as ferric citrate as compared to ferric EDTA. As a consequence, growth media with iron concentration in the range 1-100 nM were rapidly iron-depleted when ferric citrate-but not ferric EDTA was the iron source. When cultured together, P. tricornutum cells overgrew the two other species in iron-sufficient conditions, but E. huxleyi was able to compete other species in iron-deficient conditions, and when iron was provided as ferric citrate instead of ferric EDTA, which points out the critical influence of the chemical form of iron on the blooms of some phytoplankton species. The use of ferric citrate and ferrous ascorbate allowed us to unravel a kind of regulation of iron uptake that was dependent on the day/night cycles and to evidence independent uptake systems for ferrous and ferric iron, which can be regulated independently and be copper-dependent or independent. The same iron sources also allowed one to identify molecular components involved in iron uptake and storage in marine micro-algae. Characterizing the mechanisms of iron metabolism in the phytoplankton constitutes a big challenge; we show here that the use of iron sources more readily available to the cells than ferric EDTA is critical for this task.

  13. Arsenic release metabolically limited to permanently water-saturated soil in Mekong Delta

    NASA Astrophysics Data System (ADS)

    Stuckey, Jason W.; Schaefer, Michael V.; Kocar, Benjamin D.; Benner, Shawn G.; Fendorf, Scott

    2016-01-01

    Microbial reduction of arsenic-bearing iron oxides in the deltas of South and Southeast Asia produces widespread arsenic-contaminated groundwater. Organic carbon is abundant both at the surface and within aquifers, but the source of organic carbon used by microbes in the reduction and release of arsenic has been debated, as has the wetland type and sedimentary depth where release occurs. Here we present data from fresh-sediment incubations, in situ model sediment incubations and a controlled field experiment with manipulated wetland hydrology and organic carbon inputs. We find that in the minimally disturbed Mekong Delta, arsenic release is limited to near-surface sediments of permanently saturated wetlands where both organic carbon and arsenic-bearing solids are sufficiently reactive for microbial oxidation of organic carbon and reduction of arsenic-bearing iron oxides. In contrast, within the deeper aquifer or seasonally saturated sediments, reductive dissolution of iron oxides is observed only when either more reactive exogenous forms of iron oxides or organic carbon are added, revealing a potential thermodynamic restriction to microbial metabolism. We conclude that microbial arsenic release is limited by the reactivity of arsenic-bearing iron oxides with respect to native organic carbon, but equally limited by organic carbon reactivity with respect to the native arsenic-bearing iron oxides.

  14. Iron deprivation results in a rapid but not sustained increase of the expression of genes involved in iron metabolism and sulfate uptake in tomato (Solanum lycopersicum L.) seedlings.

    PubMed

    Paolacci, Anna Rita; Celletti, Silvia; Catarcione, Giulio; Hawkesford, Malcolm J; Astolfi, Stefania; Ciaffi, Mario

    2014-01-01

    Characterization of the relationship between sulfur and iron in both Strategy I and Strategy II plants, has proven that low sulfur availability often limits plant capability to cope with iron shortage. Here it was investigated whether the adaptation to iron deficiency in tomato (Solanum lycopersicum L.) plants was associated with an increased root sulfate uptake and translocation capacity, and modified dynamics of total sulfur and thiols accumulation between roots and shoots. Most of the tomato sulfate transporter genes belonging to Groups 1, 2, and 4 were significantly upregulated in iron-deficient roots, as it commonly occurs under S-deficient conditions. The upregulation of the two high affinity sulfate transporter genes, SlST1.1 and SlST1.2, by iron deprivation clearly suggests an increased root capability to take up sulfate. Furthermore, the upregulation of the two low affinity sulfate transporter genes SlST2.1 and SlST4.1 in iron-deficient roots, accompanied by a substantial accumulation of total sulfur and thiols in shoots of iron-starved plants, likely supports an increased root-to-shoot translocation of sulfate. Results suggest that tomato plants exposed to iron-deficiency are able to change sulfur metabolic balance mimicking sulfur starvation responses to meet the increased demand for methionine and its derivatives, allowing them to cope with this stress.

  15. Superparamagnetic iron oxide nanoparticle uptake alters M2 macrophage phenotype, iron metabolism, migration and invasion.

    PubMed

    Rojas, José M; Sanz-Ortega, Laura; Mulens-Arias, Vladimir; Gutiérrez, Lucía; Pérez-Yagüe, Sonia; Barber, Domingo F

    2016-05-01

    Superparamagnetic iron oxide nanoparticles (SPIONs) have shown promise as contrast agents and nanocarriers for drug delivery. Their impact on M2-polarised macrophages has nonetheless not been well studied. Here we explored the effects of SPIONs coated with dimercaptosuccinic acid, aminopropyl silane or aminodextran in two M2 macrophage models (murine primary IL-4-activated bone marrow-derived macrophages and human M2-like differentiated THP-1 cells). All SPIONs were internalised and no cell toxicity was observed. SPION treatment produced reactive oxygen species and activated the extracellular signal-regulated kinase and AKT pathways. After 24-h SPION incubation, M2 macrophages switched their iron metabolism towards an iron-replete state. SPION treatment in both M2 macrophage models altered their M2 activation profiles, promoted IL-10 production, and stimulated protease-dependent invasion. These results highlight the need to evaluate the interactions between SPIONs and cells to take full advantage of the intrinsic properties of these nanoparticles in biological systems. Superparamagnetic iron oxide nanoparticles (SPIONs) have been used as an MRI contrast agent in many experimental studies. The authors here investigated the effects of these nanoparticles on M2 macrophages after cellular uptake. The findings of cell activation further enhanced our current knowledge on the interaction of SPIONS with macrophages. Copyright © 2015 Elsevier Inc. All rights reserved.

  16. Hepcidin-(In)dependent Mechanisms of Iron Metabolism Regulation during Infection by Listeria and Salmonella.

    PubMed

    Moreira, Ana C; Neves, João V; Silva, Tânia; Oliveira, Patrícia; Gomes, Maria S; Rodrigues, Pedro N

    2017-09-01

    During bacterial infection, the pathogenic agent and the host battle for iron, due to its importance for fundamental cellular processes. However, iron redistribution and sequestration during infection can culminate in anemia. Although hepcidin has been recognized as the key regulator of iron metabolism, in some infections its levels remain unaffected, suggesting the involvement of other players in iron metabolism deregulation. In this work, we use a mouse model to elucidate the main cellular and molecular mechanisms that lead to iron redistribution during infection with two different pathogens: Listeria monocytogenes and Salmonella enterica serovar Typhimurium. Both infections clearly impacted iron metabolism, causing iron redistribution, decreasing serum iron levels, decreasing the saturation of transferrin, and increasing iron accumulation in the liver. Both infections were accompanied by the release of proinflammatory cytokines. However, when analyzing iron-related gene expression in the liver, we observed that hepcidin was induced by S Typhimurium but not by L. monocytogenes In the latter model, the downregulation of hepatic ferroportin mRNA and protein levels suggested that ferroportin plays a major role in iron redistribution. On the other hand, S Typhimurium infection induced the expression of hepcidin mRNA, and we show here, for the first time in vivo, that this induction is Toll-like receptor 4 (TLR4) dependent. In this work, we compare several aspects of iron metabolism alterations induced by two different pathogens and suggest that hepcidin-(in)dependent mechanisms contribute to iron redistribution upon infection. Copyright © 2017 American Society for Microbiology.

  17. Catecholamines promote Actinobacillus pleuropneumoniae growth by regulating iron metabolism.

    PubMed

    Li, Lu; Chen, Zhaohui; Bei, Weicheng; Su, Zhipeng; Huang, Qi; Zhang, Liang; Chen, Huanchun; Zhou, Rui

    2015-01-01

    Catecholamines are host stress hormones that can induce the growth of many bacteria by facilitating iron utilization and/or regulate the expression of virulence genes through specific hormone receptors. Whether these two responsive pathways are interconnected is unknown. In our previous study, it was found that catecholamines can regulate the expression of a great number of genes of Actinobacillus pleuropneumoniae, an important swine respiratory pathogen. However, bacterial growth was not affected by catecholamines in rich medium. In this study, it was discovered that catecholamines affected A. pleuropneumoniae growth in chemically defined medium (CDM). We found that serum inhibited A. pleuropneumoniae growth in CDM, while epinephrine, norepinephrine and dopamine promoted A. pleuropneumoniae growth in the CDM containing serum. The known bacterial hormone receptor QseC didn't play roles in this process. Ion-supplementation and transcriptome analysis indicated that serum addition resulted in iron-restricted conditions which were alleviated by the addition of catecholamines. Transferrin, one of the components in serum, inhibited the growth of A. pleuropneumoniae in CDM, an effect reversed by addition of catecholamines in a TonB2-dependent manner. Our data demonstrate that catecholamines promote A. pleuropneumoniae growth by regulating iron-acquisition and metabolism, which is independent of the adrenergic receptor QseC.

  18. Catecholamines Promote Actinobacillus pleuropneumoniae Growth by Regulating Iron Metabolism

    PubMed Central

    Li, Lu; Chen, Zhaohui; Bei, Weicheng; Su, Zhipeng; Huang, Qi; Zhang, Liang; Chen, Huanchun; Zhou, Rui

    2015-01-01

    Catecholamines are host stress hormones that can induce the growth of many bacteria by facilitating iron utilization and/or regulate the expression of virulence genes through specific hormone receptors. Whether these two responsive pathways are interconnected is unknown. In our previous study, it was found that catecholamines can regulate the expression of a great number of genes of Actinobacillus pleuropneumoniae, an important swine respiratory pathogen. However, bacterial growth was not affected by catecholamines in rich medium. In this study, it was discovered that catecholamines affected A. pleuropneumoniae growth in chemically defined medium (CDM). We found that serum inhibited A. pleuropneumoniae growth in CDM, while epinephrine, norepinephrine and dopamine promoted A. pleuropneumoniae growth in the CDM containing serum. The known bacterial hormone receptor QseC didn’t play roles in this process. Ion-supplementation and transcriptome analysis indicated that serum addition resulted in iron-restricted conditions which were alleviated by the addition of catecholamines. Transferrin, one of the components in serum, inhibited the growth of A. pleuropneumoniae in CDM, an effect reversed by addition of catecholamines in a TonB2-dependent manner. Our data demonstrate that catecholamines promote A. pleuropneumoniae growth by regulating iron-acquisition and metabolism, which is independent of the adrenergic receptor QseC. PMID:25849041

  19. A synergistic role of IRP1 and FBXL5 proteins in coordinating iron metabolism during cell proliferation

    PubMed Central

    Johnson, Nathan B.; Deck, Kathryn M.; Nizzi, Christopher P.; Eisenstein, Richard S.

    2017-01-01

    Iron-regulatory protein 1 (IRP1) belongs to a family of RNA-binding proteins that modulate metazoan iron metabolism. Multiple mechanisms are employed to control the action of IRP1 in dictating changes in the uptake and metabolic fate of iron. Inactivation of IRP1 RNA binding by iron primarily involves insertion of a [4Fe-4S] cluster by the cytosolic iron–sulfur cluster assembly (CIA) system, converting it into cytosolic aconitase (c-acon), but can also involve iron-mediated degradation of IRP1 by the E3 ligase FBXL5 that also targets IRP2. How CIA and FBXL5 collaborate to maintain cellular iron homeostasis through IRP1 and other pathways is poorly understood. Because impaired Fe-S cluster biogenesis associates with human disease, we determined the importance of FBXL5 for regulating IRP1 when CIA is impaired. Suppression of FBXL5 expression coupled with induction of an IRP1 mutant (IRP13C>3S) that cannot insert the Fe-S cluster, or along with knockdown of the CIA factors NUBP2 or FAM96A, reduced cell viability. Iron supplementation reversed this growth defect and was associated with FBXL5-dependent polyubiquitination of IRP1. Phosphorylation of IRP1 at Ser-138 increased when CIA was inhibited and was required for iron rescue. Impaired CIA activity, as noted by reduced c-acon activity, was associated with enhanced FBXL5 expression and a concomitant reduction in IRP1 and IRP2 protein level and RNA-binding activity. Conversely, expression of either IRP induced FBXL5 protein level, demonstrating a negative feedback loop limiting excessive accumulation of iron-response element RNA-binding activity, whose disruption reduces cell growth. We conclude that a regulatory circuit involving FBXL5 and CIA acts through both IRPs to control iron metabolism and promote optimal cell growth. PMID:28768766

  20. Effect of iron limitation and fur gene inactivation on the transcriptional profile of the strict anaerobe Clostridium acetobutylicum.

    PubMed

    Vasileva, Delyana; Janssen, Holger; Hönicke, Daniel; Ehrenreich, Armin; Bahl, Hubert

    2012-07-01

    Iron is a nutrient of critical importance for the strict anaerobe Clostridium acetobutylicum, as it is involved in numerous basic cellular functions and metabolic pathways. A gene encoding a putative ferric uptake regulator (Fur) has been identified in the genome of C. acetobutylicum. In this work, we inactivated the fur gene by using insertional mutagenesis. The resultant mutant showed a slow-growing phenotype and enhanced sensitivity to oxidative stress, but essentially no dramatic change in its fermentation pattern. A unique feature of its physiology was the overflowing production of riboflavin. To gain further insights into the role of the Fur protein and the mechanisms for establishment of iron balance in C. acetobutylicum, we characterized and compared the gene-expression profile of the fur mutant and the iron-limitation stimulon of the parental strain. Not surprisingly, a repertoire of iron-transport systems was upregulated in both microarray datasets, suggesting that they are regulated by Fur according to the availability of iron. In addition, iron limitation and inactivation of fur affected the expression of several genes involved in energy metabolism. Among them, two genes, encoding a lactate dehydrogenase and a flavodoxin, were highly induced. In order to support the function of the latter, the ribDBAH operon responsible for riboflavin biosynthesis was also upregulated significantly. Furthermore, the iron-starvation response of C. acetobutylicum involved transcriptional modifications that were not detected in the fur mutant, suggesting that there exist additional mechanisms for adaptation to low-iron environments. Collectively, these results demonstrate that the strict anaerobe C. acetobutylicum senses and responds to availability of iron on multiple levels using a sophisticated system, and that Fur plays an important role in this process.

  1. Iron Speciation in the Trondheim Fjord from the Perspective of Iron Limitation for Phytoplankton

    NASA Astrophysics Data System (ADS)

    Öztürk, M.; Steinnes, E.; Sakshaug, E.

    2002-08-01

    Concentrations of different Fe species in the Trondheim fjord waters were determined in different seasons by serial columns. Colloidal Fe (ColFe), Anionic organic-Fe complexes (AnOFe), Hydrophobix-lyphophlic organic-Fe complexes (HphOFe) and Chelex labile iron (ClxLFe) were determined before, during and after large river discharges and phytoplankton blooms. Time series of Fe species were obtained at a single location accompanied by data for humic substances, major nutrients, and phytoplankton biomass. Marked seasonal changes in the concentration of iron in various species were evident, and were directly associated with river discharge, especially in the surface waters, but also due to phytoplankton blooms. ColFe dominated in surface waters when the river discharge was high, but decreased with increasing depth. ClxLFe concentrations were lower than that of ColFe formed during the blooms and high river discharge periods. A clear association between the concentration of ClxLFe and phytoplankton blooms implies that ClxLFe may constitute most of the easily available Fe forms. AnOFe was high only during periods of high river discharge. HphOFe increased with phytoplankton bloom. The close correspondence between the distribution of colloidal Fe and dissolved humic substances with fluorophores (fHS), and between Fe (II), particulate Fe (PFe), and fHS in surface waters, made apparent the role of HS on iron speciation, the formation of colloidal Fe and Fe removal. Iron removal seems to be more effective than the riverine inputs and replenishment of Fe to control the dissolved Fe distribution in the fjord. Therefore, phytoplankton growth rate can be sporadically limited by iron in the Trondheim fjord and adjacent coastal waters especially if there will be enhancement of major nutrients.

  2. Limits to Success. The Iron Law of Verhulst

    NASA Astrophysics Data System (ADS)

    Kunsch, P. L.

    In this chapter we develop the point of view that Verhulst is a major initiator of systems thinking. His logistic equation is a system archetype, i.e. a simple system built with few feedback loops. In the Fifth Discipline [19] Peter Senge calls this particular archetype "Limits to Success". It can also be called the "Iron law of Verhulst", expressing that trees can never grow to heaven. In a deeper analysis this equation illustrates the shifting loop dominance, one of the basic principles of system dynamics. The basic message is that the combination of some few archetypes, like the logistic growth, can afford valuable insight into many complex systems such as the economy, environment, organisations, etc. This fruitful concept is illustrated by a simple model in behavioural finance describing the equity price evolution, and based on the interplay of three main growth archetypes: "Limits to Success", "Tragedy of the Commons", and "Balancing Loop with Delay".

  3. The influence of iron limitation on the growth and activity of Crocosphaera watsonii, an unicellular diazotrophic cyanobacterium

    NASA Astrophysics Data System (ADS)

    Jacq, V.; Ridame, C.

    2012-04-01

    Diazotrophic cyanobacteria are able to use atmospheric dinitrogen (N2) dissolved in seawater as source of nitrogen for primary production. This metabolic function confers an ecological advantage for such organisms in N-limited environments, such as tropical oligotrophic regions. There, N2 fixation represents a significant source of new nitrogen in the euphotic zone which is available for the non diazotrophic phytoplankton community. Thus, diazotrophic cyanobacteria contribute significantly to new production and play a key role in the global cycling of carbon and nitrogen. The filamentous diazotrophic cyanobacterium Trichodesmium is the best known and most studied marine diazotroph. However, recent research has highlighted the biogeochemical importance of unicellular diazotrophic cyanobacteria (UCYN), such as Crocosphaera watsonii. The factors that control N2 fixation have been intensively studied. Due to the high iron content of the nitrogenase enzyme complex, N2 fixation and growth of diazotrophic cyanobacteria can be controlled by iron bioavailability. Many studies have been conducted on the impact of iron limitation on Trichodesmium, but less is known for UCYN. Here, for the first time, we address the issue of iron limitation on the N2 fixation and growth of UCYN, namely Crocosphaera watsonii. We have designed a study on cultures of Crocosphaera watsonii strain WH8501 grown under a range of dissolved iron, from 2 nM to 400 nM, with a constant EDTA concentration of 2 µM. Our experiment encompasses low iron concentrations (2 nM), representative of those measured in the field. Preliminary findings demonstrate a major control of iron availability on the biomass and growth of Crocosphaera watsonii. These results, complemented with data on photosynthetic and diazotrophic activities, significantly contribute to our understanding of the dynamics of N2 fixation by unicellular diazotrophic cyanobacteria and of the role of iron in controlling this process. Keywords: N2

  4. Mitochondrial mayhem: the mitochondrion as a modulator of iron metabolism and its role in disease.

    PubMed

    Huang, Michael Li-Hsuan; Lane, Darius J R; Richardson, Des R

    2011-12-15

    The mitochondrion plays vital roles in various aspects of cellular metabolism, ranging from energy transduction and apoptosis to the synthesis of important molecules such as heme. Mitochondria are also centrally involved in iron metabolism, as exemplified by disruptions in mitochondrial proteins that lead to perturbations in whole-cell iron processing. Recent investigations have identified a host of mitochondrial proteins (e.g., mitochondrial ferritin; mitoferrins 1 and 2; ABCBs 6, 7, and 10; and frataxin) that may play roles in the homeostasis of mitochondrial iron. These mitochondrial proteins appear to participate in one or more processes of iron storage, iron uptake, and heme and iron-sulfur cluster synthesis. In this review, we present and critically discuss the evidence suggesting that the mitochondrion may contribute to the regulation of whole-cell iron metabolism. Further, human diseases that arise from a dysregulation of these mitochondrial molecules reveal the ability of the mitochondrion to communicate with cytosolic iron metabolism to coordinate whole-cell iron processing and to fulfill the high demands of this organelle for iron. This review highlights new advances in understanding iron metabolism in terms of novel molecular players and diseases associated with its dysregulation.

  5. Insights into the structure and metabolic function of microbes that shape pelagic iron-rich aggregates ("iron snow").

    PubMed

    Lu, Shipeng; Chourey, Karuna; Reiche, Marco; Nietzsche, Sandor; Shah, Manesh B; Neu, Thomas R; Hettich, Robert L; Küsel, Kirsten

    2013-07-01

    Microbial ferrous iron [Fe(II)] oxidation leads to the formation of iron-rich macroscopic aggregates ("iron snow") at the redoxcline in a stratified lignite mine lake in east-central Germany. We aimed to identify the abundant Fe-oxidizing and Fe-reducing microorganisms likely to be involved in the formation and transformation of iron snow present in the redoxcline in two basins of the lake that differ in their pH values. Nucleic acid- and lipid-stained microbial cells of various morphologies detected by confocal laser scanning microscopy were homogeneously distributed in all iron snow samples. The dominant iron mineral appeared to be schwertmannite, with shorter needles in the northern than in the central basin samples. Total bacterial 16S rRNA gene copies ranged from 5.0 × 10(8) copies g (dry weight)(-1) in the acidic central lake basin (pH 3.3) to 4.0 × 10(10) copies g (dry weight)(-1) in the less acidic (pH 5.9) northern basin. Total RNA-based quantitative PCR assigned up to 61% of metabolically active microbial communities to Fe-oxidizing- and Fe-reducing-related bacteria, indicating that iron metabolism was an important metabolic strategy. Molecular identification of abundant groups suggested that iron snow surfaces were formed by chemoautotrophic iron oxidizers, such as Acidimicrobium, Ferrovum, Acidithiobacillus, Thiobacillus, and Chlorobium, in the redoxcline and were rapidly colonized by heterotrophic iron reducers, such as Acidiphilium, Albidiferax-like, and Geobacter-like groups. Metaproteomics yielded 283 different proteins from northern basin iron snow samples, and protein identification provided a glimpse into some of their in situ metabolic processes, such as primary production (CO2 fixation), respiration, motility, and survival strategies.

  6. Insights into the Structure and Metabolic Function of Microbes That Shape Pelagic Iron-Rich Aggregates (“Iron Snow”)

    PubMed Central

    Lu, Shipeng; Chourey, Karuna; Reiche, Marco; Nietzsche, Sandor; Shah, Manesh B.; Neu, Thomas R.; Hettich, Robert L.

    2013-01-01

    Microbial ferrous iron [Fe(II)] oxidation leads to the formation of iron-rich macroscopic aggregates (“iron snow”) at the redoxcline in a stratified lignite mine lake in east-central Germany. We aimed to identify the abundant Fe-oxidizing and Fe-reducing microorganisms likely to be involved in the formation and transformation of iron snow present in the redoxcline in two basins of the lake that differ in their pH values. Nucleic acid- and lipid-stained microbial cells of various morphologies detected by confocal laser scanning microscopy were homogeneously distributed in all iron snow samples. The dominant iron mineral appeared to be schwertmannite, with shorter needles in the northern than in the central basin samples. Total bacterial 16S rRNA gene copies ranged from 5.0 × 108 copies g (dry weight)−1 in the acidic central lake basin (pH 3.3) to 4.0 × 1010 copies g (dry weight)−1 in the less acidic (pH 5.9) northern basin. Total RNA-based quantitative PCR assigned up to 61% of metabolically active microbial communities to Fe-oxidizing- and Fe-reducing-related bacteria, indicating that iron metabolism was an important metabolic strategy. Molecular identification of abundant groups suggested that iron snow surfaces were formed by chemoautotrophic iron oxidizers, such as Acidimicrobium, Ferrovum, Acidithiobacillus, Thiobacillus, and Chlorobium, in the redoxcline and were rapidly colonized by heterotrophic iron reducers, such as Acidiphilium, Albidiferax-like, and Geobacter-like groups. Metaproteomics yielded 283 different proteins from northern basin iron snow samples, and protein identification provided a glimpse into some of their in situ metabolic processes, such as primary production (CO2 fixation), respiration, motility, and survival strategies. PMID:23645202

  7. Iron homeostasis: An anthropocentric perspective.

    PubMed

    Coffey, Richard; Ganz, Tomas

    2017-08-04

    The regulation of iron metabolism in biological systems centers on providing adequate iron for cellular function while limiting iron toxicity. Because mammals cannot excrete iron, mechanisms have evolved to control iron acquisition, storage, and distribution at both systemic and cellular levels. Hepcidin, the master regulator of iron homeostasis, controls iron flows into plasma through inhibition of the only known mammalian cellular iron exporter ferroportin. Hepcidin is feedback-regulated by iron status and strongly modulated by inflammation and erythropoietic demand. This review highlights recent advances that have changed our understanding of iron metabolism and its regulation. © 2017 by The American Society for Biochemistry and Molecular Biology, Inc.

  8. Sleep disorders: A review of the interface between restless legs syndrome and iron metabolism

    PubMed Central

    Daubian-Nosé, Paulo; Frank, Miriam K.; Esteves, Andrea Maculano

    2014-01-01

    Restless legs syndrome (RLS) is characterized by unpleasant sensations mainly in the legs. 43% of RLS-associated conditions have also been associated with systemic iron deficiency. The objective of this study was to review in the literature the relationship between iron metabolism and RLS. With an initial search using the keywords combination “Iron Metabolism OR Iron Deficiency AND Restless Legs Syndrome,” 145 articles were screened, and 20 articles were selected. Few studies were found for this review in the period of 2001–2014, however, the correlation between RLS and iron was evident. PMID:26483934

  9. Gallium Disrupts Iron Metabolism of Mycobacteria Residing within Human Macrophages

    PubMed Central

    Olakanmi, Oyebode; Britigan, Bradley E.; Schlesinger, Larry S.

    2000-01-01

    Mycobacterium tuberculosis and M. avium complex (MAC) enter and multiply within monocytes and macrophages in phagosomes. In vitro growth studies using standard culture media indicate that siderophore-mediated iron (Fe) acquisition plays a critical role in the growth and metabolism of both M. tuberculosis and MAC. However, the applicability of such studies to conditions within the macrophage phagosome is unclear, due in part to the absence of experimental means to inhibit such a process. Based on the ability of gallium (Ga3+) to concentrate within mononuclear phagocytes and on evidence that Ga disrupts cellular Fe-dependent metabolic pathways by substituting for Fe3+ and failing to undergo redox cycling, we hypothesized that Ga could disrupt Fe acquisition and Fe-dependent metabolic pathways of mycobacteria. We find that Ga(NO3)3 and Ga-transferrin produce an Fe-reversible concentration-dependent growth inhibition of M. tuberculosis strains and MAC grown extracellularly and within human macrophages. Ga is bactericidal for M. tuberculosis growing extracellularly and within macrophages. Finally, we provide evidence that exogenously added Fe is acquired by intraphagosomal M. tuberculosis and that Ga inhibits this Fe acquisition. Thus, Ga(NO3)3 disruption of mycobacterial Fe metabolism may serve as an experimental means to study the mechanism of Fe acquisition by intracellular mycobacteria and the role of Fe in intracellular survival. Furthermore, given the inability of biological systems to discriminate between Ga and Fe, this approach could have broad applicability to the study of Fe metabolism of other intracellular pathogens. PMID:10992462

  10. Recent advances in disorders of iron metabolism: mutations, mechanisms and modifiers.

    PubMed

    Roy, C N; Andrews, N C

    2001-10-01

    The spectrum of known disorders of iron metabolism has expanded dramatically over the past few years. Identification of HFE, the gene most commonly mutated in patients with hereditary hemochromatosis, has allowed molecular diagnosis and paved the way for identification of other genes, such as TFR2, that are important in non-HFE-associated iron overload. There are clearly several other, unidentified, iron overload disease genes yet to be found. In parallel, our understanding of iron transport has expanded through identification of Fpn1/Ireg1/MTP1, Sfxn1 and DCYTB: Ongoing studies of Friedreich's ataxia, sideroblastic anemia, aceruloplasminemia and neurodegeneration with brain-iron accumulation are clarifying the role for iron in the nervous system. Finally, as the number of known iron metabolic genes increases and their respective functions are ascertained, new opportunities have arisen to identify genetic modifiers of iron homeostasis.

  11. Like iron in the blood of the people: the requirement for heme trafficking in iron metabolism

    PubMed Central

    Korolnek, Tamara; Hamza, Iqbal

    2014-01-01

    Heme is an iron-containing porphyrin ring that serves as a prosthetic group in proteins that function in diverse metabolic pathways. Heme is also a major source of bioavailable iron in the human diet. While the synthesis of heme has been well-characterized, the pathways for heme trafficking remain poorly understood. It is likely that heme transport across membranes is highly regulated, as free heme is toxic to cells. This review outlines the requirement for heme delivery to various subcellular compartments as well as possible mechanisms for the mobilization of heme to these compartments. We also discuss how these trafficking pathways might function during physiological events involving inter- and intra-cellular mobilization of heme, including erythropoiesis, erythrophagocytosis, heme absorption in the gut, as well as heme transport pathways supporting embryonic development. Lastly, we aim to question the current dogma that heme, in toto, is not mobilized from one cell or tissue to another, outlining the evidence for these pathways and drawing parallels to other well-accepted paradigms for copper, iron, and cholesterol homeostasis. PMID:24926267

  12. Update on iron metabolism and molecular perspective of common genetic and acquired disorder, hemochromatosis.

    PubMed

    Yun, Seongseok; Vincelette, Nicole D

    2015-07-01

    Iron is an essential component of erythropoiesis and its metabolism is tightly regulated by a variety of internal and external cues including iron storage, tissue hypoxia, inflammation and degree of erythropoiesis. There has been remarkable improvement in our understanding of the molecular mechanisms of iron metabolism past decades. The classical model of iron metabolism with iron response element/iron response protein (IRE/IRP) is now extended to include hepcidin model. Endogenous and exogenous signals funnel down to hepcidin via wide range of signaling pathways including Janus Kinase/Signal Transducer and Activator of Transcription 3 (JAK/STAT3), Bone Morphogenetic Protein/Hemojuvelin/Mothers Against Decapentaplegic Homolog (BMP/HJV/SMAD), and Von Hippel Lindau/Hypoxia-inducible factor/Erythropoietin (VHL/HIF/EPO), then relay to ferroportin, which directly regulates intra- and extracellular iron levels. The successful molecular delineation of iron metabolism further enhanced our understanding of common genetic and acquired disorder, hemochromatosis. The majority of the hereditary hemochromatosis (HH) patients are now shown to have mutations in the genes coding either upstream or downstream proteins of hepcidin, resulting in iron overload. The update on hepcidin centered mechanisms of iron metabolism and their clinical perspective in hemochromatosis will be discussed in this review.

  13. EXPLORING THE LIMITS TO LIGNINS' METABOLIC PLASTICITY

    USDA-ARS?s Scientific Manuscript database

    Just how far can lignification be pushed with the aim of improving wood processing (and possibly solid wood properties)? We will explore the limits to which the 3 traditional monolignols can be manipulated, but also broaden our scope to begin thinking about how the entire monomer pool for lignificat...

  14. Duodenal Cytochrome b (DCYTB) in Iron Metabolism: An Update on Function and Regulation

    PubMed Central

    Lane, Darius J. R.; Bae, Dong-Hun; Merlot, Angelica M.; Sahni, Sumit; Richardson, Des R.

    2015-01-01

    Iron and ascorbate are vital cellular constituents in mammalian systems. The bulk-requirement for iron is during erythropoiesis leading to the generation of hemoglobin-containing erythrocytes. Additionally, both iron and ascorbate are required as co-factors in numerous metabolic reactions. Iron homeostasis is controlled at the level of uptake, rather than excretion. Accumulating evidence strongly suggests that in addition to the known ability of dietary ascorbate to enhance non-heme iron absorption in the gut, ascorbate regulates iron homeostasis. The involvement of ascorbate in dietary iron absorption extends beyond the direct chemical reduction of non-heme iron by dietary ascorbate. Among other activities, intra-enterocyte ascorbate appears to be involved in the provision of electrons to a family of trans-membrane redox enzymes, namely those of the cytochrome b561 class. These hemoproteins oxidize a pool of ascorbate on one side of the membrane in order to reduce an electron acceptor (e.g., non-heme iron) on the opposite side of the membrane. One member of this family, duodenal cytochrome b (DCYTB), may play an important role in ascorbate-dependent reduction of non-heme iron in the gut prior to uptake by ferrous-iron transporters. This review discusses the emerging relationship between cellular iron homeostasis, the emergent “IRP1-HIF2α axis”, DCYTB and ascorbate in relation to iron metabolism. PMID:25835049

  15. Deciphering Fur transcriptional regulatory network highlights its complex role beyond iron metabolism in Escherichia coli.

    PubMed

    Seo, Sang Woo; Kim, Donghyuk; Latif, Haythem; O'Brien, Edward J; Szubin, Richard; Palsson, Bernhard O

    2014-09-15

    The ferric uptake regulator (Fur) plays a critical role in the transcriptional regulation of iron metabolism. However, the full regulatory potential of Fur remains undefined. Here we comprehensively reconstruct the Fur transcriptional regulatory network in Escherichia coli K-12 MG1655 in response to iron availability using genome-wide measurements. Integrative data analysis reveals that a total of 81 genes in 42 transcription units are directly regulated by three different modes of Fur regulation, including apo- and holo-Fur activation and holo-Fur repression. We show that Fur connects iron transport and utilization enzymes with negative-feedback loop pairs for iron homeostasis. In addition, direct involvement of Fur in the regulation of DNA synthesis, energy metabolism and biofilm development is found. These results show how Fur exhibits a comprehensive regulatory role affecting many fundamental cellular processes linked to iron metabolism in order to coordinate the overall response of E. coli to iron availability.

  16. Discrete Responses to Limitation for Iron and Manganese in Agrobacterium tumefaciens: Influence on Attachment and Biofilm Formation

    PubMed Central

    Hibbing, Michael E.; Xu, Jing; Natarajan, Ramya; Buechlein, Aaron M.

    2015-01-01

    ABSTRACT Transition metals such as iron and manganese are crucial trace nutrients for the growth of most bacteria, functioning as catalytic cofactors for many essential enzymes. Dedicated uptake and regulatory systems have evolved to ensure their acquisition for growth, while preventing toxicity. Transcriptomic analysis of the iron- and manganese-responsive regulons of Agrobacterium tumefaciens revealed that there are discrete regulatory networks that respond to changes in iron and manganese levels. Complementing earlier studies, the iron-responsive gene network is quite large and includes many aspects of iron-dependent metabolism and the iron-sparing response. In contrast, the manganese-responsive network is restricted to a limited number of genes, many of which can be linked to transport and utilization of the transition metal. Several of the target genes predicted to drive manganese uptake are required for growth under manganese-limited conditions, and an A. tumefaciens mutant with a manganese transport deficiency is attenuated for plant virulence. Iron and manganese limitation independently inhibit biofilm formation by A. tumefaciens, and several candidate genes that could impact biofilm formation were identified in each regulon. The biofilm-inhibitory effects of iron and manganese do not rely on recognized metal-responsive transcriptional regulators, suggesting alternate mechanisms influencing biofilm formation. However, under low-manganese conditions the dcpA operon is upregulated, encoding a system that controls levels of the cyclic di-GMP second messenger. Mutation of this regulatory pathway dampens the effect of manganese limitation. IMPORTANCE Responses to changes in transition metal levels, such as those of manganese and iron, are important for normal metabolism and growth in bacteria. Our study used global gene expression profiling to understand the response of the plant pathogen Agrobacterium tumefaciens to changes of transition metal availability

  17. Discrete Responses to Limitation for Iron and Manganese in Agrobacterium tumefaciens: Influence on Attachment and Biofilm Formation.

    PubMed

    Heindl, Jason E; Hibbing, Michael E; Xu, Jing; Natarajan, Ramya; Buechlein, Aaron M; Fuqua, Clay

    2015-12-28

    Transition metals such as iron and manganese are crucial trace nutrients for the growth of most bacteria, functioning as catalytic cofactors for many essential enzymes. Dedicated uptake and regulatory systems have evolved to ensure their acquisition for growth, while preventing toxicity. Transcriptomic analysis of the iron- and manganese-responsive regulons of Agrobacterium tumefaciens revealed that there are discrete regulatory networks that respond to changes in iron and manganese levels. Complementing earlier studies, the iron-responsive gene network is quite large and includes many aspects of iron-dependent metabolism and the iron-sparing response. In contrast, the manganese-responsive network is restricted to a limited number of genes, many of which can be linked to transport and utilization of the transition metal. Several of the target genes predicted to drive manganese uptake are required for growth under manganese-limited conditions, and an A. tumefaciens mutant with a manganese transport deficiency is attenuated for plant virulence. Iron and manganese limitation independently inhibit biofilm formation by A. tumefaciens, and several candidate genes that could impact biofilm formation were identified in each regulon. The biofilm-inhibitory effects of iron and manganese do not rely on recognized metal-responsive transcriptional regulators, suggesting alternate mechanisms influencing biofilm formation. However, under low-manganese conditions the dcpA operon is upregulated, encoding a system that controls levels of the cyclic di-GMP second messenger. Mutation of this regulatory pathway dampens the effect of manganese limitation. Responses to changes in transition metal levels, such as those of manganese and iron, are important for normal metabolism and growth in bacteria. Our study used global gene expression profiling to understand the response of the plant pathogen Agrobacterium tumefaciens to changes of transition metal availability. Among the properties

  18. Fixing frataxin: ‘ironing out’ the metabolic defect in Friedreich's ataxia

    PubMed Central

    Anzovino, A; Lane, D J R; Huang, M L-H; Richardson, D R

    2014-01-01

    The metabolically active and redox-active mitochondrion appears to play a major role in the cellular metabolism of the transition metal, iron. Frataxin, a mitochondrial matrix protein, has been identified as playing a key role in the iron metabolism of this organelle due to its iron-binding properties and is known to be essential for iron–sulphur cluster formation. However, the precise function of frataxin remains elusive. The decrease in frataxin expression, as seen in the inherited disorder Friedreich's ataxia, markedly alters cellular and mitochondrial iron metabolism in both the mitochondrion and the cell. The resulting dysregulation of iron trafficking damages affects tissues leading to neuro-and cardiodegeneration. This disease underscores the importance of iron homeostasis in the redox-active environment of the mitochondrion and the molecular players involved. Unravelling the mechanisms of altered iron metabolism in Friedreich's ataxia will help elucidate a biochemical function for frataxin. Consequently, this will enable the development of more effective and rationally designed treatments. This review will focus on the emerging function of frataxin in relation to the observed alterations in mitochondrial iron metabolism in Friedreich's ataxia. Tissue-specific alterations due to frataxin loss will also be discussed, as well as current and emerging therapeutic strategies. Linked Articles This article is part of a themed issue on Mitochondrial Pharmacology: Energy, Injury & Beyond. To view the other articles in this issue visit http://dx.doi.org/10.1111/bph.2014.171.issue-8 PMID:24138602

  19. Mechanisms Linking Glucose Homeostasis and Iron Metabolism Toward the Onset and Progression of Type 2 Diabetes.

    PubMed

    Fernández-Real, José Manuel; McClain, Donald; Manco, Melania

    2015-11-01

    The bidirectional relationship between iron metabolism and glucose homeostasis is increasingly recognized. Several pathways of iron metabolism are modified according to systemic glucose levels, whereas insulin action and secretion are influenced by changes in relative iron excess. We aimed to update the possible influence of iron on insulin action and secretion and vice versa. The mechanisms that link iron metabolism and glucose homeostasis in the main insulin-sensitive tissues and insulin-producing β-cells were revised according to their possible influence on the development of type 2 diabetes (T2D). The mechanisms leading to dysmetabolic hyperferritinemia and hepatic overload syndrome were diverse, including diet-induced alterations in iron absorption, modulation of gluconeogenesis, heme-mediated disruption of circadian glucose rhythm, impaired hepcidin secretion and action, and reduced copper availability. Glucose metabolism in adipose tissue seems to be affected by both iron deficiency and excess through interaction with adipocyte differentiation, tissue hyperplasia and hypertrophy, release of adipokines, lipid synthesis, and lipolysis. Reduced heme synthesis and dysregulated iron uptake or export could also be contributing factors affecting glucose metabolism in the senescent muscle, whereas exercise is known to affect iron and glucose status. Finally, iron also seems to modulate β-cells and insulin secretion, although this has been scarcely studied. Iron is increasingly recognized to influence glucose metabolism at multiple levels. Body iron stores should be considered as a potential target for therapy in subjects with T2D or those at risk for developing T2D. Further research is warranted. © 2015 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.

  20. Coordinated remodeling of cellular metabolism during iron deficiency through targeted mRNA degradation.

    PubMed

    Puig, Sergi; Askeland, Eric; Thiele, Dennis J

    2005-01-14

    Iron (Fe) is an essential micronutrient for virtually all organisms and serves as a cofactor for a wide variety of vital cellular processes. Although Fe deficiency is the primary nutritional disorder in the world, cellular responses to Fe deprivation are poorly understood. We have discovered a posttranscriptional regulatory process controlled by Fe deficiency, which coordinately drives widespread metabolic reprogramming. We demonstrate that, in response to Fe deficiency, the Saccharomyces cerevisiae Cth2 protein specifically downregulates mRNAs encoding proteins that participate in many Fe-dependent processes. mRNA turnover requires the binding of Cth2, an RNA binding protein conserved in plants and mammals, to specific AU-rich elements in the 3' untranslated region of mRNAs targeted for degradation. These studies elucidate coordinated global metabolic reprogramming in response to Fe deficiency and identify a mechanism for achieving this by targeting specific mRNA molecules for degradation, thereby facilitating the utilization of limited cellular Fe levels.

  1. Metabolic Factors Limiting Performance in Marathon Runners

    PubMed Central

    Rapoport, Benjamin I.

    2010-01-01

    Each year in the past three decades has seen hundreds of thousands of runners register to run a major marathon. Of those who attempt to race over the marathon distance of 26 miles and 385 yards (42.195 kilometers), more than two-fifths experience severe and performance-limiting depletion of physiologic carbohydrate reserves (a phenomenon known as ‘hitting the wall’), and thousands drop out before reaching the finish lines (approximately 1–2% of those who start). Analyses of endurance physiology have often either used coarse approximations to suggest that human glycogen reserves are insufficient to fuel a marathon (making ‘hitting the wall’ seem inevitable), or implied that maximal glycogen loading is required in order to complete a marathon without ‘hitting the wall.’ The present computational study demonstrates that the energetic constraints on endurance runners are more subtle, and depend on several physiologic variables including the muscle mass distribution, liver and muscle glycogen densities, and running speed (exercise intensity as a fraction of aerobic capacity) of individual runners, in personalized but nevertheless quantifiable and predictable ways. The analytic approach presented here is used to estimate the distance at which runners will exhaust their glycogen stores as a function of running intensity. In so doing it also provides a basis for guidelines ensuring the safety and optimizing the performance of endurance runners, both by setting personally appropriate paces and by prescribing midrace fueling requirements for avoiding ‘the wall.’ The present analysis also sheds physiologically principled light on important standards in marathon running that until now have remained empirically defined: The qualifying times for the Boston Marathon. PMID:20975938

  2. Model of reticuloendothelial iron metabolism in humans: Abnormal behavior in idiopathic hemochromatosis and in inflammation

    SciTech Connect

    Fillet, G.; Beguin, Y.; Baldelli, L. )

    1989-08-01

    Iron transport in the reticuloendothelial (RE) system plays a central role in iron metabolism, but its regulation has not been characterized physiologically in vivo in humans. In particular, why serum iron is elevated and RE cells are much less iron-loaded than parenchymal cells in idiopathic hemochromatosis is not known. The processing of erythrocyte iron by the RE system was studied after intravenous (IV) injection of 59Fe heat-damaged RBCs (HDRBCs) and 55Fe transferrin in normal subjects and in patients with iron deficiency, idiopathic hemochromatosis, inflammation, marrow aplasia, or hyperplastic erythropoiesis. Early release of 59Fe by the RE system was calculated from the plasma iron turnover and the 59Fe plasma reappearance curve. Late release was calculated from the ratio of 59Fe/55Fe RBC utilization in 2 weeks. The partitioning of iron between the early (release from heme catabolism) and late (release from RE stores) phases depended on the size of RE iron stores, as illustrated by the inverse relationship observed between early release and plasma ferritin (P less than .001). There was a strong correlation between early release and the rate of change of serum iron levels during the first three hours in normal subjects (r = .85, P less than .001). Inflammation produced a blockade of the early release phase, whereas in idiopathic hemochromatosis early release was considerably increased as compared with subjects with similar iron stores. Based on these results, we describe a model of RE iron metabolism in humans. We conclude that the RE system appears to determine the diurnal fluctuations in serum iron levels through variations in the immediate output of heme iron. In idiopathic hemochromatosis, a defect of the RE cell in withholding iron freed from hemoglobin could be responsible for the high serum iron levels and low RE iron stores.

  3. The factors influencing urinary arsenic excretion and metabolism of workers in steel and iron smelting foundry.

    PubMed

    Shuhua, Xi; Qingshan, Sun; Fei, Wang; Shengnan, Liu; Ling, Yan; Lin, Zhang; Yingli, Song; Nan, Yan; Guifan, Sun

    2014-01-01

    In order to evaluate the degree of arsenic (As) exposure and the factors influencing urinary As excretion and metabolism, 192 workers from a steel and iron smelting plant, with different type of work in production such as roller, steel smelting, iron smelting and metallic charge preparation, were recruited. Information about characteristics of each subject was obtained by questionnaire and inorganic As (iAs), monomethylarsonic acid (MMA), dimethylarsinic acid (DMA) in urine were determined. The results showed that steel smelters had significantly higher concentrations of DMA and total As (TAs) than rollers and metallic charge preparation workers, and iron and steel smelters had a higher value of primary methylation index and lower proportion of the iAs (iAs%) than rollers and metallic charge preparation workers. In steel smelters, urinary As level exceeded the biological exposure index (BEI) limit for urinary As of 35 μg/l by 65.52%, and higher than metallic charge preparation workers (35.14%). The individuals consumed seafood in recent 3 days had a higher TAs than the individuals without seafood consumption. Multivariate logistic regression analysis showed that different jobs, taken Chinese medicine of bezoar and seafood consumption in recent 3 days were significantly associated with urinary TAs exceeded BEI limit value 35 μg/l. Our results suggest that workers in steel and iron smelting plant had a lower level of As exposure, and seafood consumption and taking Chinese medicine of bezoar also could increase the risk of urinary TAs exceeded BEI limit value.

  4. The Effect of Iron Limitation on the Transcriptome and Proteome of Pseudomonas fluorescens Pf-5

    PubMed Central

    Lim, Chee Kent; Hassan, Karl A.; Tetu, Sasha G.; Loper, Joyce E.; Paulsen, Ian T.

    2012-01-01

    One of the most important micronutrients for bacterial growth is iron, whose bioavailability in soil is limited. Consequently, rhizospheric bacteria such as Pseudomonas fluorescens employ a range of mechanisms to acquire or compete for iron. We investigated the transcriptomic and proteomic effects of iron limitation on P. fluorescens Pf-5 by employing microarray and iTRAQ techniques, respectively. Analysis of this data revealed that genes encoding functions related to iron homeostasis, including pyoverdine and enantio-pyochelin biosynthesis, a number of TonB-dependent receptor systems, as well as some inner-membrane transporters, were significantly up-regulated in response to iron limitation. Transcription of a ribosomal protein L36-encoding gene was also highly up-regulated during iron limitation. Certain genes or proteins involved in biosynthesis of secondary metabolites such as 2,4-diacetylphloroglucinol (DAPG), orfamide A and pyrrolnitrin, as well as a chitinase, were over-expressed under iron-limited conditions. In contrast, we observed that expression of genes involved in hydrogen cyanide production and flagellar biosynthesis were down-regulated in an iron-depleted culture medium. Phenotypic tests revealed that Pf-5 had reduced swarming motility on semi-solid agar in response to iron limitation. Comparison of the transcriptomic data with the proteomic data suggested that iron acquisition is regulated at both the transcriptional and post-transcriptional levels. PMID:22723948

  5. A General Map of Iron Metabolism and Tissue-specific Subnetworks

    PubMed Central

    Hower, Valerie; Mendes, Pedro; Torti, Frank M.; Laubenbacher, Reinhard; Akman, Steven; Shulaev, Vladmir; Torti, Suzy V.

    2009-01-01

    Iron is required for survival of mammalian cells. Recently, understanding of iron metabolism and trafficking has increased dramatically, revealing a complex, interacting network largely unknown just a few years ago. This provides an excellent model for systems biology development and analysis. The first step in such an analysis is the construction of a structural network of iron metabolism, which we present here. This network was created using CellDesigner version 3.5.2 and includes reactions occurring in mammalian cells of numerous tissue types. The iron metabolic network contains 151 chemical species and 107 reactions and transport steps. Starting from this general model, we construct iron networks for specific tissues and cells that are fundamental to maintaining body iron homeostasis. We include subnetworks for cells of the intestine and liver, tissues important in iron uptake and storage, respectively; as well as the reticulocyte and macrophage, key cells in iron utilization and recycling. The addition of kinetic information to our structural network will permit the simulation of iron metabolism in different tissues as well as in health and disease. PMID:19381358

  6. Divergent Responses of Coastal and Oceanic Synechococcus to Iron Limitation

    NASA Astrophysics Data System (ADS)

    Mackey, K. R.; McIlvin, M.; Post, A.; Saito, M. A.

    2014-12-01

    Marine Synechococcus are some of the most diverse and ubiquitous phytoplankton in the ocean, and are major contributors to global primary productivity. Iron (Fe) is a micronutrient required for maintenance of the photosynthetic apparatus that limits productivity in many parts of the ocean. To investigate how marine Synechococcus strains adapt and acclimate to Fe availability, we compared the growth, photophysiology, and protein abundance in two Synechococcus strains over a range of Fe concentrations. Synechococcus strain WH8102, from the permanently stratified southern Sargasso Sea in a region that receives significant dust deposition, had few acclimation strategies under low Fe and showed impaired growth rates and photophysiology as Fe declined. Coastal isolate WH8020, from the dynamic, seasonally variable North Atlantic Ocean, displayed a range of acclimation responses, including changes in Fe acquisition, storage, and photosynthetic electron transport proteins, substitution of flavodoxin for ferredoxin, and modified photophysiology. Each of these acclimation responses occurred at different Fe threshold concentrations over which growth rate remained remarkably stable. This study demonstrates that genomic streamlining in waters with low nitrogen and phosphorus may favor the loss of Fe acclimation genes when the Fe supply is consistent over time, and expands the regions where Fe stress is thought to occur to most coastal environments.

  7. β-thalassemia: a model for elucidating the dynamic regulation of ineffective erythropoiesis and iron metabolism

    PubMed Central

    Rivella, Stefano

    2011-01-01

    β-thalassemia is a disease characterized by anemia and is associated with ineffective erythropoiesis and iron dysregulation resulting in iron overload. The peptide hormone hepcidin regulates iron metabolism, and insufficient hepcidin synthesis is responsible for iron overload in minimally transfused patients with this disease. Understanding the crosstalk between erythropoiesis and iron metabolism is an area of active investigation in which patients with and models of β-thalassemia have provided significant insight. The dependence of erythropoiesis on iron presupposes that iron demand for hemoglobin synthesis is involved in the regulation of iron metabolism. Major advances have been made in understanding iron availability for erythropoiesis and its dysregulation in β-thalassemia. In this review, we describe the clinical characteristics and current therapeutic standard in β-thalassemia, explore the definition of ineffective erythropoiesis, and discuss its role in hepcidin regulation. In preclinical experiments using interventions such as transferrin, hepcidin agonists, and JAK2 inhibitors, we provide evidence of potential new treatment alternatives that elucidate mechanisms by which expanded or ineffective erythropoiesis may regulate iron supply, distribution, and utilization in diseases such as β-thalassemia. PMID:21768301

  8. Iron limitation of microbial phosphorus acquisition in the tropical North Atlantic

    PubMed Central

    Browning, T. J.; Achterberg, E. P.; Yong, J. C.; Rapp, I.; Utermann, C.; Engel, A.; Moore, C. M.

    2017-01-01

    In certain regions of the predominantly nitrogen limited ocean, microbes can become co-limited by phosphorus. Within such regions, a proportion of the dissolved organic phosphorus pool can be accessed by microbes employing a variety of alkaline phosphatase (APase) enzymes. In contrast to the PhoA family of APases that utilize zinc as a cofactor, the recent discovery of iron as a cofactor in the more widespread PhoX and PhoD implies the potential for a biochemically dependant interplay between oceanic zinc, iron and phosphorus cycles. Here we demonstrate enhanced natural community APase activity following iron amendment within the low zinc and moderately low iron Western North Atlantic. In contrast we find no evidence for trace metal limitation of APase activity beneath the Saharan dust plume in the Eastern Atlantic. Such intermittent iron limitation of microbial phosphorus acquisition provides an additional facet in the argument for iron controlling the coupling between oceanic nitrogen and phosphorus cycles. PMID:28524880

  9. Iron limitation of microbial phosphorus acquisition in the tropical North Atlantic

    NASA Astrophysics Data System (ADS)

    Browning, T. J.; Achterberg, E. P.; Yong, J. C.; Rapp, I.; Utermann, C.; Engel, A.; Moore, C. M.

    2017-05-01

    In certain regions of the predominantly nitrogen limited ocean, microbes can become co-limited by phosphorus. Within such regions, a proportion of the dissolved organic phosphorus pool can be accessed by microbes employing a variety of alkaline phosphatase (APase) enzymes. In contrast to the PhoA family of APases that utilize zinc as a cofactor, the recent discovery of iron as a cofactor in the more widespread PhoX and PhoD implies the potential for a biochemically dependant interplay between oceanic zinc, iron and phosphorus cycles. Here we demonstrate enhanced natural community APase activity following iron amendment within the low zinc and moderately low iron Western North Atlantic. In contrast we find no evidence for trace metal limitation of APase activity beneath the Saharan dust plume in the Eastern Atlantic. Such intermittent iron limitation of microbial phosphorus acquisition provides an additional facet in the argument for iron controlling the coupling between oceanic nitrogen and phosphorus cycles.

  10. Surplus Photosynthetic Antennae Complexes Underlie Diagnostics of Iron Limitation in a Cyanobacterium

    PubMed Central

    Schrader, Paul S.; Milligan, Allen J.; Behrenfeld, Michael J.

    2011-01-01

    Chlorophyll fluorescence from phytoplankton provides a tool to assess iron limitation in the oceans, but the physiological mechanism underlying the fluorescence response is not understood. We examined fluorescence properties of the model cyanobacterium Synechocystis PCC6803 and a ΔisiA knock-out mutant of the same species grown under three culture conditions which simulate nutrient conditions found in the open ocean: (1) nitrate and iron replete, (2) limiting-iron and high-nitrate, representative of natural high-nitrate, low-chlorophyll regions, and (3) iron and nitrogen co-limiting. We show that low variable fluorescence, a key diagnostic of iron limitation, results from synthesis of antennae complexes far in excess of what can be accommodated by the iron-restricted pool of photosynthetic reaction centers. Under iron and nitrogen co-limiting conditions, there are no excess antennae complexes and variable fluorescence is high. These results help to explain the well-established fluorescence characteristics of phytoplankton in high-nutrient, low-chlorophyll ocean regions, while also accounting for the lack of these properties in low-iron, low-nitrogen regions. Importantly, our results complete the link between unique molecular consequences of iron stress in phytoplankton and global detection of iron stress in natural populations from space. PMID:21533084

  11. Cellular hallmarks reveal restricted aerobic metabolism at thermal limits

    PubMed Central

    Neves, Aitana; Busso, Coralie; Gönczy, Pierre

    2015-01-01

    All organisms live within a given thermal range, but little is known about the mechanisms setting the limits of this range. We uncovered cellular features exhibiting signature changes at thermal limits in Caenorhabditis elegans embryos. These included changes in embryo size and shape, which were also observed in Caenorhabditis briggsae, indicating evolutionary conservation. We hypothesized that such changes could reflect restricted aerobic capacity at thermal limits. Accordingly, we uncovered that relative respiration in C. elegans embryos decreases at the thermal limits as compared to within the thermal range. Furthermore, by compromising components of the respiratory chain, we demonstrated that the reliance on aerobic metabolism is reduced at thermal limits. Moreover, embryos thus compromised exhibited signature changes in size and shape already within the thermal range. We conclude that restricted aerobic metabolism at the thermal limits contributes to setting the thermal range in a metazoan organism. DOI: http://dx.doi.org/10.7554/eLife.04810.001 PMID:25929283

  12. The iron stimulon and fur regulon of Geobacter sulfurreducens and their role in energy metabolism.

    PubMed

    Embree, Mallory; Qiu, Yu; Shieu, Wendy; Nagarajan, Harish; O'Neil, Regina; Lovley, Derek; Zengler, Karsten

    2014-05-01

    Iron plays a critical role in the physiology of Geobacter species. It serves as both an essential component for proteins and cofactors and an electron acceptor during anaerobic respiration. Here, we investigated the iron stimulon and ferric uptake regulator (Fur) regulon of Geobacter sulfurreducens to examine the coordination between uptake of Fe(II) and the reduction of Fe(III) at the transcriptional level. Gene expression studies across a variety of different iron concentrations in both the wild type and a Δfur mutant strain were used to determine the iron stimulon. The stimulon consists of a broad range of gene products, ranging from iron-utilizing to central metabolism and iron reduction proteins. Integration of gene expression and chromatin immunoprecipitation (ChIP) data sets assisted in the identification of the Fur transcriptional regulatory network and Fur's role as a regulator of the iron stimulon. Additional physiological and transcriptional analyses of G. sulfurreducens grown with various Fe(II) concentrations revealed the depth of Fur's involvement in energy metabolism and the existence of redundancy within the iron-regulatory network represented by IdeR, an alternative iron transcriptional regulator. These characteristics enable G. sulfurreducens to thrive in environments with fluctuating iron concentrations by providing it with a robust mechanism to maintain tight and deliberate control over intracellular iron homeostasis.

  13. Microbial Iron Redox Metabolism in Circumneutral pH Environments

    NASA Astrophysics Data System (ADS)

    Roden, E. E.

    2016-12-01

    Redox cycling of iron (Fe) is a key process governing energy flow as well as the speciation and mobility of a wide variety of aqueous and solid-phase constituents in soil and sedimentary environments. Both reduction and oxidation of Fe are microbially catalyzed, and available evidence suggests that microbial Fe redox metabolism takes place across a wide range of spatial and temporal scales natural systems. The coupling of microbial Fe reduction and oxidation has been proposed in various situations where a redox transition zone is observed. This talk will review and synthesize several case studies of the potential for Fe redox cycling in circumneutral pH subsurface environments. Of specific interest are novel pathways and organisms involved in the oxidation of insoluble reduced Fe phases with oxygen or nitrate, and the coupling of Fe oxidation and reduction in field and experimental systems that model potential redox gradients and fluctuations in the subsurface. Recent cultivation studies and physiological experiments indicate that a variety of Proteobacteria are able to oxidize Fe(II)-silicates (e.g. biotite, smectite) and other insoluble Fe(II)-bearing minerals (e.g. pyrite). These findings, together with recent genomic insights from pure and mixed cultures, set the stage for rapid expansion in our knowledge of the range of extracellular electron transfer mechanisms utilized by subsurface microorganisms. These mechanisms permit both closely coupled oxidation and reduction of Fe, as well as previously unrecognized pathways for microbial acceleration of neutral-pH oxidative weathering processes.

  14. Paving a Path to Understanding Metabolic Responses to Iron Bioavailability: Global Proteomic Analysis of Crocosphaera watsonii

    NASA Astrophysics Data System (ADS)

    Gauglitz, J.; McIlvin, M. R.; Moran, D. M.; Waterbury, J. B.; Saito, M. A.

    2016-02-01

    Marine diazotrophic cyanobacteria provide a key source of new nitrogen into the oceans and are important contributors to primary production. The geographic distribution of these cyanobacteria is impacted by available iron and phosphorus as well as environmental conditions such as temperature, however available iron concentrations are thought to be particularly critical due to the high demand for iron in cellular processes. Iron bioavailability and microorganismal adaptations to low iron environments may thus play a key role in dictating community structure, however the mechanisms by which cyanobacteria acquire iron and regulate its uptake are not well defined. In this study, the unicellular diazotroph, Crocosphaera watsonii WH8501, was acclimated to a range of bioavailable iron concentrations (from 0.001nM to 8.13nM Fe') using trace metal clean culturing techniques and the proteomes were analyzed by LC/MS-MS. Physiological and proteomic data indicate three distinct phenotypic ranges: iron-replete, iron-limited, and iron-starved. Trends in photosynthetic, carbon fixation and iron storage proteins across the iron gradient indicate that the C. watsonii proteome responds directly to iron availability. Further analysis of relative protein expression, which describes the physiological state of the cell, will lead to insights into how C. watsonii is able to adapt to iron-limited conditions and the resulting biogeochemical implications will be discussed.

  15. [The role of iron metabolism and oxidative stress in the pathogenesis of endometriosis].

    PubMed

    Polak, Grzegorz; Wertel, Iwona; Kwaśniewski, Wojciech; Derewianka-Polak, Magdalena; Kotarski, Jan

    2013-01-01

    Despite many years of extensive investigations and increasing number of studies, the pathogenesis of endometriosis remains unclear Accumulated data suggests that disrupted iron metabolism may induce oxidative stress in the peritoneal cavity of endometriosis patients.

  16. Advantages and disadvantages of the animal models v. in vitro studies in iron metabolism: a review.

    PubMed

    García, Y; Díaz-Castro, J

    2013-10-01

    Iron deficiency is the most common nutritional deficiency in the world. Special molecules have evolved for iron acquisition, transport and storage in soluble, nontoxic forms. Studies about the effects of iron on health are focused on iron metabolism or nutrition to prevent or treat iron deficiency and anemia. These studies are focused in two main aspects: (1) basic studies to elucidate iron metabolism and (2) nutritional studies to evaluate the efficacy of iron supplementation to prevent or treat iron deficiency and anemia. This paper reviews the advantages and disadvantages of the experimental models commonly used as well as the methods that are more used in studies related to iron. In vitro studies have used different parts of the gut. In vivo studies are done in humans and animals such as mice, rats, pigs and monkeys. Iron metabolism is a complex process that includes interactions at the systemic level. In vitro studies, despite physiological differences to humans, are useful to increase knowledge related to this essential micronutrient. Isotopic techniques are the most recommended in studies related to iron, but their high cost and required logistic, making them difficult to use. The depletion-repletion of hemoglobin is a method commonly used in animal studies. Three depletion-repletion techniques are mostly used: hemoglobin regeneration efficiency, relative biological values (RBV) and metabolic balance, which are official methods of the association of official analytical chemists. These techniques are well-validated to be used as studies related to iron and their results can be extrapolated to humans. Knowledge about the main advantages and disadvantages of the in vitro and animal models, and methods used in these studies, could increase confidence of researchers in the experimental results with less costs.

  17. Silicon enhances leaf remobilization of iron in cucumber under limited iron conditions.

    PubMed

    Pavlovic, Jelena; Samardzic, Jelena; Kostic, Ljiljana; Laursen, Kristian H; Natic, Maja; Timotijevic, Gordana; Schjoerring, Jan K; Nikolic, Miroslav

    2016-08-01

    Retranslocation of iron (Fe) from source tissues enhances plant tolerance to Fe deficiency. Previous work has shown that silicon (Si) can alleviate Fe deficiency by enhancing acquisition and root to shoot translocation of Fe. Here the role of Si in Fe mobilization in older leaves and the subsequent retranslocation of Fe to young leaves of cucumber (Cucumis sativus) plants growing under Fe-limiting conditions was investigated. Iron ((57)Fe or naturally occurring isotopes) was measured in leaves at different positions on plants hydroponically growing with or without Si supply. In parallel, the concentration of the Fe chelator nicotianamine (NA) along with the expression of nicotianamine synthase (NAS) involved in its biosynthesis and the expression of yellow stripe-like (YSL) transcripts mediating Fe-NA transport were also determined. In plants not receiving Si, approximately half of the total Fe content remained in the oldest leaf. In contrast, Si-treated plants showed an almost even Fe distribution among leaves with four different developmental stages, thus providing evidence of enhanced Fe remobilization from source leaves. This Si-stimulated Fe export was paralleled by an increased NA accumulation and expression of the YSL1 transporter for phloem loading/unloading of the Fe-NA complex. The results suggest that Si enhances remobilization of Fe from older to younger leaves by a more efficient NA-mediated Fe transport via the phloem. In addition, from this and previous work, a model is proposed of how Si acts to improve Fe homeostasis under Fe deficiency in cucumber. © The Author 2016. Published by Oxford University Press on behalf of the Annals of Botany Company. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  18. Silicon enhances leaf remobilization of iron in cucumber under limited iron conditions

    PubMed Central

    Pavlovic, Jelena; Samardzic, Jelena; Kostic, Ljiljana; Laursen, Kristian H.; Natic, Maja; Timotijevic, Gordana; Schjoerring, Jan K.; Nikolic, Miroslav

    2016-01-01

    Background and Aims Retranslocation of iron (Fe) from source tissues enhances plant tolerance to Fe deficiency. Previous work has shown that silicon (Si) can alleviate Fe deficiency by enhancing acquisition and root to shoot translocation of Fe. Here the role of Si in Fe mobilization in older leaves and the subsequent retranslocation of Fe to young leaves of cucumber (Cucumis sativus) plants growing under Fe-limiting conditions was investigated. Methods Iron (57Fe or naturally occurring isotopes) was measured in leaves at different positions on plants hydroponically growing with or without Si supply. In parallel, the concentration of the Fe chelator nicotianamine (NA) along with the expression of nicotianamine synthase (NAS) involved in its biosynthesis and the expression of yellow stripe-like (YSL) transcripts mediating Fe–NA transport were also determined. Key Results In plants not receiving Si, approximately half of the total Fe content remained in the oldest leaf. In contrast, Si-treated plants showed an almost even Fe distribution among leaves with four different developmental stages, thus providing evidence of enhanced Fe remobilization from source leaves. This Si-stimulated Fe export was paralleled by an increased NA accumulation and expression of the YSL1 transporter for phloem loading/unloading of the Fe–NA complex. Conclusions The results suggest that Si enhances remobilization of Fe from older to younger leaves by a more efficient NA-mediated Fe transport via the phloem. In addition, from this and previous work, a model is proposed of how Si acts to improve Fe homeostasis under Fe deficiency in cucumber. PMID:27371693

  19. Persistence of iron limitation in the western subarctic Pacific SEEDS II mesoscale fertilization experiment

    NASA Astrophysics Data System (ADS)

    Wells, Mark L.; Trick, Charles G.; Cochlan, William P.; Beall, Ben

    2009-12-01

    The cumulative evidence from more than a dozen mesoscale iron-enrichment studies in high nitrate low chlorophyll (HNLC) waters demonstrates that iron limitation is widespread and very likely affects atmospheric carbon dioxide and thus global climate. However, the responses of microphytoplankton (>20 μm), predominantly diatoms, vary greatly among these mesoscale experiments even though similar amounts of iron were added, making it difficult to quantitatively incorporate iron effects into global climate models. Nowhere is this difference more dramatic than between the massive bloom observed during Subarctic Pacific Iron Experiment for Ecosystem Dynamics Study (SEEDS) I and the order of magnitude smaller ecosystem response in SEEDS II; two mesocale experiments performed in the same HNLC region of the western subarctic Pacific in different years. Deckboard incubation experiments initiated during the early, middle, and late stages of the 32-day SEEDS II experiment show that while the two iron infusions increased phytoplankton growth, diatoms remained significantly limited by iron availability, despite total dissolved Fe concentrations in the patch being well above the diffusion-limited threshold for rapid diatom growth. This iron limitation was apparent <6 days after the initial iron infusion and was not alleviated by the second, smaller iron infusion. In contrast, smaller phytoplankton (<20 μm) showed a more restricted response to further iron amendments, indicating that their iron nutrition was near optimal. Iron complexed to desferrioximine B, a commonly available siderophore produced by at least one marine bacterium, was poorly available to diatoms throughout the patch evolution, indicating that these diatoms lacked the ability to induce high-affinity iron uptake systems. These results suggest that the strong organic complexation of Fe(III) observed in the SEEDS II-fertilized patch was not compatible with rapid diatom growth. In contrast, iron associated with

  20. Multi-Copper Oxidases and Human Iron Metabolism

    PubMed Central

    Vashchenko, Ganna; MacGillivray, Ross T. A.

    2013-01-01

    Multi-copper oxidases (MCOs) are a small group of enzymes that oxidize their substrate with the concomitant reduction of dioxygen to two water molecules. Generally, multi-copper oxidases are promiscuous with regards to their reducing substrates and are capable of performing various functions in different species. To date, three multi-copper oxidases have been detected in humans—ceruloplasmin, hephaestin and zyklopen. Each of these enzymes has a high specificity towards iron with the resulting ferroxidase activity being associated with ferroportin, the only known iron exporter protein in humans. Ferroportin exports iron as Fe2+, but transferrin, the major iron transporter protein of blood, can bind only Fe3+ effectively. Iron oxidation in enterocytes is mediated mainly by hephaestin thus allowing dietary iron to enter the bloodstream. Zyklopen is involved in iron efflux from placental trophoblasts during iron transfer from mother to fetus. Release of iron from the liver relies on ferroportin and the ferroxidase activity of ceruloplasmin which is found in blood in a soluble form. Ceruloplasmin, hephaestin and zyklopen show distinctive expression patterns and have unique mechanisms for regulating their expression. These features of human multi-copper ferroxidases can serve as a basis for the precise control of iron efflux in different tissues. In this manuscript, we review the biochemical and biological properties of the three human MCOs and discuss their potential roles in human iron homeostasis. PMID:23807651

  1. Hepcidin: an important iron metabolism regulator in chronic kidney disease.

    PubMed

    Antunes, Sandra Azevedo; Canziani, Maria Eugênia Fernandes

    2016-01-01

    Anemia is a common complication and its impact on morbimortality in patients with chronic kidney disease (CKD) is well known. The discovery of hepcidin and its functions has contributed to a better understanding of iron metabolism disorders in CKD anemia. Hepcidin is a peptide mainly produced by hepatocytes and, through a connection with ferroportin, it regulates iron absorption in the duodenum and its release of stock cells. High hepcidin concentrations described in patients with CKD, especially in more advanced stages are attributed to decreased renal excretion and increased production. The elevation of hepcidin has been associated with infection, inflammation, atherosclerosis, insulin resistance and oxidative stress. Some strategies were tested to reduce the effects of hepcidin in patients with CKD, however more studies are necessary to assess the impact of its modulation in the management of anemia in this population. Resumo Anemia é uma complicação frequente e seu impacto na morbimortalidade é bem conhecido em pacientes com doença renal crônica (DRC). A descoberta da hepcidina e de suas funções contribuíram para melhor compreensão dos distúrbios do metabolismo de ferro na anemia da DRC. Hepcidina é um peptídeo produzido principalmente pelos hepatócitos, e através de sua ligação com a ferroportina, regula a absorção de ferro no duodeno e sua liberação das células de estoque. Altas concentrações de hepcidina descritas em pacientes com DRC, principalmente em estádios mais avançados, são atribuídas à diminuição da excreção renal e ao aumento de sua produção. Elevação de hepcidina tem sido associada à ocorrência de infecção, inflamação, aterosclerose, resistência à insulina e estresse oxidativo. Algumas estratégias foram testadas para diminuir os efeitos da hepcidina em pacientes com DRC, entretanto, serão necessários mais estudos para avaliar o impacto de sua modulação no manejo da anemia nessa população.

  2. Gene expression profiling in Entamoeba histolytica identifies key components in iron uptake and metabolism.

    PubMed

    Hernández-Cuevas, Nora Adriana; Weber, Christian; Hon, Chung-Chau; Guillen, Nancy

    2014-01-01

    Entamoeba histolytica is an ameboid parasite that causes colonic dysentery and liver abscesses in humans. The parasite encounters dramatic changes in iron concentration during its invasion of the host, with relatively low levels in the intestinal lumen and then relatively high levels in the blood and liver. The liver notably contains sources of iron; therefore, the parasite's ability to use these sources might be relevant to its survival in the liver and thus the pathogenesis of liver abscesses. The objective of the present study was to identify factors involved in iron uptake, use and storage in E. histolytica. We compared the respective transcriptomes of E. histolytica trophozoites grown in normal medium (containing around 169 µM iron), low-iron medium (around 123 µM iron), iron-deficient medium (around 91 µM iron), and iron-deficient medium replenished with hemoglobin. The differentially expressed genes included those coding for the ATP-binding cassette transporters and major facilitator transporters (which share homology with bacterial siderophores and heme transporters) and genes involved in heme biosynthesis and degradation. Iron deficiency was associated with increased transcription of genes encoding a subset of cell signaling molecules, some of which have previously been linked to adaptation to the intestinal environment and virulence. The present study is the first to have assessed the transcriptome of E. histolytica grown under various iron concentrations. Our results provide insights into the pathways involved in iron uptake and metabolism in this parasite.

  3. Gene Expression Profiling in Entamoeba histolytica Identifies Key Components in Iron Uptake and Metabolism

    PubMed Central

    Hernández-Cuevas, Nora Adriana; Weber, Christian; Hon, Chung-Chau; Guillen, Nancy

    2014-01-01

    Entamoeba histolytica is an ameboid parasite that causes colonic dysentery and liver abscesses in humans. The parasite encounters dramatic changes in iron concentration during its invasion of the host, with relatively low levels in the intestinal lumen and then relatively high levels in the blood and liver. The liver notably contains sources of iron; therefore, the parasite's ability to use these sources might be relevant to its survival in the liver and thus the pathogenesis of liver abscesses. The objective of the present study was to identify factors involved in iron uptake, use and storage in E. histolytica. We compared the respective transcriptomes of E. histolytica trophozoites grown in normal medium (containing around 169 µM iron), low-iron medium (around 123 µM iron), iron-deficient medium (around 91 µM iron), and iron-deficient medium replenished with hemoglobin. The differentially expressed genes included those coding for the ATP-binding cassette transporters and major facilitator transporters (which share homology with bacterial siderophores and heme transporters) and genes involved in heme biosynthesis and degradation. Iron deficiency was associated with increased transcription of genes encoding a subset of cell signaling molecules, some of which have previously been linked to adaptation to the intestinal environment and virulence. The present study is the first to have assessed the transcriptome of E. histolytica grown under various iron concentrations. Our results provide insights into the pathways involved in iron uptake and metabolism in this parasite. PMID:25210888

  4. Magnetotactic bacterial abundance in pelagic marine environments is limited by availability of dissolved iron and organic carbon flux

    NASA Astrophysics Data System (ADS)

    Florindo, F.; Roberts, A. P.; Villa, G.; Chang, L.; Jovane, L.; Bohaty, S. M.; Larrasoaña, J. C.

    2011-12-01

    Despite the fact that magnetotactic bacteria intracellularly biomineralize magnetite of an ideal grain size for recording paleomagnetic signals, bacterial magnetite is not widely reported in the pre-Quaternary geological record. Most magnetotactic bacteria are gradient organisms that live in chemically stratified environments near the oxic-anoxic interface. Thus, when magnetofossils are eventually buried within anoxic environments, the fine-grained magnetite undergoes dissolution and is therefore not preserved in the geological record. Pelagic carbonate sediments provide optimal environments for preserving bacterial magnetite because they have expanded pore-water redox zonations that often do not become anoxic for hundreds of meters. Nevertheless, the biogeochemical factors that control magnetotactic bacterial populations in such settings are not well known. We document bacterial magnetite preservation throughout Eocene carbonates from the southern Kerguelen Plateau, Southern Ocean. We provide evidence that iron fertilization, via increased eolian dust deposition, enhanced primary productivity, which controlled bacterial magnetite abundance via export of organic carbon to the seafloor. Increased burial of eolian iron-bearing phases also delivered iron to the seafloor, some of which became bioavailable through iron reduction. Increased organic carbon fluxes to the seafloor provided nutrients needed for bacterial metabolism and increased bioavailable iron needed for magnetosome mineralization. These factors therefore appear to have provided important controls on the concentration of magnetotactic bacteria, which increased with enhanced delivery of organic carbon and bioavailable iron to the seafloor. While several other limiting factors also influence primary productivity in oligotrophic waters, our results suggest that magnetotactic bacterial populations are particularly sensitive to iron and organic carbon limitation.

  5. Fungal Morphology, Iron Homeostasis, and Lipid Metabolism Regulated by a GATA Transcription Factor in Blastomyces dermatitidis

    PubMed Central

    Marty, Amber J.; Broman, Aimee T.; Zarnowski, Robert; Dwyer, Teigan G.; Bond, Laura M.; Lounes-Hadj Sahraoui, Anissa; Fontaine, Joël; Ntambi, James M.; Keleş, Sündüz; Kendziorski, Christina; Gauthier, Gregory M.

    2015-01-01

    In response to temperature, Blastomyces dermatitidis converts between yeast and mold forms. Knowledge of the mechanism(s) underlying this response to temperature remains limited. In B. dermatitidis, we identified a GATA transcription factor, SREB, important for the transition to mold. Null mutants (SREBΔ) fail to fully complete the conversion to mold and cannot properly regulate siderophore biosynthesis. To capture the transcriptional response regulated by SREB early in the phase transition (0–48 hours), gene expression microarrays were used to compare SREB∆ to an isogenic wild type isolate. Analysis of the time course microarray data demonstrated SREB functioned as a transcriptional regulator at 37°C and 22°C. Bioinformatic and biochemical analyses indicated SREB was involved in diverse biological processes including iron homeostasis, biosynthesis of triacylglycerol and ergosterol, and lipid droplet formation. Integration of microarray data, bioinformatics, and chromatin immunoprecipitation identified a subset of genes directly bound and regulated by SREB in vivo in yeast (37°C) and during the phase transition to mold (22°C). This included genes involved with siderophore biosynthesis and uptake, iron homeostasis, and genes unrelated to iron assimilation. Functional analysis suggested that lipid droplets were actively metabolized during the phase transition and lipid metabolism may contribute to filamentous growth at 22°C. Chromatin immunoprecipitation, RNA interference, and overexpression analyses suggested that SREB was in a negative regulatory circuit with the bZIP transcription factor encoded by HAPX. Both SREB and HAPX affected morphogenesis at 22°C; however, large changes in transcript abundance by gene deletion for SREB or strong overexpression for HAPX were required to alter the phase transition. PMID:26114571

  6. Compartmentalization and regulation of iron metabolism proteins protect male germ cells from iron overload.

    PubMed

    Leichtmann-Bardoogo, Yael; Cohen, Lyora A; Weiss, Avital; Marohn, Britta; Schubert, Stephanie; Meinhardt, Andreas; Meyron-Holtz, Esther G

    2012-06-15

    The universal importance of iron, its high toxicity, and complex chemistry present a challenge to biological systems in general and to protected compartments in particular. The high mitotic rate and avid mitochondriogenesis of developing male germ cells imply high iron requirements. Yet access to germ cells is tightly regulated by the blood-testis barrier that protects the meiotic and postmeiotic germ cells. To elucidate how iron is supplied to developing male germ cells, we analyzed iron deposition and iron transport proteins in testes of mice with iron overload and with genetic ablation of the iron regulators Hfe and iron regulatory protein 2. Iron accumulated mainly around seminiferous tubules, and only small amounts localized within the seminiferous tubules. The localization and regulation of proteins involved in iron import, storage, and export such as transferrin, transferrin receptor, the divalent metal transporter-1, cytosolic ferritin, and ferroportin strongly support a model of a largely autonomous iron cycle within seminiferous tubules. We show evidence that ferritin secretion from Sertoli cells may play an important role in iron acquisition of primary spermatocytes. During spermatogenic development iron is carried along from primary spermatocytes to spermatids, and from spermatids iron is recycled to the apical compartment of Sertoli cells, which traffic it back to a new generation of spermatocytes. Losses are replenished by the peripheral circulation. Such an internal iron cycle essentially detaches the iron homeostasis within the seminiferous tubule from the periphery and protects developing germ cells from iron fluctuations. This model explains how compartmentalization can optimize cellular and systemic nutrient homeostasis.

  7. Metabolic response in roots of Prunus rootstocks submitted to iron chlorosis.

    PubMed

    Jiménez, Sergio; Ollat, Nathalie; Deborde, Catherine; Maucourt, Mickaël; Rellán-Álvarez, Rubén; Moreno, María Ángeles; Gogorcena, Yolanda

    2011-03-15

    Iron deficiency induces several responses to iron shortage in plants. Metabolic changes occur to sustain the increased iron uptake capacity of Fe-deficient plants. We evaluated the metabolic changes of three Prunus rootstocks submitted to iron chlorosis and their different responses for tolerance using measurements of metabolites and enzymatic activities. The more tolerant rootstocks Adesoto (Prunus insititia) and GF 677 (Prunus amygdalus×Prunus persica), and the more sensitive Barrier (P. persica×Prunus davidiana) were grown hydroponically in iron-sufficient and -deficient conditions over two weeks. Sugar, organic and amino acid concentrations of root tips were determined after two weeks of iron shortage by proton nuclear magnetic resonance spectroscopy of extracts. Complementary analyses of organic acids were performed by liquid chromatography coupled to mass spectrometry. The major soluble sugars found were glucose and sucrose. The major organic acids were malic and citric acids, and the major amino acid was asparagine. Iron deficiency increased root sucrose, total organic and amino acid concentrations and phosphoenolpyruvate carboxylase activity. After two weeks of iron deficiency, the malic, citric and succinic acid concentrations increased in the three rootstocks, although no significant differences were found among genotypes with different tolerance to iron chlorosis. The tolerant rootstock Adesoto showed higher total organic and amino acid concentrations. In contrast, the susceptible rootstock Barrier showed lower total amino acid concentration and phosphoenolpyruvate carboxylase activity values. These results suggest that the induction of this enzyme activity under iron deficiency, as previously shown in herbaceous plants, indicates the tolerance level of rootstocks to iron chlorosis. The analysis of other metabolic parameters, such as organic and amino acid concentrations, provides complementary information for selection of genotypes tolerant to iron

  8. IscR of Rhodobacter sphaeroides functions as repressor of genes for iron-sulfur metabolism and represents a new type of iron-sulfur-binding protein

    PubMed Central

    Remes, Bernhard; Eisenhardt, Benjamin D; Srinivasan, Vasundara; Klug, Gabriele

    2015-01-01

    IscR proteins are known as transcriptional regulators for Fe–S biogenesis. In the facultatively phototrophic bacterium, Rhodobacter sphaeroides IscR is the product of the first gene in the isc-suf operon. A major role of IscR in R. sphaeroides iron-dependent regulation was suggested in a bioinformatic study (Rodionov et al., PLoS Comput Biol 2:e163, 2006), which predicted a binding site in the upstream regions of several iron uptake genes, named Iron-Rhodo-box. Most known IscR proteins have Fe–S clusters featuring (Cys)3(His)1 ligation. However, IscR proteins from Rhodobacteraceae harbor only a single-Cys residue and it was considered unlikely that they can ligate an Fe–S cluster. In this study, the role of R. sphaeroides IscR as transcriptional regulator and sensor of the Fe–S cluster status of the cell was analyzed. A mutant lacking IscR is more impaired in growth under iron limitation than the wild-type and exhibits significantly increased ROS levels in iron-replete and iron-deplete conditions. Expression studies reveal that R. sphaeroides IscR in its cluster-bound form functions as transcriptional repressor of genes involved in iron metabolism by direct binding to the promoter region of genes preceded by the motif. A total of 110 genes are directly or indirectly affected by IscR. Furthermore, IscR possesses a unique Fe–S cluster ligation scheme with only a single cysteine involved. PMID:26235649

  9. IDENTIFICATION OF ERYTHROFERRONE AS AN ERYTHROID REGULATOR OF IRON METABOLISM

    PubMed Central

    Kautz, Léon; Jung, Grace; Valore, Erika V.; Rivella, Stefano; Nemeth, Elizabeta; Ganz, Tomas

    2014-01-01

    Recovery from blood loss requires a greatly enhanced supply of iron to support expanded erythropoiesis. After hemorrhage, suppression of the iron-regulatory hormone hepcidin allows increased iron absorption and mobilization from stores. We identified a new hormone, erythroferrone (ERFE), which mediates hepcidin suppression during stress erythropoiesis. ERFE is produced by erythroblasts in response to erythropoietin. ERFE-deficient mice fail to suppress hepcidin rapidly after hemorrhage and exhibit a delay in recovery from blood loss. ERFE expression is greatly increased in murine HbbTh3/+ thalassemia intermedia where it contributes to the suppression of hepcidin and systemic iron overload characteristic of this disease. PMID:24880340

  10. The Crossroads of Iron with Hypoxia and Cellular Metabolism. Implications in the Pathobiology of Pulmonary Hypertension

    PubMed Central

    Graham, Brian B.; Rouault, Tracey C.; Tuder, Rubin M.

    2014-01-01

    The pathologic hallmark of pulmonary arterial hypertension (PAH) is pulmonary vascular remodeling, characterized by endothelial cell proliferation, smooth muscle hypertrophy, and perivascular inflammation, ultimately contributing to increased pulmonary arterial pressures. Several recent studies have observed that iron deficiency in patients with various forms of PAH is associated with worsened clinical outcome. Iron plays a key role in many cellular processes regulating the response to hypoxia, oxidative stress, cellular proliferation, and cell metabolism. Given the potential importance of iron supplementation in patients with the disease and the broad cellular functions of iron, we review its role in processes that pertain to PAH. PMID:24988529

  11. Mild copper deficiency alters gene expression of proteins involved in iron metabolism.

    PubMed

    Auclair, Sylvain; Feillet-Coudray, Christine; Coudray, Charles; Schneider, Susanne; Muckenthaler, Martina U; Mazur, Andrzej

    2006-01-01

    Iron and copper homeostasis share common proteins and are therefore closely linked to each other. For example, copper-containing proteins like ceruloplasmin and hephaestin oxidize Fe(2+) during cellular export processes for transport in the circulation bound to transferrin. Indeed, copper deficiency provokes iron metabolism disorders leading to anemia and liver iron accumulation. The aim of the present work was to understand the cross-talk between copper status and iron metabolism. For this purpose we have established dietary copper deficiency in C57BL6 male mice during twelve weeks. Hematological parameters, copper and iron status were evaluated. cDNA microarray studies were performed to investigate gene expression profiles of proteins involved in iron metabolism in the liver, duodenum and spleen. Our results showed that copper deficiency induces microcytic and hypochromic anemia as well as liver iron overload. Gene expression profiles, however, indicate that hepatic and intestinal mRNA expression neither compensates for hepatic iron overload nor the anemia observed in this mouse model. Instead, major modifications of gene expression occurred in the spleen. We observed increased mRNA levels of the transferrin receptors 1 and 2 and of several proteins involved in the heme biosynthesis pathway (ferrochelatase, UroD, UroS,...). These results suggest that copper-deficient mice respond to the deficiency induced anemia by an adaptation leading to an increase in erythrocyte synthesis.

  12. Status of Iron Metabolism 10 Years After Roux-En-Y Gastric Bypass.

    PubMed

    Monaco-Ferreira, Daniela Vicinansa; Leandro-Merhi, Vânia Aparecida

    2017-08-01

    The aim of this study is to investigate changes in iron metabolism and verify whether biochemical parameters are related to the use of oral iron supplement 10 years after Roux-en-Y gastric bypass. This longitudinal retrospective study included 151 patients submitted to Roux-en-Y gastric bypass. The collected data included use of an oral iron supplement, hemoglobin, hematocrit, serum iron, and ferritin. The chi-squared or Fisher's exact test was used to analyze the association between use of iron supplement and nutritional deficiency. The generalized estimating equations (GEEs) analyzed the nutritional deficiencies over time. Of the study patients with iron-deficiency anemia (n = 15) in the 12-month follow-up, 73.33% (n = 11) were taking an iron supplement, and 26.67% (n = 4) were not (p = 0.0010). The effect of time was significant for hemoglobin, ferritin, iron overload (p < 0.0001), and hematocrit (p = 0.0007). Of the patients who remained in the study until the 120-month follow-up, 37.5 and 45.0% were diagnosed with iron-deficiency anemia, defined as ferritin <15 μg/L and ferritin <30 μg/L, respectively. Iron-deficiency anemia increased over time even in patients taking oral iron supplements.

  13. Confirmation of iron limitation of phytoplankton photosynthesis in the equatorial Pacific Ocean

    NASA Astrophysics Data System (ADS)

    Behrenfeld, Michael J.; Bale, Anthony J.; Kolber, Zbigniew S.; Aiken, James; Falkowski, Paul G.

    1996-10-01

    THE eastern equatorial Pacific Ocean is one of only three open-ocean regions where low phytoplankton chlorophyll biomass persists despite perennially high nitrate and phosphate nutrient concentrations1. In 1993, an area within this region was artificially enriched with a single dose of soluble iron to test whether phytoplankton are physiologically prevented from utilizing the available nutrients by the low natural iron concentrations2,3. Although photosynthesis was stimulated4, the observed lack of a bloom or a significant decrease in nutrient concentrations could not be attributed unequivocally to zooplankton grazing5-7, further iron limitation or secondary nutrient limitation2,4. In 1995, a second iron-enrichment experiment (IronEx II) was conducted in which the same total dosage of iron was added, but over eight days8. A massive phytoplankton bloom developed, significantly reducing surface-water nutrient and CO2 concentrations8-10. Here we report in situ measurements of fluorescence during IronEx II, which show that the iron enrichment triggered biophysical alterations of the phytoplankton's photosynthetic apparatus, resulting in increased photosynthetic capacities throughout the experiment and, hence, the observed bloom. These results unequivocally establish physiological limitation of phytoplankton by iron as the cause of the high-nitrate, low-chlorophyll phenomenon in this ocean region.

  14. Iron-dependent changes in cellular energy metabolism: influence on citric acid cycle and oxidative phosphorylation.

    PubMed

    Oexle, H; Gnaiger, E; Weiss, G

    1999-11-10

    Iron modulates the expression of the critical citric acid cycle enzyme aconitase via a translational mechanism involving iron regulatory proteins. Thus, the present study was undertaken to investigate the consequences of iron perturbation on citric acid cycle activity, oxidative phosphorylation and mitochondrial respiration in the human cell line K-562. In agreement with previous data iron increases the activity of mitochondrial aconitase while it is reduced upon addition of the iron chelator desferrioxamine (DFO). Interestingly, iron also positively affects three other citric acid cycle enzymes, namely citrate synthase, isocitric dehydrogenase, and succinate dehydrogenase, while DFO decreases the activity of these enzymes. Consequently, iron supplementation results in increased formation of reducing equivalents (NADH) by the citric acid cycle, and thus in increased mitochondrial oxygen consumption and ATP formation via oxidative phosphorylation as shown herein. This in turn leads to downregulation of glucose utilization. In contrast, all these metabolic pathways are reduced upon iron depletion, and thus glycolysis and lactate formation are significantly increased in order to compensate for the decrease in ATP production via oxidative phosphorylation in the presence of DFO. Our results point to a complex interaction between iron homeostasis, oxygen supply and cellular energy metabolism in human cells.

  15. Pro-hepcidin and iron metabolism parameters in multi-time blood donors.

    PubMed

    Boinska, J; Zekanowska, E; Kwapisz, J

    2010-10-01

    A high number of blood donations may cause iron depletion. The pathophysiology behind this process may involve hepcidin, a recently discovered peptide that acts by inhibiting iron absorption and promoting iron retention in reticuloendothelial macrophages. The aim of this study was to determine serum pro-hepcidin levels and iron metabolism parameters in multi-time blood donors. The study group consisted of 132 multi-time male blood donors and 25 healthy male volunteers (nondonors). Complete blood cell count and iron status including serum iron, ferritin, soluble transferrin receptor (sTfR), total iron binding capacity (TIBC), unsaturated iron binding capacity (UIBC), erythropoietin and pro-hepcidin (ELISA) were assessed. In blood donors, ferritin level drops markedly in relation to donation frequency (P < 0.001). In contrast, TIBC and UIBC levels increase progressively corresponding to annual donation frequency. Pro-hepcidin concentration increases significantly with the number of donations per year (P = 0.0290). In blood donors having donated blood with the highest frequency per year, pro-hepcidin levels were positively correlated with haemoglobin (R = 0.31, P < 0.05) and negatively with sTfR (R = -0.31, P < 0.05). Pro-hepcidin levels increase in relation to blood donation frequency per year. Longitudinal studies focusing on changes in serum hepcidin levels are required to address the question whether hepcidin may contribute to iron metabolism disturbances in multi-times blood donors.

  16. Modulation of iron metabolism by iron chelation regulates intracellular calcium and increases sensitivity to doxorubicin

    PubMed Central

    Yalcintepe, Leman; Halis, Emre

    2016-01-01

    Increased intracellular iron levels can both promote cell proliferation and death, as such; iron has a “two-sided effect” in the delicate balance of human health. Though the role of iron in the development of cancer remains unclear, investigations of iron chelators as anti-tumor agents have revealed promising results. Here, we investigated the influence of iron and desferrioxamine (DFO), the iron chelating agent on intracellular calcium in a human leukemia cell line, K562. Iron uptake is associated with increased reactive oxygen species (ROS) generation. Therefore, we showed that iron also caused dose-dependent ROS generation in K562 cells. The measurement of intracellular calcium was determined using Furo-2 with a fluorescence spectrophotometer. The iron delivery process to the cytoplasmic iron pool was examined by monitoring the fluorescence of cells loaded with calcein-acetoxymethyl. Our data showed that iron increased intracellular calcium, and this response was 8 times higher when cells were incubated with DFO. K562 cells with DFO caused a 3.5 times increase of intracellular calcium in the presence of doxorubicin (DOX). In conclusion, DFO induces intracellular calcium and increases their sensitivity to DOX, a chemotherapeutic agent. PMID:26773173

  17. Metabolic analysis of mouse brains that have compromised iron storage.

    PubMed

    Ill, Amanda M; Mitchell, Todd R; Neely, Elizabeth B; Connor, James R

    2006-09-01

    Iron is a critical component of the CNS that must be tightly regulated; too little iron can result in energy insufficiency and too much iron can result in oxidative stress. The intracellular iron storage protein ferritin is central to the regulation of iron. In this study, we determined the neurochemical profile of brains of animals deficient in heavy-chain ferritin (H-ferritin) using high-resolution magic angle spin proton magnetic resonance spectroscopy (HR-MAS (1)H MRS). Spectra of 2 mm-thick coronal tissue punches ( approximately 4 mg) were obtained using a CPMG pulse sequence on Bruker Avance 500 and quantified (nmol/mg tissue) using customized LCModel software (16 metabolites). In H-ferritin deficient mice, we found significant increases in striatal glutamate, hippocampal choline, and N-acetyl-aspartyl-glutamate in both the cortex and the hippocampus (t-test, p < 0.05). Neurochemical profiling with principal component analysis (PCA) revealed increased glutamate in the hippocampus, striatum, and ventral tegmental area (VTA) in H-ferritin deficient animals as compared to wild-type. While lactate was increased in the VTA of deficient animals, it was decreased in the striatum. Also, GABA was increased in both cortical and striatal regions of deficient mice. These changes reveal the importance of proper iron management for maintaining neurochemical balance and provide new evidence for region specific differences in neurochemical profiles as a result of compromised ability of neurons to store iron while overall iron status is normal. Because H-ferritin is predominantly expressed in neurons, the neurochemical profile is suggestive of neuronal iron deficiency and may have relevance to the functional consequences associated with brain iron deficiency.

  18. The effect of iron limitation on the transcriptome and proteome of Pseudomonas fluorescens Pf-5

    USDA-ARS?s Scientific Manuscript database

    We investigated the transcriptomic and proteomic effects of iron limitation on Pf-5 by employing microarray and iTRAQ techniques, respectively. Analysis of this data revealed that molecular elements involved in iron homeostasis, including the pyoverdine and enantio-pyochelin biosynthesis clusters a...

  19. Effects of Iron Limitation on Photosystem II Composition and Light Utilization in Dunaliella tertiolecta.

    PubMed Central

    Vassiliev, I. R.; Kolber, Z.; Wyman, K. D.; Mauzerall, D.; Shukla, V. K.; Falkowski, P. G.

    1995-01-01

    The effects of iron limitation on photosystem II (PSII) composition and photochemical energy conversion efficiency were studied in the unicellular chlorophyte alga Dunaliella tertiolecta. The quantum yield of photochemistry in PSII, inferred from changes in variable fluorescence normalized to the maximum fluorescence yield, was markedly lower in iron-limited cells and increased 3-fold within 20 h following the addition of iron. The decrease in the quantum yield of photochemistry was correlated with increased fluorescence emission from the antenna. In iron-limited cells, flash intensity saturation profiles of variable fluorescence closely followed a cumulative one-hit Poisson model, suggesting that PSII reaction centers are energetically isolated, whereas in iron-replete cells, the slope of the profile was steeper and the calculated probability of energy transfer between reaction centers increased to >0.6. Immunoassays revealed that in iron-limited cells the reaction center proteins, D1, CP43, and CP47, were markedly reduced relative to the peripheral light-harvesting Chl-protein complex of PSII, whereas the [alpha] subunit of cytochrome b559 was about 10-fold higher. Spectroscopic analysis established that the cytochrome b559 peptide did not contain an associated functional heme. We conclude that the photochemical conversion of absorbed excitation energy in iron-limited cells is limited by the number of photochemical traps per unit antenna. PMID:12228645

  20. Effects of Iron Limitation on Photosystem II Composition and Light Utilization in Dunaliella tertiolecta.

    PubMed

    Vassiliev, I. R.; Kolber, Z.; Wyman, K. D.; Mauzerall, D.; Shukla, V. K.; Falkowski, P. G.

    1995-11-01

    The effects of iron limitation on photosystem II (PSII) composition and photochemical energy conversion efficiency were studied in the unicellular chlorophyte alga Dunaliella tertiolecta. The quantum yield of photochemistry in PSII, inferred from changes in variable fluorescence normalized to the maximum fluorescence yield, was markedly lower in iron-limited cells and increased 3-fold within 20 h following the addition of iron. The decrease in the quantum yield of photochemistry was correlated with increased fluorescence emission from the antenna. In iron-limited cells, flash intensity saturation profiles of variable fluorescence closely followed a cumulative one-hit Poisson model, suggesting that PSII reaction centers are energetically isolated, whereas in iron-replete cells, the slope of the profile was steeper and the calculated probability of energy transfer between reaction centers increased to >0.6. Immunoassays revealed that in iron-limited cells the reaction center proteins, D1, CP43, and CP47, were markedly reduced relative to the peripheral light-harvesting Chl-protein complex of PSII, whereas the [alpha] subunit of cytochrome b559 was about 10-fold higher. Spectroscopic analysis established that the cytochrome b559 peptide did not contain an associated functional heme. We conclude that the photochemical conversion of absorbed excitation energy in iron-limited cells is limited by the number of photochemical traps per unit antenna.

  1. Blood Transcriptomic Meta-analysis Identifies Dysregulation of Hemoglobin and Iron Metabolism in Parkinson' Disease.

    PubMed

    Santiago, Jose A; Potashkin, Judith A

    2017-01-01

    Disrupted iron metabolism has been implicated in the pathogenesis of Parkinson's disease (PD), a progressive neurodegenerative disorder that severely affects movement and coordination, yet the molecular mechanisms underlying this association remain unknown. To this end, we performed a transcriptomic meta-analysis of four blood microarrays in PD. We observed a significant downregulation of genes related to hemoglobin including, hemoglobin delta (HBD), alpha hemoglobin stabilizing protein (ASHP), genes implicated in iron metabolism including, solute carrier family 11 member 2 (SLC11A2), ferrochelatase (FECH), and erythrocyte-specific genes including erythrocyte membrane protein (EPB42), and 5'-aminolevulinate synthase 2 (ALAS2). Pathway and network analysis identified enrichment in processes related to mitochondrial membrane, oxygen transport, oxygen and heme binding, hemoglobin complex, erythrocyte development, tetrapyrrole metabolism and the spliceosome. Collectively, we identified a subnetwork of genes in blood that may provide a molecular explanation for the disrupted hemoglobin and iron metabolism in the pathogenesis of PD.

  2. Transferrin Receptor 2 Dependent Alterations of Brain Iron Metabolism Affect Anxiety Circuits in the Mouse

    PubMed Central

    Pellegrino, Rosa Maria; Boda, Enrica; Montarolo, Francesca; Boero, Martina; Mezzanotte, Mariarosa; Saglio, Giuseppe; Buffo, Annalisa; Roetto, Antonella

    2016-01-01

    The Transferrin Receptor 2 (Tfr2) modulates systemic iron metabolism through the regulation of iron regulator Hepcidin (Hepc) and Tfr2 inactivation causes systemic iron overload. Based on data demonstrating Tfr2 expression in brain, we analysed Tfr2-KO mice in order to examine the molecular, histological and behavioural consequences of Tfr2 silencing in this tissue. Tfr2 abrogation caused an accumulation of iron in specific districts in the nervous tissue that was not accompanied by a brain Hepc response. Moreover, Tfr2-KO mice presented a selective overactivation of neurons in the limbic circuit and the emergence of an anxious-like behaviour. Furthermore, microglial cells showed a particular sensitivity to iron perturbation. We conclude that Tfr2 is a key regulator of brain iron homeostasis and propose a role for Tfr2 alpha in the regulation of anxiety circuits. PMID:27477597

  3. Insights into the Structure and Metabolic Function of Microbes That Shape Pelagic Iron-Rich Aggregates ( Iron Snow )

    SciTech Connect

    Lu, S; Chourey, Karuna; REICHE, M; Nietzsche, S; Shah, Manesh B; Hettich, Robert {Bob} L; Kusel, K

    2013-01-01

    Metaproteomics combined with total nucleic acid-based methods aided in deciphering the roles of microorganisms in the formation and transformation of iron-rich macroscopic aggregates (iron snow) formed in the redoxcline of an acidic lignite mine lake. Iron snow had high total bacterial 16S rRNA gene copies, with 2 x 109 copies g (dry wt)-1 in the acidic (pH 3.5) central lake basin and 4 x 1010 copies g (dry wt)-1 in the less acidic (pH 5.5) northern lake basin. Active microbial communities in the central basin were dominated by Alphaproteobacteria (36.6%) and Actinobacteria (21.4%), and by Betaproteobacteria (36.2%) in the northern basin. Microbial Fe-cycling appeared to be the dominant metabolism in the schwertmannite-rich iron snow, because cloning and qPCR assigned up to 61% of active bacteria as Fe-cycling bacteria (FeB). Metaproteomics revealed 70 unique proteins from central basin iron snow and 283 unique proteins from 43 genera from northern basin. Protein identification provided a glimpse into in situ processes, such as primary production, motility, metabolism of acidophilic FeB, and survival strategies of neutrophilic FeB. Expression of carboxysome shell proteins and RubisCO indicated active CO2 fixation by Fe(II) oxidizers. Flagellar proteins from heterotrophs indicated their activity to reach and attach surfaces. Gas vesicle proteins related to CO2-fixing Chlorobium suggested that microbes could influence iron snow sinking. We suggest that iron snow formed by autotrophs in the redoxcline acts as a microbial parachute, since it is colonized by motile heterotrophs during sinking which start to dissolve schwertmannite.

  4. The effects of phosphorus limitation on carbon metabolism in diatoms.

    PubMed

    Brembu, Tore; Mühlroth, Alice; Alipanah, Leila; Bones, Atle M

    2017-09-05

    Phosphorus is an essential element for life, serving as an integral component of nucleic acids, lipids and a diverse range of other metabolites. Concentrations of bioavailable phosphorus are low in many aquatic environments. Microalgae, including diatoms, apply physiological and molecular strategies such as phosphorus scavenging or recycling as well as adjusting cell growth in order to adapt to limiting phosphorus concentrations. Such strategies also involve adjustments of the carbon metabolism. Here, we review the effect of phosphorus limitation on carbon metabolism in diatoms. Two transcriptome studies are analysed in detail, supplemented by other transcriptome, proteome and metabolite data, to gain an overview of different pathways and their responses. Phosphorus, nitrogen and silicon limitation responses are compared, and similarities and differences discussed. We use the current knowledge to propose a suggestive model for the carbon flow in phosphorus-replete and phosphorus-limited diatom cells.This article is part of the themed issue 'The peculiar carbon metabolism in diatoms'. © 2017 The Authors.

  5. Abnormal iron metabolism in fibroblasts from a patient with the neurodegenerative disease hereditary ferritinopathy

    PubMed Central

    2010-01-01

    Background Nucleotide duplications in exon 4 of the ferritin light polypeptide (FTL) gene cause the autosomal dominant neurodegenerative disease neuroferritinopathy or hereditary ferritinopathy (HF). Pathologic examination of patients with HF has shown abnormal ferritin and iron accumulation in neurons and glia in the central nervous system (CNS) as well as in cells of other organ systems, including skin fibroblasts. To gain some understanding on the molecular basis of HF, we characterized iron metabolism in primary cultures of human skin fibroblasts from an individual with the FTL c.497_498dupTC mutation. Results Compared to normal controls, HF fibroblasts showed abnormal iron metabolism consisting of increased levels of ferritin polypeptides, divalent metal transporter 1, basal iron content and reactive oxygen species, and decreased levels of transferrin receptor-1 and IRE-IRP binding activity. Conclusions Our data indicates that HF fibroblasts replicate the abnormal iron metabolism observed in the CNS of patients with HF. We propose that HF fibroblasts are a unique cellular model in which to study the role of abnormal iron metabolism in the pathogenesis of HF without artifacts derived from over-expression or lack of endogenous translational regulatory elements. PMID:21067605

  6. Toward new perspectives on the interaction of iron and sulfur metabolism in plants

    PubMed Central

    Forieri, Ilaria; Wirtz, Markus; Hell, Rüdiger

    2013-01-01

    The deficiency of nutrients has been extensively investigated because of its impact on plant growth and yield. So far, the effects of a combined nutrient limitation have rarely been analyzed, although such situations are likely to occur in agroecosystems. Iron (Fe) is a prerequisite for many essential cellular functions. Its availability is easily becoming limiting for plant growth and thus higher plants have evolved different strategies to cope with Fe deficiency. Sulfur (S) is an essential macro-nutrient and the responses triggered by shortage situations have been well characterized. The interaction between these two nutrients is less investigated but might be of particular importance because most of the metabolically active Fe is bound to S in Fe–S clusters. The biosynthesis of Fe–S clusters requires the provision of reduced S and chelated Fe in a defined stoichiometric ratio, strongly suggesting coordination between the metabolisms of the two nutrients. Here the available information on interactions between Fe and S nutritional status is evaluated. Experiments with Arabidopsis thaliana and crop plants indicate a co-regulation and point to a possible role of Fe–S cluster synthesis or abundance in the Fe/S network. PMID:24106494

  7. [The specific features of copper and manganese metabolism in the use of iron-containing preparations].

    PubMed

    Zaĭtseva, I P; Nasolodin, V V; Zaĭtsev, O N; Gladkikh, I P; Dvorkin, V A

    2012-01-01

    To comparatively evaluate the efficiency of preventive treatment with various iron preparations on copper, manganese, and iron metabolic features in adult athletes. Forty adult highly qualified sambo wrestlers were examined and divided into 4 groups of 10 persons in each. Group 1 athletes took iron-containing Sorbifer Durules in combination with ascorbic acid; Group 2 received Ferro Gradumet Vitamin C; Group 3 had Hemofer and ascorbic acid; Group 4 took ascorbic acid tablets. The latter group served as a control. Blood samples (15-20 ml) to be tested were taken at the beginning and end of 2-week use of iron preparations. The daily balance of iron, copper, and manganese was estimated following 7-day intake of these preparations. The use of iron-containing preparations in combination with ascorbic acid was ascertained to be accompanied by an increment in the plasma concentration of iron and blood corpuscles, indicating an increased need for this biotic and its deficiency in athletes. When the dose of iron was increased in the iron preparations, there was a substantial rise in the excretion of copper, manganese in particular, through the gastrointestinal tract and kidney and a negative balance of these trace elements in the body. Dietary addition of foods containing large amounts of ferrous iron, copper, and manganese is indicated for athletes exposed to higher intensity exercises.

  8. Haemolysis and Perturbations in the Systemic Iron Metabolism of Suckling, Copper-Deficient Mosaic Mutant Mice – An Animal Model of Menkes Disease

    PubMed Central

    Lenartowicz, Małgorzata; Starzyński, Rafał R.; Krzeptowski, Wojciech; Grzmil, Paweł; Bednarz, Aleksandra; Ogórek, Mateusz; Pierzchała, Olga; Staroń, Robert; Gajowiak, Anna; Lipiński, Paweł

    2014-01-01

    The biological interaction between copper and iron is best exemplified by the decreased activity of multicopper ferroxidases under conditions of copper deficiency that limits the availability of iron for erythropoiesis. However, little is known about how copper deficiency affects iron homeostasis through alteration of the activity of other copper-containing proteins, not directly connected with iron metabolism, such as superoxide dismutase 1 (SOD1). This antioxidant enzyme scavenges the superoxide anion, a reactive oxygen species contributing to the toxicity of iron via the Fenton reaction. Here, we analyzed changes in the systemic iron metabolism using an animal model of Menkes disease: copper-deficient mosaic mutant mice with dysfunction of the ATP7A copper transporter. We found that the erythrocytes of these mutants are copper-deficient, display decreased SOD1 activity/expression and have cell membrane abnormalities. In consequence, the mosaic mice show evidence of haemolysis accompanied by haptoglobin-dependent elimination of haemoglobin (Hb) from the circulation, as well as the induction of haem oxygenase 1 (HO1) in the liver and kidney. Moreover, the hepcidin-ferroportin regulatory axis is strongly affected in mosaic mice. These findings indicate that haemolysis is an additional pathogenic factor in a mouse model of Menkes diseases and provides evidence of a new indirect connection between copper deficiency and iron metabolism. PMID:25247420

  9. Characterization of iron metabolism and erythropoiesis in erythrocyte membrane defects and thalassemia traits.

    PubMed

    Sulovska, Lucie; Holub, Dusan; Zidova, Zuzana; Divoka, Martina; Hajduch, Marian; Mihal, Vladimir; Vrbkova, Jana; Horvathova, Monika; Pospisilova, Dagmar

    2016-06-01

    Erythropoiesis is closely related to iron metabolism in a balanced homeostasis. Analyses of diverse erythroid and iron metabolism disorders have shown that disrupted erythropoiesis negatively affects iron homeostasis and vice versa. The aim of this study was to characterize the relationship between erythropoietic activity and iron homeostasis in pediatric patients with erythrocyte membrane defects and thalassemia traits. Selected markers of erythropoietic activity (erythropoietin, soluble transferrin receptor - sTfR and growth differentiation factor 15) and iron status parameters (serum iron, ferritin and hepcidin) were evaluated in pediatric patients with erythrocyte membrane defects and thalassemia traits. The patients with erythrocyte membrane defects and thalassemia traits had altered iron homeostasis due to disturbed erythropoiesis. In comparison with healthy controls, they had a normal to low hepcidin/ferritin ratio and concomitantly elevated sTfR. The findings suggest that pediatric patients with erythrocyte membrane defects and thalassemia traits are more susceptible to iron overload than the general population and that the (hepcidin/ferritin)/sTfR ratio can be used to monitor any worsening of the disease.

  10. Genetic modification of iron metabolism in mice affects the gut microbiota.

    PubMed

    Buhnik-Rosenblau, Keren; Moshe-Belizowski, Shirly; Danin-Poleg, Yael; Meyron-Holtz, Esther G

    2012-10-01

    The composition of the gut microbiota is affected by environmental factors as well as host genetics. Iron is one of the important elements essential for bacterial growth, thus we hypothesized that changes in host iron homeostasis, may affect the luminal iron content of the gut and thereby the composition of intestinal bacteria. The iron regulatory protein 2 (Irp2) and one of the genes mutated in hereditary hemochromatosis Hfe , are both proteins involved in the regulation of systemic iron homeostasis. To test our hypothesis, fecal metal content and a selected spectrum of the fecal microbiota were analyzed from Hfe-/-, Irp2-/- and their wild type control mice. Elevated levels of iron as well as other minerals in feces of Irp2-/- mice compared to wild type and Hfe-/- mice were observed. Interestingly significant variation in the general fecal-bacterial population-patterns was observed between Irp2-/- and Hfe-/- mice. Furthermore the relative abundance of five species, mainly lactic acid bacteria, was significantly different among the mouse lines. Lactobacillus (L.) murinus and L. intestinalis were highly abundant in Irp2-/- mice, Enterococcus faecium species cluster and a species most similar to Olsenella were highly abundant in Hfe-/- mice and L. johnsonii was highly abundant in the wild type mice. These results suggest that deletion of iron metabolism genes in the mouse host affects the composition of its intestinal bacteria. Further studying the relationship between gut microbiota and genetic mutations affecting systemic iron metabolism in human should lead to clinical implications.

  11. Genome-Wide Search for Genes Required for Bifidobacterial Growth under Iron-Limitation

    PubMed Central

    Lanigan, Noreen; Bottacini, Francesca; Casey, Pat G.; O'Connell Motherway, Mary; van Sinderen, Douwe

    2017-01-01

    Bacteria evolved over millennia in the presence of the vital micronutrient iron. Iron is involved in numerous processes within the cell and is essential for nearly all living organisms. The importance of iron to the survival of bacteria is obvious from the large variety of mechanisms by which iron may be acquired from the environment. Random mutagenesis and global gene expression profiling led to the identification of a number of genes, which are essential for Bifidobacterium breve UCC2003 survival under iron-restrictive conditions. These genes encode, among others, Fe-S cluster-associated proteins, a possible ferric iron reductase, a number of cell wall-associated proteins, and various DNA replication and repair proteins. In addition, our study identified several presumed iron uptake systems which were shown to be essential for B. breve UCC2003 growth under conditions of either ferric and/or ferrous iron chelation. Of these, two gene clusters encoding putative iron-uptake systems, bfeUO and sifABCDE, were further characterised, indicating that sifABCDE is involved in ferrous iron transport, while the bfeUO-encoded transport system imports both ferrous and ferric iron. Transcription studies showed that bfeUO and sifABCDE constitute two separate transcriptional units that are induced upon dipyridyl-mediated iron limitation. In the anaerobic gastrointestinal environment ferrous iron is presumed to be of most relevance, though a mutation in the sifABCDE cluster does not affect B. breve UCC2003's ability to colonise the gut of a murine model. PMID:28620359

  12. Red blood cell and iron metabolism during space flight

    NASA Technical Reports Server (NTRS)

    Smith, Scott M.

    2002-01-01

    Space flight anemia is a widely recognized phenomenon in astronauts. Reduction in circulating red blood cells and plasma volume results in a 10% to 15% decrement in circulatory volume. This effect appears to be a normal physiologic adaptation to weightlessness and results from the removal of newly released blood cells from the circulation. Iron availability increases, and (in the few subjects studied) iron stores increase during long-duration space flight. The consequences of these changes are not fully understood.

  13. Red blood cell and iron metabolism during space flight

    NASA Technical Reports Server (NTRS)

    Smith, Scott M.

    2002-01-01

    Space flight anemia is a widely recognized phenomenon in astronauts. Reduction in circulating red blood cells and plasma volume results in a 10% to 15% decrement in circulatory volume. This effect appears to be a normal physiologic adaptation to weightlessness and results from the removal of newly released blood cells from the circulation. Iron availability increases, and (in the few subjects studied) iron stores increase during long-duration space flight. The consequences of these changes are not fully understood.

  14. System analysis of metabolism and the transcriptome in Arabidopsis thaliana roots reveals differential co-regulation upon iron, sulfur and potassium deficiency.

    PubMed

    Forieri, Ilaria; Sticht, Carsten; Reichelt, Michael; Gretz, Norbert; Hawkesford, Malcolm J; Malagoli, Mario; Wirtz, Markus; Hell, Ruediger

    2017-01-01

    Deprivation of mineral nutrients causes significant retardation of plant growth. This retardation is associated with nutrient-specific and general stress-induced transcriptional responses. In this study, we adjusted the external supply of iron, potassium and sulfur to cause the same retardation of shoot growth. Nevertheless, limitation by individual nutrients resulted in specific morphological adaptations and distinct shifts within the root metabolite fingerprint. The metabolic shifts affected key metabolites of primary metabolism and the stress-related phytohormones, jasmonic, salicylic and abscisic acid. These phytohormone signatures contributed to specific nutrient deficiency-induced transcriptional regulation. Limitation by the micronutrient iron caused the strongest regulation and affected 18% of the root transcriptome. Only 130 genes were regulated by all nutrients. Specific co-regulation between the iron and sulfur metabolic routes upon iron or sulfur deficiency was observed. Interestingly, iron deficiency caused regulation of a different set of genes of the sulfur assimilation pathway compared with sulfur deficiency itself, which demonstrates the presence of specific signal-transduction systems for the cross-regulation of the pathways. Combined iron and sulfur starvation experiments demonstrated that a requirement for a specific nutrient can overrule this cross-regulation. The comparative metabolomics and transcriptomics approach used dissected general stress from nutrient-specific regulation in roots of Arabidopsis. © 2016 John Wiley & Sons Ltd.

  15. [Effect of hepcidin on iron metabolism in athletes].

    PubMed

    Domínguez, Raúl; Garnacho-Castaño, Manuel Vicente; Maté-Muñoz, José Luis

    2014-12-01

    The role of iron in the human body is essential, and athletes must always try to keep an adequate iron status. Hepcidin is proposed as the main hormone responsible for the control of iron reserves in the body, given its ability to induce degradation of ferroportin. The action of hepcidin on ferroportin leads to a decreased dietary iron absorption, as well as to a decrease in macrophages. Several factors such as the iron status, the amount of dietary iron, the inflammation, the hypoxia, the testosterone and the physical exercise have been pointed out as affecting the synthesis of hepcidin. This study has aimed at analysing the researches on hepcidin response to exercise, as well as designing a specific strategy to prevent a potential ferropenic status in athletes. The main findings are an association between exercise at an intensity over 65% VO2max and transient increases in the synthesis of hepcidin, and a possible regulatory effect of intermittent hypoxic stimuli in the early post-exercise recovery. Other factors such as the training volume, sex, kind of exercise or the type of surface where the training takes place do not seem to affect the response of hepcidin to exercise.

  16. Clinical Consequences of New Insights in the Pathophysiology of Disorders of Iron and Heme Metabolism.

    PubMed

    Brittenham, Gary M.; Weiss, Günter; Brissot, Pierre; Lainé, Fabrice; Guillygomarc'h, Anne; Guyader, Dominique; Moirand, Romain; Deugnier, Yves

    2000-01-01

    This review examines the clinical consequences for the practicing hematologist of remarkable new insights into the pathophysiology of disorders of iron and heme metabolism. The familiar proteins of iron transport and storage-transferrin, transferrin receptor, and ferritin-have recently been joined by a host of newly identified proteins that play critical roles in the molecular management of iron homeostasis. These include the iron-regulatory proteins (IRP-1 and -2), HFE (the product of the HFE gene that is mutated in most patients with hereditary hemochromatosis), the divalent metal transporter (DMT1), transferrin receptor 2, ceruloplasmin, hephaestin, the "Stimulator of Fe Transport" (SFT), frataxin, ferroportin 1 and others. The growing appreciation of the roles of these newly identified proteins has fundamental implications for the clinical understanding and laboratory evaluation of iron metabolism and its alterations with iron deficiency, iron overload, infection, and inflammation. In Section I, Dr. Brittenham summarizes current concepts of body and cellular iron supply and storage and reviews new means of evaluating the full range of body iron stores including genetic testing for mutations in the HFE gene, measurement of serum ferritin iron, transferrin receptor, reticulocyte hemoglobin content and measurement of tissue iron by computed tomography, magnetic resonance imaging and magnetic susceptometry using superconducting quantum interference device (SQUID) instrumentation. In Section II, Dr. Weiss discusses the improved understanding of the molecular mechanisms underlying alterations in iron metabolism due to chronic inflammatory disorders. The anemia of chronic disorders remains the most common form of anemia found in hospitalized patients. The network of interactions that link iron metabolism with cellular immune effector functions involving pro- and anti-inflammatory cytokines, acute phase proteins and oxidative stress is described, with an emphasis on

  17. [Influence of dinitrosyl iron complexes on blood metabolism in rats with thermal trauma].

    PubMed

    Martusevich, A K; Solov'eva, A G; Peteriagin, S P; Davydiuk, A V

    2014-01-01

    The dynamics in the oxidative and energy metabolism and enzyme systems of blood detoxification in animals with thermal trauma injected with dinitrosyl iron complexes was explored. The positive effect of dinitrosyl iron complexes on the state of blood pro- and antioxidant systems in animals with experimental thermal injury having profound oxidative stress is shown. This effect is observed as a considerable reduction of the intensity (normalization) of lipid peroxidation processes against significant elevation of antioxidant potential of blood plasma. This tendency was also fixed in erythrocyte membranes. It is also stated, that dinitrosyl iron complexes clearly normalized erythrocyte energy metabolism already by the 3rd day after trauma. In addition, infusions of dinitrosyl iron complexes caused marked stimulation of aldehyde dehydrogenase catalytic activity in burned rats via mechanism, associated with enzyme detoxification properties.

  18. Studying disorders of vertebrate iron and heme metabolism using zebrafish

    PubMed Central

    van der Vorm, Lisa N.; Paw, Barry H.

    2017-01-01

    Iron is a crucial component of heme- and iron-sulfur clusters, involved in vital cellular functions such as oxygen transport, DNA synthesis, and respiration. Both excess and insufficient levels of iron and heme-precursors cause human disease, such as iron-deficiency anemia, hemochromatosis, and porphyrias. Hence, their levels must be tightly regulated, requiring a complex network of transporters and feedback mechanisms. The use of zebrafish to study these pathways and the underlying genetics offers many advantages, among others their optical transparency, ex-vivo development and high genetic and physiological conservations. This chapter first reviews well-established methods, such as large-scale mutagenesis screens that have led to the initial identification of a series of iron and heme transporters and the generation of a variety of mutant lines. Other widely used techniques are based on injection of RNA, including complementary morpholino knockdown and gene overexpression. In addition, we highlight several recently developed approaches, most notably endonuclease-based gene knockouts such as TALENs or the CRISPR/Cas9 system that have been used to study how loss of function can induce human disease phenocopies in zebrafish. Rescue by chemical complementation with iron-based compounds or small molecules can subsequently be used to confirm causality of the genetic defect for the observed phenotype. All together, zebrafish have proven to be – and will continue to serve as an ideal model to advance our understanding of the pathogenesis of human iron and heme-related diseases and to develop novel therapies to treat these conditions. PMID:28129844

  19. Effects of Iron on Vitamin D Metabolism: A Systematic Review

    PubMed Central

    Azizi-Soleiman, Fatemeh; Vafa, Mohammadreza; Abiri, Behnaz; Safavi, Morteza

    2016-01-01

    Vitamin D is a prohormone nutrient, which is involved in skeletal and extra-skeletal functions. Iron is another essential nutrient that is necessary for the production of red blood cells and oxygen transport. This element plays important roles in enzymatic systems including those required for Vitamin D activation. To the best of our knowledge, there is no exclusive review on the relationship between iron deficiency anemia (IDA), as the most prevalent type of anemia, and Vitamin D deficiency and the effect of recovery from iron deficiency on Vitamin D status. The aim of this study was to conduct a systematic search of observational and clinical trials in this field. The databases of PubMed, ProQuest, Cochrane Library, ISI Web of Knowledge, and SCOPUS were searched comprehensively. English-language human studies conducted on iron deficient patients or interventions on the effect of iron therapy on Vitamin D were extracted (n = 10). Our initial search yielded 938 articles. A total of 23 papers met the inclusion criteria. Thirteen studies were excluded because they were not relevant or not defining anemia types. The final analysis was performed on ten articles (3 cross-sectional and 7 interventional studies). Observational data indicated a positive relationship between iron status and Vitamin D, while trials did not support the effectiveness of iron supplementation on improving Vitamin D status. The mechanism underlying this association may involve the reduction of the activation of hydroxylases that yield calcitriol. Future randomized controlled trials with large sample sizes and proper designs are needed to highlight underlying mechanisms. PMID:28028427

  20. Studying disorders of vertebrate iron and heme metabolism using zebrafish.

    PubMed

    van der Vorm, Lisa N; Paw, Barry H

    2017-01-01

    Iron is a crucial component of heme- and iron-sulfur clusters, involved in vital cellular functions such as oxygen transport, DNA synthesis, and respiration. Both excess and insufficient levels of iron and heme-precursors cause human disease, such as iron-deficiency anemia, hemochromatosis, and porphyrias. Hence, their levels must be tightly regulated, requiring a complex network of transporters and feedback mechanisms. The use of zebrafish to study these pathways and the underlying genetics offers many advantages, among others their optical transparency, ex-vivo development and high genetic and physiological conservations. This chapter first reviews well-established methods, such as large-scale mutagenesis screens that have led to the initial identification of a series of iron and heme transporters and the generation of a variety of mutant lines. Other widely used techniques are based on injection of RNA, including complementary morpholino knockdown and gene overexpression. In addition, we highlight several recently developed approaches, most notably endonuclease-based gene knockouts such as TALENs or the CRISPR/Cas9 system that have been used to study how loss of function can induce human disease phenocopies in zebrafish. Rescue by chemical complementation with iron-based compounds or small molecules can subsequently be used to confirm causality of the genetic defect for the observed phenotype. All together, zebrafish have proven to be - and will continue to serve as an ideal model to advance our understanding of the pathogenesis of human iron and heme-related diseases and to develop novel therapies to treat these conditions. Copyright © 2017 Elsevier Inc. All rights reserved.

  1. Modeling iron limitation of primary production in the coastal Gulf of Alaska

    NASA Astrophysics Data System (ADS)

    Fiechter, Jerome; Moore, Andrew M.; Edwards, Christopher A.; Bruland, Kenneth W.; Di Lorenzo, Emanuele; Lewis, Craig V. W.; Powell, Thomas M.; Curchitser, Enrique N.; Hedstrom, Kate

    2009-12-01

    A lower trophic level NPZD ecosystem model with explicit iron limitation on nutrient uptake is coupled to a three-dimensional coastal ocean circulation model to investigate the regional ecosystem dynamics of the northwestern coastal Gulf of Alaska (CGOA). Iron limitation is included in the NPZD model by adding governing equations for two micro-nutrient compartments: dissolved iron and phytoplankton-associated iron. The model has separate budgets for nitrate (the limiting macro-nutrient in the standard NPZD model) and for iron, with iron limitation on nitrate uptake being imposed as a function of the local phytoplankton realized Fe:C ratio. While the ecosystem model represents a simple approximation of the complex lower trophic level ecosystem of the northwestern CGOA, simulated chlorophyll concentrations reproduce the main characteristics of the spring bloom, high shelf primary production, and "high-nutrient, low-chlorophyll" (HNLC) environment offshore. Over the 1998-2004 period, model-data correlations based on spatially averaged, monthly mean chlorophyll concentrations are on average 0.7, with values as high as 0.9 and as low as 0.5 for individual years. The model also provides insight on the importance of micro- and macro-nutrient limitation on the shelf and offshore, with the shelfbreak region acting as a transition zone where both nitrate and iron availability significantly impact phytoplankton growth. Overall, the relative simplicity of the ecosystem model provides a useful platform to perform long-term simulations to investigate the seasonal and interannual CGOA ecosystem variability, as well as to conduct sensitivity studies to evaluate the robustness of simulated fields to ecosystem model parameterization and forcing. The ability of the model to differentiate between nitrate-limited, and iron-limited growth conditions, and to identify their spatial and temporal occurrences, is also a first step towards understanding the role of environmental gradients in

  2. MYB10 and MYB72 Are Required for Growth under Iron-Limiting Conditions

    PubMed Central

    Palmer, Christine M.; Hindt, Maria N.; Schmidt, Holger; Clemens, Stephan; Guerinot, Mary Lou

    2013-01-01

    Iron is essential for photosynthesis and is often a limiting nutrient for plant productivity. Plants respond to conditions of iron deficiency by increasing transcript abundance of key genes involved in iron homeostasis, but only a few regulators of these genes have been identified. Using genome-wide expression analysis, we searched for transcription factors that are induced within 24 hours after transferring plants to iron-deficient growth conditions. Out of nearly 100 transcription factors shown to be up-regulated, we identified MYB10 and MYB72 as the most highly induced transcription factors. Here, we show that MYB10 and MYB72 are functionally redundant and are required for plant survival in alkaline soil where iron availability is greatly restricted. myb10myb72 double mutants fail to induce transcript accumulation of the nicotianamine synthase gene NAS4. Both myb10myb72 mutants and nas4-1 mutants have reduced iron concentrations, chlorophyll levels, and shoot mass under iron-limiting conditions, indicating that these genes are essential for proper plant growth. The double myb10myb72 mutant also showed nickel and zinc sensitivity, similar to the nas4 mutant. Ectopic expression of NAS4 rescues myb10myb72 plants, suggesting that loss of NAS4 is the primary defect in these plants and emphasizes the importance of nicotianamine, an iron chelator, in iron homeostasis. Overall, our results provide evidence that MYB10 and MYB72 act early in the iron-deficiency regulatory cascade to drive gene expression of NAS4 and are essential for plant survival under iron deficiency. PMID:24278034

  3. Chronic Administration of 2-Acetylaminofluorene Alters the Cellular Iron Metabolism in Rat Liver

    PubMed Central

    Shpyleva, Svitlana I.; Muskhelishvili, Levan; Tryndyak, Volodymyr P.; Koturbash, Igor; Tokar, Erik J.; Waalkes, Michael P.; Beland, Frederick A.; Pogribny, Igor P.

    2011-01-01

    Dysregulated intracellular iron homeostasis has been found not only in rodent and human hepatocellular carcinomas but also in several preneoplastic pathological states associated with hepatocarcinogenesis; however, the precise underlying mechanisms of metabolic iron disturbances in preneoplastic liver and the role of these disturbances remain unexplored. In the present study, using an in vivo model of rat hepatocarcinogenesis induced by 2-acetylaminofluorene, we found extensive alterations in cellular iron metabolism at preneoplastic stages of liver carcinogenesis. These were characterized by a substantial decrease in the levels of cytoplasmic non-heme iron in foci of initiated hepatocytes and altered expression of the major genes responsible for the proper maintenance of intracellular iron homeostasis. Gene expression analysis revealed that the decreased intracellular levels of iron in preneoplastic foci might be attributed to increased iron export from the cells, driven by upregulation of ferroportin (Fpn1), the only known non-heme iron exporter. Likewise, increased Fpn1 gene expression was found in vitro in TRL1215 rat liver cells with an acquired malignant phenotype, suggesting that upregulation of Fpn1 might be a specific feature of neoplastically transformed cells. Other changes observed in vivo included the downregulation of hepcidin (Hamp) gene, a key regulator of Fpn1, and this was accompanied by decreased levels of CCAAT/enhancer binding proteins alpha and beta, especially at the Hamp promoter. In conclusion, our results demonstrate the significance of altered intracellular iron metabolism in the progression of liver carcinogenesis and suggest that correction of these alterations could possibly affect liver cancer development. PMID:21785164

  4. Iron deficiency affects nitrogen metabolism in cucumber (Cucumis sativus L.) plants

    PubMed Central

    2012-01-01

    Background Nitrogen is a principal limiting nutrient in plant growth and development. Among factors that may limit NO3- assimilation, Fe potentially plays a crucial role being a metal cofactor of enzymes of the reductive assimilatory pathway. Very few information is available about the changes of nitrogen metabolism occurring under Fe deficiency in Strategy I plants. The aim of this work was to study how cucumber (Cucumis sativus L.) plants modify their nitrogen metabolism when grown under iron deficiency. Results The activity of enzymes involved in the reductive assimilation of nitrate and the reactions that produce the substrates for the ammonium assimilation both at root and at leaf levels in Fe-deficient cucumber plants were investigated. Under Fe deficiency, only nitrate reductase (EC 1.7.1.1) activity decreased both at the root and leaf level, whilst for glutamine synthetase (EC 6.3.1.2) and glutamate synthase (EC 1.4.1.14) an increase was found. Accordingly, the transcript analysis for these enzymes showed the same behaviour except for root nitrate reductase which increased. Furthermore, it was found that amino acid concentration greatly decreased in Fe-deficient roots, whilst it increased in the corresponding leaves. Moreover, amino acids increased in the xylem sap of Fe-deficient plants. Conclusions The data obtained in this work provided new insights on the responses of plants to Fe deficiency, suggesting that this nutritional disorder differentially affected N metabolism in root and in leaf. Indeed under Fe deficiency, roots respond more efficiently, sustaining the whole plant by furnishing metabolites (i.e. aa, organic acids) to the leaves. PMID:23057967

  5. Iron deficiency affects nitrogen metabolism in cucumber (Cucumis sativus L.) plants.

    PubMed

    Borlotti, Andrea; Vigani, Gianpiero; Zocchi, Graziano

    2012-10-11

    Nitrogen is a principal limiting nutrient in plant growth and development. Among factors that may limit NO3- assimilation, Fe potentially plays a crucial role being a metal cofactor of enzymes of the reductive assimilatory pathway. Very few information is available about the changes of nitrogen metabolism occurring under Fe deficiency in Strategy I plants. The aim of this work was to study how cucumber (Cucumis sativus L.) plants modify their nitrogen metabolism when grown under iron deficiency. The activity of enzymes involved in the reductive assimilation of nitrate and the reactions that produce the substrates for the ammonium assimilation both at root and at leaf levels in Fe-deficient cucumber plants were investigated. Under Fe deficiency, only nitrate reductase (EC 1.7.1.1) activity decreased both at the root and leaf level, whilst for glutamine synthetase (EC 6.3.1.2) and glutamate synthase (EC 1.4.1.14) an increase was found. Accordingly, the transcript analysis for these enzymes showed the same behaviour except for root nitrate reductase which increased. Furthermore, it was found that amino acid concentration greatly decreased in Fe-deficient roots, whilst it increased in the corresponding leaves. Moreover, amino acids increased in the xylem sap of Fe-deficient plants. The data obtained in this work provided new insights on the responses of plants to Fe deficiency, suggesting that this nutritional disorder differentially affected N metabolism in root and in leaf. Indeed under Fe deficiency, roots respond more efficiently, sustaining the whole plant by furnishing metabolites (i.e. aa, organic acids) to the leaves.

  6. New perspectives on the molecular basis of the interaction between oxygen homeostasis and iron metabolism

    PubMed Central

    Recalcati, Stefania; Gammella, Elena; Cairo, Gaetano

    2015-01-01

    Oxygen and iron are two elements closely related from a (bio)chemical point of view. Moreover, they share the characteristic of being indispensable for life, while also being potentially toxic. Therefore, their level is strictly monitored, and sophisticated pathways have evolved to face variations in either element. In addition, the expression of proteins involved in iron and oxygen metabolism is mainly controlled by a complex interplay of proteins that sense both iron levels and oxygen availability (ie, prolyl hydroxylases, hypoxia inducible factors, and iron regulatory proteins), and in turn activate feedback mechanisms to re-establish homeostasis. In this review, we describe how cells and organisms utilize these intricate networks to regulate responses to changes in oxygen and iron levels. We also explore the role of these pathways in some pathophysiological settings. PMID:27774486

  7. The complex interplay of iron metabolism, reactive oxygen species, and reactive nitrogen species: insights into the potential of various iron therapies to induce oxidative and nitrosative stress.

    PubMed

    Koskenkorva-Frank, Taija S; Weiss, Günter; Koppenol, Willem H; Burckhardt, Susanna

    2013-12-01

    Production of minute concentrations of superoxide (O2(*-)) and nitrogen monoxide (nitric oxide, NO*) plays important roles in several aspects of cellular signaling and metabolic regulation. However, in an inflammatory environment, the concentrations of these radicals can drastically increase and the antioxidant defenses may become overwhelmed. Thus, biological damage may occur owing to redox imbalance-a condition called oxidative and/or nitrosative stress. A complex interplay exists between iron metabolism, O2(*-), hydrogen peroxide (H2O2), and NO*. Iron is involved in both the formation and the scavenging of these species. Iron deficiency (anemia) (ID(A)) is associated with oxidative stress, but its role in the induction of nitrosative stress is largely unclear. Moreover, oral as well as intravenous (iv) iron preparations used for the treatment of ID(A) may also induce oxidative and/or nitrosative stress. Oral administration of ferrous salts may lead to high transferrin saturation levels and, thus, formation of non-transferrin-bound iron, a potentially toxic form of iron with a propensity to induce oxidative stress. One of the factors that determine the likelihood of oxidative and nitrosative stress induced upon administration of an iv iron complex is the amount of labile (or weakly-bound) iron present in the complex. Stable dextran-based iron complexes used for iv therapy, although they contain only negligible amounts of labile iron, can induce oxidative and/or nitrosative stress through so far unknown mechanisms. In this review, after summarizing the main features of iron metabolism and its complex interplay with O2(*-), H2O2, NO*, and other more reactive compounds derived from these species, the potential of various iron therapies to induce oxidative and nitrosative stress is discussed and possible underlying mechanisms are proposed. Understanding the mechanisms, by which various iron formulations may induce oxidative and nitrosative stress, will help us

  8. Drug discovery strategies in the field of tumor energy metabolism: Limitations by metabolic flexibility and metabolic resistance to chemotherapy.

    PubMed

    Amoedo, N D; Obre, E; Rossignol, R

    2017-02-16

    The search for new drugs capable of blocking the metabolic vulnerabilities of human tumors has now entered the clinical evaluation stage, but several projects already failed in phase I or phase II. In particular, very promising in vitro studies could not be translated in vivo at preclinical stage and beyond. This was the case for most glycolysis inhibitors that demonstrated systemic toxicity. A more recent example is the inhibition of glutamine catabolism in lung adenocarcinoma that failed in vivo despite a strong addiction of several cancer cell lines to glutamine in vitro. Such contradictory findings raised several questions concerning the optimization of drug discovery strategies in the field of cancer metabolism. For instance, the cell culture models in 2D or 3D might already show strong limitations to mimic the tumor micro- and macro-environment. The microenvironment of tumors is composed of cancer cells of variegated metabolic profiles, supporting local metabolic exchanges and symbiosis, but also of immune cells and stroma that further interact with and reshape cancer cell metabolism. The macroenvironment includes the different tissues of the organism, capable of exchanging signals and fueling the tumor 'a distance'. Moreover, most metabolic targets were identified from their increased expression in tumor transcriptomic studies, or from targeted analyses looking at the metabolic impact of particular oncogenes or tumor suppressors on selected metabolic pathways. Still, very few targets were identified from in vivo analyses of tumor metabolism in patients because such studies are difficult and adequate imaging methods are only currently being developed for that purpose. For instance, perfusion of patients with [(13)C]-glucose allows deciphering the metabolomics of tumors and opens a new area in the search for effective targets. Metabolic imaging with positron emission tomography and other techniques that do not involve [(13)C] can also be used to evaluate tumor

  9. Phosphate and iron limitation of phytoplankton biomass in Lake Tahoe

    USGS Publications Warehouse

    Chang, Cecily C.Y.; Kuwabara, J.S.; Pasilis, S.P.

    1992-01-01

    Bioassays were carried out to assess the response of inoculated, single-species diatom populations (Cyclotella meneghiniana and Aulocosiera italica) to additions of synthetic chelators and phosphate. A chemical speciation model along with the field data was also used to predict how trace metal speciation, and hence bioavailability, was affected by the chelator additions. Results suggest that phosphate was limiting to phytoplankton biomass. Other solutes, Fe in particular, may also exert controls on biomass. Nitrate limitation seems less likely, although Fe-limiting conditions may have led to an effective N limitation because algae require Fe to carry out nitrate reduction. -from Authors

  10. Iron and phosphorus co-limit nitrogen fixation in the eastern tropical North Atlantic

    NASA Astrophysics Data System (ADS)

    Mills, Matthew M.; Ridame, Celine; Davey, Margaret; La Roche, Julie; Geider, Richard J.

    2004-05-01

    The role of iron in enhancing phytoplankton productivity in high nutrient, low chlorophyll oceanic regions was demonstrated first through iron-addition bioassay experiments and subsequently confirmed by large-scale iron fertilization experiments. Iron supply has been hypothesized to limit nitrogen fixation and hence oceanic primary productivity on geological timescales, providing an alternative to phosphorus as the ultimate limiting nutrient. Oceanographic observations have been interpreted both to confirm and refute this hypothesis, but direct experimental evidence is lacking. We conducted experiments to test this hypothesis during the Meteor 55 cruise to the tropical North Atlantic. This region is rich in diazotrophs and strongly impacted by Saharan dust input. Here we show that community primary productivity was nitrogen-limited, and that nitrogen fixation was co-limited by iron and phosphorus. Saharan dust addition stimulated nitrogen fixation, presumably by supplying both iron and phosphorus. Our results support the hypothesis that aeolian mineral dust deposition promotes nitrogen fixation in the eastern tropical North Atlantic.

  11. Iron Limitation Triggers Early Egress by the Intracellular Bacterial Pathogen Legionella pneumophila

    PubMed Central

    Zheng, Huaixin; VanRheenen, Susan M.; Ghosh, Soma; Cianciotto, Nicholas P.; Isberg, Ralph R.

    2016-01-01

    Legionella pneumophila is an intracellular bacterial pathogen that replicates in alveolar macrophages, causing a severe form of pneumonia. Intracellular growth of the bacterium depends on its ability to sequester iron from the host cell. In the L. pneumophila strain 130b, one mechanism used to acquire this essential nutrient is the siderophore legiobactin. Iron-bound legiobactin is imported by the transport protein LbtU. Here, we describe the role of LbtP, a paralog of LbtU, in iron acquisition in the L. pneumophila strain Philadelphia-1. Similar to LbtU, LbtP is a siderophore transport protein and is required for robust growth under iron-limiting conditions. Despite their similar functions, however, LbtU and LbtP do not contribute equally to iron acquisition. The Philadelphia-1 strain lacking LbtP is more sensitive to iron deprivation in vitro. Moreover, LbtP is important for L. pneumophila growth within macrophages while LbtU is dispensable. These results demonstrate that LbtP plays a dominant role over LbtU in iron acquisition. In contrast, loss of both LbtP and LbtU does not impair L. pneumophila growth in the amoebal host Acanthamoeba castellanii, demonstrating a host-specific requirement for the activities of these two transporters in iron acquisition. The growth defect of the ΔlbtP mutant in macrophages is not due to alterations in growth kinetics. Instead, the absence of LbtP limits L. pneumophila replication and causes bacteria to prematurely exit the host cell. These results demonstrate the existence of a preprogrammed exit strategy in response to iron limitation that allows L. pneumophila to abandon the host cell when nutrients are exhausted. PMID:27185787

  12. Phytoplankton Bloom in Iron Limitation Environment of the Amundsen Polynya, Southern Ocean

    NASA Astrophysics Data System (ADS)

    Park, J.; Gorbunov, M. Y.; Ha, S. Y.; Kim, H. C.; Lee, S.

    2014-12-01

    We have conducted three times intensive Antarctic cruises in the Amundsen Sea (west Antarctic) in early (2010/2011 and 2013/2014) and late (2011/2012) austral summertime. These cruises were conducted as a Korea Polar Research Institute (KOPRI) Amundsen project. Amundsen polynya is one of the most productive Antarctic coastal polynya, and high chlorophylls (observed and satellite induced) were concentrated in polynya center rather than in the edge of polynya both in early and late summer. To examine phytoplankton dynamics in severely iron limited environment, the phytoplankton physiological parameters were measured by Fluorescence Induction and Relaxation (FIRe) system. In addition, we carried out iron assimilation experiments on board to demonstrate that iron enrichment responses of natural phytoplankton assemblages. Possible implications of iron limitation and controlling factors of phytoplankton growth in this polynya system will be discussed.

  13. Insights into the pathophysiology of iron metabolism in Pythium insidiosum infections.

    PubMed

    Zanette, R A; Bitencourt, P E R; Alves, S H; Fighera, R A; Flores, M M; Wolkmer, P; Hecktheuer, P A; Thomas, L R; Pereira, P L; Loreto, E S; Santurio, J M

    2013-03-23

    Pythium insidiosum causes life-threatening disease in mammals. Animals with pythiosis usually develop anemia, and most human patients are reported to have thalassemia and the major consequence of thalassemia, iron overload. Therefore, this study evaluated the iron metabolism in rabbits experimentally infected with P. insidiosum. Ten infected rabbits were divided into two groups: one groups received a placebo, and the other was treated with immunotherapy. Five rabbits were used as negative controls. The hematological and biochemical parameters, including the iron profile, were evaluated. Microcytic hypochromic anemia was observed in the infected animals, and this condition was more accentuated in the untreated group. The serum iron level was decreased, whereas the transferrin level was increased, resulting in low saturation. The level of stainable iron in hepatocytes was markedly decreased in the untreated group. A high correlation was observed between the total iron binding capacity and the lesion size, and this correlation likely confirms the affinity of P. insidiosum for iron. The data from this study corroborate the previous implications of iron in the pathogenesis of pythiosis in humans and animals. Copyright © 2012 Elsevier B.V. All rights reserved.

  14. Glucose metabolism in the Belgrade rat, a model of iron-loading anemia.

    PubMed

    Jia, Xuming; Kim, Jonghan; Veuthey, Tania; Lee, Chih-Hao; Wessling-Resnick, Marianne

    2013-06-15

    The iron-diabetes hypothesis proposes an association between iron overload and glucose metabolism that is supported by a number of epidemiological studies. The prevalence of type 2 diabetes in patients with hereditary hemochromatosis and iron-loading thalassemia supports this hypothesis. The Belgrade rat carries a mutation in the iron transporter divalent metal transporter 1 (DMT1) resulting in iron-loading anemia. In this study, we characterized the glycometabolic status of the Belgrade rat. Belgrade rats displayed normal glycemic control. Insulin signaling and secretion were not impaired, and pancreatic tissue did not incur damage despite high levels of nonheme iron. These findings suggest that loss of DMT1 protects against oxidative damage to the pancreas and helps to maintain insulin sensitivity despite iron overload. Belgrade rats had lower body weight but increased food consumption compared with heterozygous littermates. The unexpected energy balance was associated with increased urinary glucose output. Increased urinary excretion of electrolytes, including iron, was also observed. Histopathological evidence suggests that altered renal function is secondary to changes in kidney morphology, including glomerulosclerosis. Thus, loss of DMT1 appears to protect the pancreas from injury but damages the integrity of kidney structure and function.

  15. Experimental hemochromatosis due to MHC class I HFE deficiency: Immune status and iron metabolism

    PubMed Central

    Bahram, Seiamak; Gilfillan, Susan; Kühn, Lukas C.; Moret, Rémy; Schulze, Johannes B.; Lebeau, Annette; Schümann, Klaus

    1999-01-01

    The puzzling linkage between genetic hemochromatosis and histocompatibility loci became even more so when the gene involved, HFE, was identified. Indeed, within the well defined, mainly peptide-binding, MHC class I family of molecules, HFE seems to perform an unusual yet essential function. As yet, our understanding of HFE function in iron homeostasis is only partial; an even more open question is its possible role in the immune system. To advance on both of these avenues, we report the deletion of HFE α1 and α2 putative ligand binding domains in vivo. HFE-deficient animals were analyzed for a comprehensive set of metabolic and immune parameters. Faithfully mimicking human hemochromatosis, mice homozygous for this deletion develop iron overload, characterized by a higher plasma iron content and a raised transferrin saturation as well as an elevated hepatic iron load. The primary defect could, indeed, be traced to an augmented duodenal iron absorption. In parallel, measurement of the gut mucosal iron content as well as iron regulatory proteins allows a more informed evaluation of various hypotheses regarding the precise role of HFE in iron homeostasis. Finally, an extensive phenotyping of primary and secondary lymphoid organs including the gut provides no compelling evidence for an obvious immune-linked function for HFE. PMID:10557317

  16. Glucose metabolism in the Belgrade rat, a model of iron-loading anemia

    PubMed Central

    Jia, Xuming; Kim, Jonghan; Veuthey, Tania; Lee, Chih-Hao

    2013-01-01

    The iron-diabetes hypothesis proposes an association between iron overload and glucose metabolism that is supported by a number of epidemiological studies. The prevalence of type 2 diabetes in patients with hereditary hemochromatosis and iron-loading thalassemia supports this hypothesis. The Belgrade rat carries a mutation in the iron transporter divalent metal transporter 1 (DMT1) resulting in iron-loading anemia. In this study, we characterized the glycometabolic status of the Belgrade rat. Belgrade rats displayed normal glycemic control. Insulin signaling and secretion were not impaired, and pancreatic tissue did not incur damage despite high levels of nonheme iron. These findings suggest that loss of DMT1 protects against oxidative damage to the pancreas and helps to maintain insulin sensitivity despite iron overload. Belgrade rats had lower body weight but increased food consumption compared with heterozygous littermates. The unexpected energy balance was associated with increased urinary glucose output. Increased urinary excretion of electrolytes, including iron, was also observed. Histopathological evidence suggests that altered renal function is secondary to changes in kidney morphology, including glomerulosclerosis. Thus, loss of DMT1 appears to protect the pancreas from injury but damages the integrity of kidney structure and function. PMID:23599042

  17. Modulation of iron metabolism in aging and in Alzheimer's disease: relevance of the choroid plexus

    PubMed Central

    Mesquita, Sandro D.; Ferreira, Ana C.; Sousa, João C.; Santos, Nadine C.; Correia-Neves, Margarida; Sousa, Nuno; Palha, Joana A.; Marques, Fernanda

    2012-01-01

    Iron is essential for mammalian cellular homeostasis. However, in excess, it promotes free radical formation and is associated with aging-related progressive deterioration and with neurodegenerative disorders such as Alzheimer's disease (AD). There are no mechanisms to excrete iron, which makes iron homeostasis a very tightly regulated process at the level of the intestinal absorption. Iron is believed to reach the brain through receptor-mediated endocytosis of iron-bound transferrin by the brain barriers, the blood-cerebrospinal fluid (CSF) barrier, formed by the choroid plexus (CP) epithelial cells and the blood-brain barrier (BBB) formed by the endothelial cells of the brain capillaries. Importantly, the CP epithelial cells are responsible for producing most of the CSF, the fluid that fills the brain ventricles and the subarachnoid space. Recently, the finding that the CP epithelial cells display all the machinery to locally control iron delivery into the CSF may suggest that the general and progressive senescence of the CP may be at the basis of the impairment of regional iron metabolism, iron-mediated toxicity, and the increase in inflammation and oxidative stress that occurs with aging and, particularly, in AD. PMID:22661928

  18. Orphan nuclear receptor SHP regulates iron metabolism through inhibition of BMP6-mediated hepcidin expression

    PubMed Central

    Kim, Don-Kyu; Kim, Yong-Hoon; Jung, Yoon Seok; Kim, Ki-Sun; Jeong, Jae-Ho; Lee, Yong-Soo; Yuk, Jae-Min; Oh, Byung-Chul; Choy, Hyon E.; Dooley, Steven; Muckenthaler, Martina U.; Lee, Chul-Ho; Choi, Hueng-Sik

    2016-01-01

    Small heterodimer partner (SHP) is a transcriptional corepressor regulating diverse metabolic processes. Here, we show that SHP acts as an intrinsic negative regulator of iron homeostasis. SHP-deficient mice maintained on a high-iron diet showed increased serum hepcidin levels, decreased expression of the iron exporter ferroportin as well as iron accumulation compared to WT mice. Conversely, overexpression of either SHP or AMP-activated protein kinase (AMPK), a metabolic sensor inducing SHP expression, suppressed BMP6-induced hepcidin expression. In addition, an inhibitory effect of AMPK activators metformin and AICAR on BMP6-mediated hepcidin gene expression was significantly attenuated by ablation of SHP expression. Interestingly, SHP physically interacted with SMAD1 and suppressed BMP6-mediated recruitment of the SMAD complex to the hepcidin gene promoter by inhibiting the formation of SMAD1 and SMAD4 complex. Finally, overexpression of SHP and metformin treatment of BMP6 stimulated mice substantially restored hepcidin expression and serum iron to baseline levels. These results reveal a previously unrecognized role for SHP in the transcriptional control of iron homeostasis. PMID:27688041

  19. Restless legs syndrome in Parkinson disease: Clinical characteristics, abnormal iron metabolism and altered neurotransmitters.

    PubMed

    Piao, Ying-Shan; Lian, Teng-Hong; Hu, Yang; Zuo, Li-Jun; Guo, Peng; Yu, Shu-Yang; Liu, Li; Jin, Zhao; Zhao, Hui; Li, Li-Xia; Yu, Qiu-Jin; Wang, Rui-Dan; Chen, Sheng-Di; Chan, Piu; Wang, Xiao-Min; Zhang, Wei

    2017-09-05

    Relationships among clinical characteristics, iron metabolism and neurotransmitters in Parkinson disease (PD) patients with restless legs syndrome (RLS) remains unclear. We divided 218 patients into PD with and with no RLS (PD-RLS and PD-NRLS) groups by RLS-rating scale (RLS-RS) score. Motor and non-motor symptoms were rated by related scales. Iron and related proteins, and neurotransmitters in cerebrospinal fluid (CSF) and serum were measured. PD-RLS frequency was 40.37%. PD-RLS group had longer duration, higher stage and scores of motor symptoms, depression, anxiety, sleep disorders, fatigue and apathy, and increased transferrin and decreased iron, ferritin, dopamine (DA) and 5-hydroxytryptamine (5-HT) in CSF. In CSF of PD-RLS group, RLS-RS score was positively correlated with transferrin level and negatively correlated with iron and ferritin levels; RLS-RS score was negatively correlated with DA and 5-HT levels; transferrin level was negatively correlated with DA and 5-HT levels, and ferritin level was positively correlated with DA level. In serum, PD-RLS group had decreased iron and transferrin levels, which were negatively correlated with RLS-RS score. PD-RLS was common and severer in motor and some non-motor symptoms. Iron deficiency induced by its metabolism dysfunctions in peripheral and central systems might cause PD-RLS through decreasing brain DA and 5-HT.

  20. Seasonally dependent iron limitation of nitrogen fixation in tropical forests of karst landscapes

    NASA Astrophysics Data System (ADS)

    Winbourne, J. B.; Brewer, S.; Houlton, B. Z.

    2015-12-01

    Limestone tropical forests in karst topography are one of the most poorly studied ecosystems on Earth, and has been substantially cleared by human activities throughout much of Central America. This ecosystem is noted for its high level of plant productivity, biomass, endemism and biological diversity compared to nearby neighboring tropical forests on volcanic rock substrates (Brewer et al. 2002). A question remains as to how limestone tropical forests are able to maintain the high nutrient demands of plant photosynthesis and tree biomass growth. Here, we demonstrate that rates of nitrogen (N) fixation are higher in limestone versus volcanic soil substrates, with direct evidence for the emergence of seasonally dependent iron limitation of N fixation in limestone tropical forest. N fixation rates showed a three-fold increase in response to iron additions, especially during the wet season when N demands of the forest trees are highest. In contrast, adjacent forests growing on the more classical acidic volcanic soils showed no response to iron or other nutrient additions. Biologically available pools of iron were exceedingly low in the limestone forest site, consistent with the complexation of iron under high pH conditions. Biological acquisition of iron, as measured by the concentration of iron chelating compounds (i.e. siderophores), provided additional evidence for iron limitation of microbial processes in limestone tropical forests, where concentrations were six times higher than those at the volcanic site. Our results suggest that the functioning of limestone tropical forest is strongly regulated by interactions between iron, soil pH, and N cycling.

  1. Simultaneous growth on citrate reduces the effects of iron limitation during toluene degradation in Pseudomonas.

    PubMed

    Dinkla, I J T; Janssen, D B

    2003-01-01

    Rhizoremediation has been suggested as an attractive bioremediation strategy for the effective breakdown of pollutants in soil. The presence of plant root exudates such as organic acids, sugars, and amino acids that may serve as carbon sources or biosynthetic building blocks and the limited bioavailability of iron may influence the degradation of pollutants in the rhizosphere. To test the effect of such compounds on hydrocarbon degradation, trace concentrations of yeast extract or mixtures of organic acids and amino acids were added to continuous cultures of Pseudomonas putida mt2 and P. putida WCS358 (TOL) growing on toluene. By addition of these compounds increased growth yields and higher specific growth rates on toluene were obtained. The effects of iron limitation on the substrate utilization pattern of both strains were tested by growing the strains on a mixture of toluene and the readily degradable carbon source citrate while the iron concentration was varied. Simultaneous use of both substrates under carbon-limited as well as iron-limited conditions was observed. Growth yields were less reduced and iron requirement was lower during iron-limited growth in the toluene + citrate grown cultures compared to cultures in which toluene was used as the sole carbon source. The kinetic properties of the cells for toluene degradation were less hampered by the lack of iron when citrate was used as an additional carbon source. The results indicate that the availability of low concentrations of natural organic compounds, such as produced in the rhizosphere, may positively influence the degradative performance of hydrocarbon-degrading bacteria.

  2. Sleep Disorders in Parkinson’s Disease: Clinical Features, Iron Metabolism and Related Mechanism

    PubMed Central

    Yu, Shu-yang; Sun, Li; Liu, Zhuo; Huang, Xi-yan; Zuo, Li-jun; Cao, Chen-jie; Zhang, Wei; Wang, Xiao-min

    2013-01-01

    Objective To investigate clinical features, iron metabolism and neuroinflammation in Parkinson’s disease (PD) patients with sleep disorders (SD). Methods 211 PD patients were evaluated by Pittsburgh Sleep Quality Index (PSQI) and a body of scales for motor symptoms and non-motor symptoms. 94 blood and 38 cerebral spinal fluid (CSF) samples were collected and iron and its metabolism-relating proteins, neuroinflammatory factors were detected and analyzed. Results 136 cases (64.5%) of PD patients were accompanied by SD. Factor with the highest score in PSQI was daytime dysfunction. Depression, restless leg syndrome, autonomic symptoms and fatigue contributed 68.6% of the variance of PSQI score. Transferrin level in serum and tumor necrosis factor–α level in CSF decreased, and the levels of iron, transferrin, lactoferrin and prostaglandin E2 in CSF increased in PD patients with SD compared with those without SD. In CSF, prostaglandin E2 level was positively correlated with the levels of transferrin and lactoferrin, and tumor necrosis factor–α level was negatively correlated with the levels of iron, transferrin and lactoferrin in CSF. Conclusions Depression, restless leg syndrome, autonomic disorders and fatigue are the important contributors for the poor sleep in PD patients. Abnormal iron metabolism may cause excessive iron deposition in brain and be related to SD in PD patients through dual potential mechanisms, including neuroinflammation by activating microglia and neurotoxicity by targeting neurons. Hence, inhibition of iron deposition-related neuroinflammation and neurotoxicity may cast a new light for drug development for SD in PD patients. PMID:24376607

  3. Stoichiometry, Metabolism and Nutrient Limitation Across the Periodic Table in Natural Flowing-Water Chemostats

    NASA Astrophysics Data System (ADS)

    Cohen, M. J.; Nifong, R. L.; Kurz, M. J.; Cropper, W. P.; Martin, J. B.

    2014-12-01

    Relative supplies of macro and micronutrients (C,N,P, various metals), along with light and water, controls ecosystem metabolism, trophic energy transfer and community structure. Here we test the hypothesis, using measurements from 41 spring-fed rivers in Florida, that tissue stoichiometry indicates autotroph nutrient limitation status. Low variation in discharge, temperature and chemical composition within springs, but large variation across springs creates an ideal setting to assess the relationship between limitation and resource supply. Molar N:P ranges from 0.4 to 90, subjecting autotrophs to dramatically different nutrient supply. Over this gradient, species-specific autotroph tissue C:N:P ratios are strictly homeostatic, and with no evidence that nutrient supply affects species composition. Expanding to include 19 metals and micronutrients revealed autotrophs are more plastic in response to micronutrient variation, particularly for iron and manganese whose supply fluxes are small compared to biotic demand. Using a Droop model modified to reflect springs conditions (benthic production, light limitation, high hydraulic turnover), we show that tissue stoichiometry transitions from homeostatic to plastic with the onset of nutrient limitation, providing a potentially powerful new tool for predicting nutrient limitation and thus eutrophication in flowing waters.

  4. Estrogen contributes to regulating iron metabolism through governing ferroportin signaling via an estrogen response element.

    PubMed

    Qian, Yi; Yin, Chunyang; Chen, Yue; Zhang, Shuping; Jiang, Li; Wang, Fudi; Zhao, Meirong; Liu, Sijin

    2015-05-01

    Ferroportin (FPN) is the only known iron exporter in mammalian cells, and is universally expressed in most types of cells. FPN signaling plays a crucial role in maintaining iron homeostasis through governing the level of intracellular iron. Serum iron storage is conversely related with the estrogen level in the female bodies, and women in post-menopause are possibly subjected to iron retention. However, the potential effects of estrogen on iron metabolism are not clearly understood. Here, FPN mRNA transcription in all selected estrogen receptor positive (ER+) cells was significantly reduced upon 17β-estradiol (E2) treatment; and this inhibitory effect could be attenuated by ER antagonist tamoxifen. Likewise, in murine bone marrow-derived macrophages (BMDMs), FPN reduction with elevated intracellular iron (reflected by increased ferritin) was observed in response to E2; however, ferritin level barely responded to E2 in FPN-null BMDMs. The observation of inhibition of FPN mRNA expression was not replicated in ER(-) cells upon E2. A functional estrogen response element (ERE) was identified within the promoter of FPN, and this ERE was responsible for the suppressive effect of E2 on FPN expression. Moreover, ovariectomized (OVX) and sham-operated (SHAM) mice were used to further confirm the in vitro finding. The expression of hepatic FPN was induced in OVX mice, compared to that in the SHAM mice. Taken together, our results demonstrated that estrogen is involved in regulating FPN expression through a functional ERE on its promoter, providing additional insights into a vital role of estrogen in iron metabolism.

  5. The Thermodynamics and Kinetics of Iron Redox Metabolism in Hot Spring Ecosystems

    NASA Astrophysics Data System (ADS)

    St Clair, B. E.; Shock, E.

    2012-12-01

    The oxidation of ferrous iron and the reduction of ferric minerals are widespread sources of metabolic energy for microorganisms in hot spring ecosystems. How these energy sources are used can be determined by combining thermodynamic calculations with kinetic experiments. By measuring concentrations of ferrous iron, total iron, pH, dissolved hydrogen and oxygen, as well as temperature and many other parameters in hot springs at Yellowstone National Park, we can calculate chemical affinities of iron redox reactions, which reveal the maximum amount of energy an organism can derive from the catalysis of a given reaction. Iron redox reactions typically involve protons, and energy yields are greatly affected by pH. The heterotrophic reduction of ferric minerals typically consumes a large stoichiometric number of protons compared to the other components. For example, the reduction of hematite (Fe2O3), to ferrous ions with glucose requires 48 moles of protons per mole of glucose oxidized. Calculations indicate this proton requirement increases the energy yield with decreasing pH. The opposite trend is observed for iron oxidation reactions. The autotrophic oxidation of ferrous iron to hematite releases four protons per mole of hematite formed. As a consequence, the energy yield from this reaction decreases with decreasing pH. How effectively energy sources are tapped depends on the efficiencies of microbial metabolism compared with the rates of abiotic mechanisms for the same redox reactions. Experiments were performed across the pH spectrum on isolated sediments incubated in situ and assayed for biological oxidation and reduction by monitoring changing concentrations of Fe2+. In hot springs with pH values <2, particularly those with large gas flows, abiological reduction is rapid. Biological reduction, nevertheless, occasionally proceeded faster than the abiological rate. The quick abiological reduction rate, combined with the high solubility of ferrous iron, leads to

  6. Mitochondria: A crossroads for lipid metabolism defect in neurodegeneration with brain iron accumulation diseases.

    PubMed

    Aoun, Manar; Tiranti, Valeria

    2015-06-01

    Neurodegeneration with brain iron accumulation (NBIA) comprises a group of brain iron deposition syndromes that lead to mixed extrapyramidal features and progressive dementia. Exact pathologic mechanism of iron deposition in NBIA remains unknown. However, it is becoming increasingly evident that many neurodegenerative diseases are hallmarked by metabolic dysfunction that often involves altered lipid profile. Among the identified disease genes, four encode for proteins localized in mitochondria, which are directly or indirectly implicated in lipid metabolism: PANK2, CoASY, PLA2G6 and C19orf12. Mutations in PANK2 and CoASY, both implicated in CoA biosynthesis that acts as a fatty acyl carrier, lead, respectively, to PKAN and CoPAN forms of NBIA. Mutations in PLA2G6, which plays a key role in the biosynthesis and remodeling of membrane phospholipids including cardiolipin, lead to PLAN. Mutations in C19orf12 lead to MPAN, a syndrome similar to that caused by mutations in PANK2 and PLA2G6. Although the function of C19orf12 is largely unknown, experimental data suggest its implication in mitochondrial homeostasis and lipid metabolism. Altogether, the identified mutated proteins localized in mitochondria and associated with different NBIA forms support the concept that dysfunctions in mitochondria and lipid metabolism play a crucial role in the pathogenesis of NBIA. This article is part of a Directed Issue entitled: Energy Metabolism Disorders and Therapies.

  7. Effects of Iron Overload on Ascorbic Acid Metabolism*

    PubMed Central

    Wapnick, A. A.; Lynch, S. R.; Krawitz, P.; Seftel, H. C.; Charlton, R. W.; Bothwell, T. H.

    1968-01-01

    Studies of the ascorbic acid status in two subjects with idiopathic haemochromatosis and in 12 with transfusional siderosis showed that all had decreased levels of white cell ascorbic acid. The urinary excretion of ascorbic acid was also diminished in those subjects in whom such measurements were made. The administration of ascorbic acid was followed by only a small rise in the urinary ascorbic acid output, while the oxalic acid levels (measured in two subjects) showed a significant rise. These findings resemble those described in siderotic Bantu, and support the thesis that increased iron stores lead to irreversible oxidation of some of the available ascorbic acid. PMID:5673960

  8. Effects of iron overload on ascorbic acid metabolism.

    PubMed

    Wapnick, A A; Lynch, S R; Krawitz, P; Seftel, H C; Charlton, R W; Bothwell, T H

    1968-09-21

    Studies of the ascorbic acid status in two subjects with idiopathic haemochromatosis and in 12 with transfusional siderosis showed that all had decreased levels of white cell ascorbic acid. The urinary excretion of ascorbic acid was also diminished in those subjects in whom such measurements were made. The administration of ascorbic acid was followed by only a small rise in the urinary ascorbic acid output, while the oxalic acid levels (measured in two subjects) showed a significant rise. These findings resemble those described in siderotic Bantu, and support the thesis that increased iron stores lead to irreversible oxidation of some of the available ascorbic acid.

  9. [Analysis of the influence of iron overload in glucose metabolism in thalassemia major patients].

    PubMed

    Liang, L Y; Lao, W Q; Meng, Z; Zhang, L N; Hou, L L; Ou, H; Liu, Z L; He, Z W; Luo, X Y; Fang, J P

    2017-06-02

    Objective: This study aimed at determining the characteristics of the glucose homeostasis and its relationship with iron overload of the patients with β-thalassemia major (β-TM). Method: From Sun Yat-sen Memorial Hospital between January 2014 and December 2015, a total of 57 transfusion-dependent β-TM patients with 5-18 years old were enrolled in this study and fasting blood glucose(FBG) and insulin level, serum ferritin (SF), serum iron, transferrin, total iron binding capacity, unsaturated iron binding capacity were determined.Insulin resistance index (IRI), insulin sensitivity index and β-cell function index (BFI) were also estimated. Besides, in 36 patients cardiac T2* and liver T2* were estimated. Result: (1) Four patients(7%) with β-TM were diagnosed diabetes mellitus, and 14(24%) had impaired fasting glucose. (2) The incidence of abnormal glucose metabolism was significantly different according to levels of SF and degrees of the cardiac iron overload(χ(2)=9.737, P<0.05; χ(2)=17.027, P<0.05). It rose while the level of SF increased and the degree of cardiac iron overload aggravated. (3) The incidence of abnormal glucose level was not significantly different in cases with different degree of liver iron overload.The severe group of liver iron overload had significantly higher levels of INS, HOMA-βFI, HOMA-ISI, HOMA-βFI than the non-severe group (Z=-2.434, -2.515, F=8.658, all P<0.05), while no differences were found in the level of FBG, HOMA-βFI between two groups. (4) The result of logistic regression analysis indicated that the cardiac T2* was a significant predictor for the incidence of abnormal glucose metabolism in TM patients (P=0.035, OR=1.182%, 95%CI=1.048 to 1.332). Conclusion: The high prevalence of abnormal glucose metabolism in β-TM patients was mainly closely related with the internal iron overload, especially in organs.The cardiac T2* was an independent risk factor for the incidence of abnormal glucose metabolism in TM patients.

  10. Metabolic models to investigate energy limited anaerobic ecosystems.

    PubMed

    Rodríguez, J; Premier, G C; Guwy, A J; Dinsdale, R; Kleerebezem, R

    2009-01-01

    Anaerobic wastewater treatment is shifting from a philosophy of solely pollutants removal to a philosophy of combined resource recovery and waste treatment. Simultaneous wastewater treatment with energy recovery in the form of energy rich products, brings renewed interest to non-methanogenic anaerobic bioprocesses such as the anaerobic production of hydrogen, ethanol, solvents, VFAs, bioplastics and even electricity from microbial fuel cells. The existing kinetic-based modelling approaches, widely used in aerobic and methanogenic wastewater treatment processes, do not seem adequate in investigating such energy limited microbial ecosystems. The great diversity of similar microbial species, which share many of the fermentative reaction pathways, makes quantify microbial groups very difficult and causes identifiability problems. A modelling approach based on the consideration of metabolic reaction networks instead of on separated microbial groups is suggested as an alternative to describe anaerobic microbial ecosystems and in particular for the prediction of product formation as a function of environmental conditions imposed. The limited number of existing relevant fermentative pathways in conjunction with the fact that anaerobic reactions proceed very close to thermodynamic equilibrium reduces the complexity of such approach and the degrees of freedom in terms of product formation fluxes. In addition, energy limitation in these anaerobic microbial ecosystems makes plausible that selective forces associated with energy further define the system activity by favouring those conversions/microorganisms which provide the most energy for growth under the conditions imposed.

  11. A comparison of iron extraction methods for the determination of degree of pyritisation and the recognition of iron-limited pyrite formation

    NASA Technical Reports Server (NTRS)

    Raiswell, R.; Canfield, D. E.; Berner, R. A.

    1994-01-01

    Measurements of degree of pyritisation require an estimate of sediment iron which is capable of reaction with dissolved sulphide to form pyrite, either directly or indirectly via iron monosulphide precursors. Three dissolution techniques (buffered dithionite, cold 1 M HCl, boiling 12 M HCl) were examined for their capacity to extract iron from a variety of iron minerals, and iron-bearing sediments, as a function of different extraction times and different grain sizes. All the iron oxides studied are quantitatively extracted by dithionite and boiling HCl (but not by cold HCl). Both HCl techniques extract more iron from silicates than does dithionite but probably about the same amounts as are potentially capable of sulphidation. Modern sediment studies indicate that most sedimentary pyrite is formed rapidly from iron oxides, with smaller amounts formed more slowly from iron silicates (if sufficient geologic time is available). It is therefore recommended that the degree of pyritisation be defined with respect to the dithionite-extractable (mainly iron oxide) pool and/or the boiling HCl-extractable pool (which includes some silicate iron) for the recognition of iron-limited pyritisation.

  12. Iron metabolism and oxidative profile of dogs naturally infected by Ehrlichia canis: Acute and subclinical disease.

    PubMed

    Bottari, Nathieli B; Crivellenti, Leandro Z; Borin-Crivellenti, Sofia; Oliveira, Jéssica R; Coelho, Stefanie B; Contin, Catarina M; Tatsch, Etiane; Moresco, Rafael N; Santana, Aureo E; Tonin, Alexandre A; Tinucci-Costa, Mirela; Da Silva, Aleksandro S

    2016-03-01

    The aim of this study was to evaluate the oxidant profile and iron metabolism in serum of dogs infected by Ehrlichia canis. Banked sera samples of dogs were divided into two groups: negative control (n = 17) and infected by E. canis on acute (n = 24), and subclinical (n = 18) phases of the disease. The eritrogram, leucogram, and platelet counts were evaluate as well as iron, ferritin, and transferrin levels, latent iron binding capacity (LIBC), and transferrin saturation index (TSI) concentration. In addition, the advanced oxidation protein products (AOPP) and ferric reducing ability of plasma (FRAP) in sera were also analyzed. Blood samples were examined for the presence of E. canis by PCR techniques. History and clinical signals were recorded for each dog. During the acute phase of the disease, infected animals showed thrombocytopenia and anemia when compared to healthy animals (P < 0.05) as a consequence of lower iron levels. Ferritin and transferrin levels were higher in both phases (acute and subclinical) of the disease. The AOPP and FRAP levels increased in infected animals on the acute phase; however, the opposite occurred in the subclinical phase. We concluded that dogs naturally infected by E. canis showed changes in the iron metabolism and developed an oxidant status in consequence of disease pathophysiology.

  13. Identifying Genes Involved in the Iron Metabolism Pathway Through Transcriptomic Analysis

    NASA Astrophysics Data System (ADS)

    Khana, D.

    2016-02-01

    Iron oxidizing bacteria are important to the biological iron cycle but the mechanism of Fe-oxidation is poorly understood. TAG-1 is a new isolate that grows on both Fe(II) and H2, thus can be used for transcriptomic analysis of gene expression involved in iron metabolism. The actB1 gene encodes for a component of alternative complex III (ACIII), which functionally replaces cytochrome bc1/b6f of the electron transport chain. We hypothesized if ACIII is involved in iron metabolism, then actB1 expression will be higher in TAG-1 cells grown on Fe(II) than H2. TAG-1 was grown on zero valent iron (ZVI) and H2 gas and direct cell counts were used to determine substrate preference. TAG-1 cells consistently grew more on ZVI. ActB1 gene expression was determined via quantitative PCR and compared to the housekeeping gene recA. ActB1 gene expression was higher in TAG-1 grown on ZVI after 48, 72, and 96 hour time points. The recA gene failed to amplify despite the use of various primers. We conclude that ActB1 was expressed in the presence of both substrates indicating a poor biomarker for Fe-oxidation.

  14. Serotonergic dysfunctions and abnormal iron metabolism: Relevant to mental fatigue of Parkinson disease.

    PubMed

    Zuo, Li-Jun; Yu, Shu-Yang; Hu, Yang; Wang, Fang; Piao, Ying-Shan; Lian, Teng-Hong; Yu, Qiu-Jin; Wang, Rui-Dan; Li, Li-Xia; Guo, Peng; Du, Yang; Zhu, Rong-Yan; Jin, Zhao; Wang, Ya-Jie; Wang, Xiao-Min; Chan, Piu; Chen, Sheng-Di; Wang, Yong-Jun; Zhang, Wei

    2016-12-01

    Fatigue is a very common non-motor symptom in Parkinson disease (PD) patients. It included physical fatigue and mental fatigue. The potential mechanisms of mental fatigue involving serotonergic dysfunction and abnormal iron metabolism are still unknown. Therefore, we evaluated the fatigue symptoms, classified PD patients into fatigue group and non-fatigue group, and detected the levels of serotonin, iron and related proteins in CSF and serum. In CSF, 5-HT level is significantly decreased and the levels of iron and transferrin are dramatically increased in fatigue group. In fatigue group, mental fatigue score is negatively correlated with 5-HT level in CSF, and positively correlated with the scores of depression and excessive daytime sleepiness, and disease duration, also, mental fatigue is positively correlated with the levels of iron and transferrin in CSF. Transferrin level is negatively correlated with 5-HT level in CSF. In serum, the levels of 5-HT and transferrin are markedly decreased in fatigue group; mental fatigue score exhibits a negative correlation with 5-HT level. Thus serotonin dysfunction in both central and peripheral systems may be correlated with mental fatigue through abnormal iron metabolism. Depression, excessive daytime sleepiness and disease duration were the risk factors for mental fatigue of PD.

  15. Liver transplantation normalizes serum hepcidin level and cures iron metabolism alterations in HFE hemochromatosis.

    PubMed

    Bardou-Jacquet, Edouard; Philip, Julie; Lorho, Richard; Ropert, Martine; Latournerie, Marianne; Houssel-Debry, Pauline; Guyader, Dominique; Loréal, Olivier; Boudjema, Karim; Brissot, Pierre

    2014-03-01

    Defects in human hemochromatosis protein (HFE) cause iron overload due to reduced hepatic hepcidin secretion. Liver transplantation (LT) is a key treatment for potential complications from HFE-related hereditary hemochromatosis (HH). This study evaluated hepcidin secretion and iron burden after LT to elucidate HH pathophysiology. Patients (n=18) homozygous for the p.Cys282Tyr mutation in the HFE gene underwent LT between 1999 and 2008. Serum iron, serum hepcidin, and hepatic iron concentrations were determined before LT and at the end of follow-up (median 57 months). Mortality and causes of death were determined. Survival was compared to that of the overall patient population that received LT. Before LT, serum hepcidin levels were low (0.54 ± 2.5 nmol/L; normal range: 4-30 nmol/L). After LT, 11 patients had iron evaluations; none received iron depletion therapy; all had normal transferrin saturation. The mean serum ferritin was 185 (± 99) μg/L. Magnetic resonance imaging showed that iron overload was absent in nine patients, mild in one patient with metabolic syndrome, and high (180 μmol/g) in one patient with hereditary spherocytosis discovered after LT. At the end of follow-up, serum hepcidin was normal in 10 patients (11.12 ± 7.6 nmol/L; P<0.05) and low in one patient with iron deficiency anemia. Survival was 83% and 67% at 1 and 5 years, respectively. Survival was similar for patients with HH and patients that received LT for other causes. In HH, LT normalized hepcidin secretion and prevented recurrence of hepatic iron overload. Survival was similar to that of patients who received LTs for other liver diseases. © 2014 by the American Association for the Study of Liver Diseases.

  16. Deregulation of Genes Related to Iron and Mitochondrial Metabolism in Refractory Anemia with Ring Sideroblasts

    PubMed Central

    del Rey, Mónica; Benito, Rocío; Fontanillo, Celia; Campos-Laborie, Francisco J.; Janusz, Kamila; Velasco-Hernández, Talía; Abáigar, María; Hernández, María; Cuello, Rebeca; Borrego, Daniel; Martín-Zanca, Dionisio; De Las Rivas, Javier; Mills, Ken I.; Hernández-Rivas, Jesús M.

    2015-01-01

    The presence of SF3B1 gene mutations is a hallmark of refractory anemia with ring sideroblasts (RARS). However, the mechanisms responsible for iron accumulation that characterize the Myelodysplastic Syndrome with ring sideroblasts (MDS-RS) are not completely understood. In order to gain insight in the molecular basis of MDS-RS, an integrative study of the expression and mutational status of genes related to iron and mitochondrial metabolism was carried out. A total of 231 low-risk MDS patients and 81 controls were studied. Gene expression analysis revealed that iron metabolism and mitochondrial function had the highest number of genes deregulated in RARS patients compared to controls and the refractory cytopenias with unilineage dysplasia (RCUD). Thus mitochondrial transporters SLC25 (SLC25A37 and SLC25A38) and ALAD genes were over-expressed in RARS. Moreover, significant differences were observed between patients with SF3B1 mutations and patients without the mutations. The deregulation of genes involved in iron and mitochondrial metabolism provides new insights in our knowledge of MDS-RS. New variants that could be involved in the pathogenesis of these diseases have been identified. PMID:25955609

  17. Iron limitation effects a massive shift in iron and flavin based antioxidant enzyme systems and their substrates in the Chlorophyte alga Dunaliella tertiolecta

    NASA Astrophysics Data System (ADS)

    Traggis, H. M.

    2012-12-01

    Ubiquitous in the neritic ocean, it is now believed that iron-limitation is the most important factor controlling primary production in oceanic phytoplankton. To investigate the effects of iron deficiency, Dunaliella tertiolecta was cultured under limiting (100 nM Fe) and replete (1μM Fe) iron concentrations. The physiological status and the Water-Water antioxidant defense system were evaluated. Iron limitation effected a 21% drop in PSII efficiency (replete= 0.634± 0.012; limiting= 0.507± 0.012) concurrent with a 17.5% reduction in photosynthetic rates (replete= 265.8 umol 02/mg chl/hr ± 5.7; limiting= 219.3 umol 02/mg chl/hr ± 5.7). Both heme and non-heme based antioxidant enzyme activities were assessed. Heme-based Ascorbate peroxidase (APX), exhibits an 84% iron limited rate reduction (replete and limited = 36.23 and 5.72 umol ascorbate mg prot-1 hr-1 ±2.96, respectively). Conversely, the flavin-based Monodehydroascorbate reductase (MDHAR), exhibits a significant rate increase, 2.16±0.19 (replete) to 3.86±0.19 umol NADH mg prot-1 hr-1 under iron-limitation. Iron deficient cultures exhibit a 34% increase in total available ascorbate. These investigations suggest that D. tertiolecta is able to maintain a stable growth rate under iron limitation by re-allocating its subcellular usage of available iron and increasing the availability of total ascorbate. Further investigations will determine the presence of additional iron/flavin based molecules involved in the photosynthetic apparatus and anti-oxidant scavenging mechanisms.

  18. Using skin to assess iron accumulation in human metabolic disorders

    NASA Astrophysics Data System (ADS)

    Guinote, I.; Fleming, R.; Silva, R.; Filipe, P.; Silva, J. N.; Veríssimo, A.; Napoleão, P.; Alves, L. C.; Pinheiro, T.

    2006-08-01

    The distribution of Fe in skin was assessed to monitor body Fe status in human hereditary hemochromatosis. The paper reports on data from nine patients with hemochromatosis that were studied along the therapeutic programme. Systemic evaluation of Fe metabolism was carried out by measuring with PIXE technique the Fe concentration in plasma and blood cells, and by determining with biochemical methods the indicators of Fe transport in serum (ferritin and transferrin). The Fe distribution and concentration in skin was assessed by nuclear microscopy and Fe deposits in liver estimated through nuclear magnetic resonance. Elevated Fe concentrations in skin were related to increased plasma Fe (p < 0.004), serum ferritin content (p < 0.01) and Fe deposits in liver (p < 0.004). The relationship of Fe deposits in organs and metabolism markers may help to better understand Fe pools mobilisation and to establish the quality of skin as a marker for the disease progression and therapy efficacy.

  19. Effect of iron limitation on photosynthesis in a marine diatom

    SciTech Connect

    Greene, R.M.; Falkowski, P.G. ); Geider, R.J. )

    1991-12-01

    The response of the marine diatom Phaeodactylum tricornutum to Fe deficiency was evaluated in the context of fundamental physiological models of growth and photosynthesis. Fe deficiency induced chlorosis, which decreased Chl a:C ratios and Chl a-specific light-saturated photosynthesis (P{sub m}{sup B}). In contrast to P{sub m}{sup B}, {alpha}{sup B} was slightly increased under Fe deficiency, and photosynthesis in Fe-deficient cells became light-saturated at lower irradiances than in Fe-replete cells grown at the same irradiance. Fe deficiency increased in vivo absorption cross section normalized to Chl a(a{sup *}), but decreased the maximum quantum yield of photosynthesis ({phi}{sub m}). Thus, the product a{sup *} {phi}{sub m}, which equals the Chl a-specific initial slope of the photosynthesis-irradiance curve ({alpha}{sup B}), was less sensitive to Fe limitation than was a{sup *} or {phi}{sub m} alone. Using a pump-and-probe fluorometer, the authors found that Fe deficiency reduced the maximum fluorescence yield ({Delta}{phi}{sub sat}), which is consistent with the reduction in {phi}{sub m}, but increased the absorption cross section of photosystem 2 ({sigma}{sub PS2}). Immunoassays of proteins separated electrophoretically indicated that the reduction in maximum fluorescence yields as accompanied by a reduction in the relative abundance of D1, the photosystem 2 reaction center protein. Light-harvesting chlorophyll proteins (LHCP) and the large and small subunits of ribulose bisphosphate carboxylase were not affected by Fe deficiency. Changes in the abundance of D1 relative to LHCP suggest an increase in the fraction of nonfunctional reaction centers under Fe-limited conditions. Fe-deficient cells, growing at <20% of their maximum growth rate, and reduced cellular C, N, and P contents, but maintained C:N:P ratios at the Redfield proportions. These results imply that C:N:P ratios do not provide and unequivocal index of relative growth rate.

  20. Investigation on Abnormal Iron Metabolism and Related Inflammation in Parkinson Disease Patients with Probable RBD

    PubMed Central

    Hu, Yang; Yu, Shu-Yang; Zuo, Li-Jun; Piao, Ying-Shan; Cao, Chen-Jie; Wang, Fang; Chen, Ze-Jie; Du, Yang; Lian, Teng-Hong; Liu, Gai-Fen; Wang, Ya-Jie; Chan, Piu; Chen, Sheng-Di; Wang, Xiao-Min; Zhang, Wei

    2015-01-01

    Objective To investigate potential mechanisms involving abnormal iron metabolism and related inflammation in Parkinson disease (PD) patients with probable rapid eye movement sleep behavior disorder (PRBD). Methods Total 210 PD patients and 31 controls were consecutively recruited. PD patients were evaluated by RBD Screening Questionnaire (RBDSQ) and classified into PRBD and probable no RBD (NPRBD) groups. Demographics information were recorded and clinical symptoms were evaluated by series of rating scales. Levels of iron and related proteins and inflammatory factors in cerebrospinal fluid (CSF) and serum were detected. Comparisons among control, NPRBD and PRBD groups and correlation analyses between RBDSQ score and levels of above factors were performed. Results (1)The frequency of PRBD in PD patients is 31.90%. (2)PRBD group has longer disease duration, more advanced disease stage, severer motor symptoms and more non-motor symptoms than NPRBD group. (3)In CSF, levels of iron, transferrin, NO and IL–1β in PRBD group are prominently increased. RBDSQ score is positively correlated with the levels of iron, transferrin, NO and IL–1β in PD group. Iron level is positively correlated with the levels of NO and IL–1β in PD group. (4)In serum, transferrin level is prominently decreased in PRBD group. PGE2 level in PRBD group is drastically enhanced. RBDSQ score exhibits a positive correlation with PGE2 level in PD group. Conclusions PRBD is common in PD patients. PRBD group has severer motor symptoms and more non-motor symptoms. Excessive iron in brain resulted from abnormal iron metabolism in central and peripheral systems is correlated with PRBD through neuroinflammation. PMID:26431210

  1. Insights into the iron and sulfur energetic metabolism of Acidithiobacillus ferrooxidans by microarray transcriptome profiling

    SciTech Connect

    R. Quatrini; C. Appia-Ayme; Y. Denis; J. Ratouchniak; F. Veloso; J. Valdes; C. Lefimil; S. Silver; F. Roberto; O. Orellana; F. Denizot; E. Jedlicki; D. Holmes; V. Bonnefoy

    2006-09-01

    Acidithiobacillus ferrooxidans is a well known acidophilic, chemolithoautotrophic, Gram negative, bacterium involved in bioleaching and acid mine drainage. In aerobic conditions, it gains energy mainly from the oxidation of ferrous iron and/or reduced sulfur compounds present in ores. After initial oxidation of the substrate, electrons from ferrous iron or sulfur enter respiratory chains and are transported through several redox proteins to oxygen. However, the oxidation of ferrous iron and reduced sulfur compounds has also to provide electrons for the reduction of NAD(P) that is subsequently required for many metabolic processes including CO2 fixation. To help to unravel the enzymatic pathways and the electron transfer chains involved in these processes, a genome-wide microarray transcript profiling analysis was carried out. Oligonucleotides corresponding to approximately 3000 genes of the A. ferrooxidans type strain ATCC23270 were spotted onto glass-slides and hybridized with cDNA retrotranscribed from RNA extracted from ferrous iron and sulfur grown cells. The genes which are preferentially transcribed in ferrous iron conditions and those preferentially transcribed in sulfur conditions were analyzed. The expression of a substantial number of these genes has been validated by real-time PCR, Northern blot hybridization and/or immunodetection analysis. Our results support and extend certain models of iron and sulfur oxidation and highlight previous observations regarding the possible presence of alternate electron pathways. Our findings also suggest ways in which iron and sulfur oxidation may be co-ordinately regulated. An accompanying paper (Appia-Ayme et al.) describes results pertaining to other metabolic functions.

  2. Mechanisms of increased Trichodesmium fitness under iron and phosphorus co-limitation in the present and future ocean

    PubMed Central

    Walworth, Nathan G.; Fu, Fei-Xue; Webb, Eric A.; Saito, Mak A.; Moran, Dawn; Mcllvin, Matthew R.; Lee, Michael D.; Hutchins, David A.

    2016-01-01

    Nitrogen fixation by cyanobacteria supplies critical bioavailable nitrogen to marine ecosystems worldwide; however, field and lab data have demonstrated it to be limited by iron, phosphorus and/or CO2. To address unknown future interactions among these factors, we grew the nitrogen-fixing cyanobacterium Trichodesmium for 1 year under Fe/P co-limitation following 7 years of both low and high CO2 selection. Fe/P co-limited cell lines demonstrated a complex cellular response including increased growth rates, broad proteome restructuring and cell size reductions relative to steady-state growth limited by either Fe or P alone. Fe/P co-limitation increased abundance of a protein containing a conserved domain previously implicated in cell size regulation, suggesting a similar role in Trichodesmium. Increased CO2 further induced nutrient-limited proteome shifts in widespread core metabolisms. Our results thus suggest that N2-fixing microbes may be significantly impacted by interactions between elevated CO2 and nutrient limitation, with broad implications for global biogeochemical cycles in the future ocean. PMID:27346420

  3. Effect of Nordic Walking training on iron metabolism in elderly women

    PubMed Central

    Kortas, Jakub; Prusik, Katarzyna; Flis, Damian; Prusik, Krzysztof; Ziemann, Ewa; Leaver, Neil; Antosiewicz, Jedrzej

    2015-01-01

    Background Despite several, well-documented pro-healthy effects of regular physical training, its influence on body iron stores in elderly people remains unknown. At the same time, body iron accumulation is associated with high risk of different morbidities. Purpose We hypothesized that Nordic Walking training would result in pro-healthy changes in an elderly group of subjects by reducing body iron stores via shifts in iron metabolism-regulating proteins. Methods Thirty-seven women aged 67.7±5.3 years participated in this study. They underwent 32 weeks of training, 1-hour sessions three times a week, between October 2012 and May 2013. Fitness level, blood morphology, CRP, vitamin D, ferritin, hepcidin, and soluble Hjv were assessed before and after the training. Results The training program caused a significant decrease in ferritin, which serves as a good marker of body iron stores. Simultaneously, the physical cardiorespiratory fitness had improved. Furthermore, blood hepcidin was positively correlated with the ferritin concentration after the training. The concentration of blood CRP dropped, but the change was nonsignificant. The applied training resulted in a blood Hjv increase, which was inversely correlated with the vitamin D concentration. Conclusion Overall the Nordic Walking training applied in elderly people significantly reduced blood ferritin concentration, which explains the observed decrease in body iron stores. PMID:26664101

  4. luxS and arcB control aerobic growth of Actinobacillus actinomycetemcomitans under iron limitation.

    PubMed

    Fong, Karen P; Gao, Ling; Demuth, Donald R

    2003-01-01

    LuxS is responsible for the production of autoinducer 2 (AI-2), which functions in Vibrio harveyi as a quorum-sensing signal that controls the cell density-dependent expression of the lux operon. In nonluminescent organisms, the physiologic role of AI-2 is not clear. We report that inactivation of luxS in Actinobacillus actinomycetemcomitans JP2 results in reduced growth of the mutant, but not the wild-type organism, under aerobic, iron-limited conditions. Stunted cultures of the luxS mutant A. actinomycetemcomitans JP2-12 grew to high cell density when subcultured under iron-replete conditions. In addition, the mutant strain grew to high cell density under iron limitation after transformation with a plasmid containing a functional copy of luxS. Results of real-time PCR showed that A. actinomycetemcomitans JP2-12 exhibited significantly reduced expression of afuA (eightfold), fecBCDE (10-fold), and ftnAB (>50-fold), which encode a periplasmic ferric transport protein, a putative ferric citrate transporter, and ferritin, respectively. The expressions of putative receptors for transferrin, hemoglobin, and hemophore binding protein were also reduced at more modest levels (two- to threefold). In contrast, expressions of sidD and frpB (encoding putative siderophore receptors) were increased 10- and 3-fold, respectively, in the luxS mutant. To better understand the mechanism of the AI-2 response, the A. actinomycetemcomitans genome was searched for homologs of the V. harveyi signal transduction proteins, LuxP, LuxQ, LuxU, and LuxO. Interestingly, ArcB was found to be most similar to LuxQ sensor/kinase. To determine whether arcB plays a role in the response of A. actinomycetemcomitans to AI-2, an arcB-deficient mutant was constructed. The isogenic arcB mutant grew poorly under anaerobic conditions but grew normally under aerobic iron-replete conditions. However, the arcB mutant failed to grow aerobically under iron limitation, and reverse transcriptase PCR showed that

  5. Transcriptional Orchestration of the Global Cellular Response of a Model Pennate Diatom to Diel Light Cycling under Iron Limitation

    PubMed Central

    McCrow, John P.; Badger, Jonathan H.; Zheng, Hong; New, Ashley M.; Dupont, Chris L.; Obata, Toshihiro; Fernie, Alisdair R.; Allen, Andrew E.

    2016-01-01

    Environmental fluctuations affect distribution, growth and abundance of diatoms in nature, with iron (Fe) availability playing a central role. Studies on the response of diatoms to low Fe have either utilized continuous (24 hr) illumination or sampled a single time of day, missing any temporal dynamics. We profiled the physiology, metabolite composition, and global transcripts of the pennate diatom Phaeodactylum tricornutum during steady-state growth at low, intermediate, and high levels of dissolved Fe over light:dark cycles, to better understand fundamental aspects of genetic control of physiological acclimation to growth under Fe-limitation. We greatly expand the catalog of genes involved in the low Fe response, highlighting the importance of intracellular trafficking in Fe-limited diatoms. P. tricornutum exhibited transcriptomic hallmarks of slowed growth leading to prolonged periods of cell division/silica deposition, which could impact biogeochemical carbon sequestration in Fe-limited regions. Light harvesting and ribosome biogenesis transcripts were generally reduced under low Fe while transcript levels for genes putatively involved in the acquisition and recycling of Fe were increased. We also noted shifts in expression towards increased synthesis and catabolism of branched chain amino acids in P. tricornutum grown at low Fe whereas expression of genes involved in central core metabolism were relatively unaffected, indicating that essential cellular function is protected. Beyond the response of P. tricornutum to low Fe, we observed major coordinated shifts in transcript control of primary and intermediate metabolism over light:dark cycles which contribute to a new view of the significance of distinctive diatom pathways, such as mitochondrial glycolysis and the ornithine-urea cycle. This study provides new insight into transcriptional modulation of diatom physiology and metabolism across light:dark cycles in response to Fe availability, providing mechanistic

  6. Cytosolic aconitase activity sustains adipogenic capacity of adipose tissue connecting iron metabolism and adipogenesis.

    PubMed

    Moreno, María; Ortega, Francisco; Xifra, Gemma; Ricart, Wifredo; Fernández-Real, José Manuel; Moreno-Navarrete, José María

    2015-04-01

    To gain insight into the regulation of intracellular iron homeostasis in adipose tissue, we investigated the role of iron regulatory protein 1/cytosolic aconitase 1 (ACO1). ACO1 gene expression and activity increased in parallel to expression of adipogenic genes during differentiation of both murine 3T3-L1 cells and human preadipocytes. Lentiviral knockdown (KD) of Aco1 in 3T3-L1 preadipocytes led to diminished cytosolic aconitase activity and isocitrate dehydrogenase 1 (NADP(+)), soluble (Idh1) mRNA levels, decreased intracellular NADPH:NADP ratio, and impaired adipogenesis during adipocyte differentiation. In addition, Aco1 KD in fully differentiated 3T3-L1 adipocytes decreased lipogenic, Idh1, Adipoq, and Glut4 gene expression. A bidirectional cross-talk was found between intracellular iron levels and ACO1 gene expression and protein activity. Although iron in excess, known to increase reactive oxygen species production, and iron depletion both resulted in decreased ACO1 mRNA levels and activity, Aco1 KD led to reduced gene expression of transferrin receptor (Tfrc) and transferrin, disrupting intracellular iron uptake. In agreement with these findings, in 2 human independent cohorts (n = 85 and n = 38), ACO1 gene expression was positively associated with adipogenic markers in subcutaneous and visceral adipose tissue. ACO1 gene expression was also positively associated with the gene expression of TFRC while negatively linked to ferroportin (solute carrier family 40 (iron-regulated transporter), member 1) mRNA levels. Altogether, these results suggest that ACO1 activity is required for the normal adipogenic capacity of adipose tissue by connecting iron, energy metabolism, and adipogenesis.

  7. Influence of zinc deficiency on iron metabolism in rats

    SciTech Connect

    Liu, H.; Loennerdal, B.; Keen, C.L. )

    1991-03-15

    It has been reported that one of the effects of dietary Zn deficiency is increased tissue Fe concentrations. One explanation for this is that Fe absorption is enhanced in Zn deficiency. An additional possibility is that Fe metabolism is altered in the deficient animal. To test this idea, the authors studied the effects of Zn deficiency on Fe metabolism in d 18 male rats fed diets ad libitum containing 0.3 ppm Zn (ZD) or 50 ppm Zn (C) for 2 wk. Following i.v. injection with a tracer dose of transferrin saturated with {sup 59}Fe, rats were killed at time intervals up to 120 min. Tissues were collected and analyzed for {sup 59}Fe radioactivity and mineral concentrations. Plasma, kidney, and liver Fe concentrations of ZD rats were higher than those of C rats while Zn concentrations were lower. At all time points, kidney and liver {sup 59}Fe retention on a per g basis was higher in the ZD rats than in the C rats. In contrast, there was no difference in the clearance of {sup 59}Fe from the plasma between the groups, implying that the higher tissue {sup 59}Fe retention in ZD rats was not due to a shortened biological half-life of Tf. The above data show that independent of Fe absorption, Zn deficiency can increase Fe retention, although the mechanism(s) underlying this effect remains to be determined.

  8. Iron limitation impact on eddy-induced ecosystem variability in the coastal Gulf of Alaska

    NASA Astrophysics Data System (ADS)

    Fiechter, Jerome; Moore, Andrew M.

    2012-04-01

    A data assimilative, coupled physical-biological model for the northwestern coastal Gulf of Alaska (CGOA) is used to characterize lower trophic level ecosystem response to eddy variability at the shelfbreak over a 5-year period (1998-2002). The ocean circulation component is an implementation of the Regional Ocean Modeling System (ROMS), the lower trophic level ecosystem component is a six-compartment Nutrient-Phytoplankton-Zooplankton-Detritus (NPZD) model with iron limitation, and the data assimilation component is the adjoint-based, four-dimensional variational (4D-Var) system available in ROMS. Assimilated observations consist of weekly satellite sea surface height and temperature, as well as bimonthly in situ temperature and salinity measurements. Overall, the model results are in agreement with earlier observational studies, and confirm that eddy-induced cross-shelf transport of biological properties can potentially enhance phytoplankton concentrations in the basin by: (1) alleviating iron limitation on phytoplankton growth by transporting iron-rich shelf waters offshore, and (2) transporting elevated shelf phytoplankton concentrations offshore. Simulated nutrient anomalies during eddy events indicate a substantial increase in dissolved iron concentrations in near-surface waters, thereby suggesting that eddy-induced offshore transport of iron-rich shelf waters is the dominant mechanism regulating locally-generated offshore production in the CGOA high nutrient-low chlorophyll (HNLC) region during eddy events. In fact, for the period 1998-2002, the model results predict that approximately two thirds of the eddy-induced production in the Yakutat/Sitka "eddy corridor" is associated with locally-generated production resulting from alleviated iron limitation conditions on phytoplankton growth. The remaining third can be attributed to eddy-induced offshore export of chlorophyll concentrations of shelf origin.

  9. Iron

    MedlinePlus

    Iron is a mineral that our bodies need for many functions. For example, iron is part of hemoglobin, a protein which carries ... It helps our muscles store and use oxygen. Iron is also part of many other proteins and ...

  10. MMS19 assembles iron-sulfur proteins required for DNA metabolism and genomic integrity

    PubMed Central

    Stehling, Oliver; Vashisht, Ajay A.; Mascarenhas, Judita; Jonsson, Zophonias O.; Sharma, Tanu; Netz, Daili J.A.; Pierik, Antonio J.; Wohlschlegel, James A.; Lill, Roland

    2012-01-01

    Instability of the nuclear genome is a hallmark of cancer and aging. MMS19 protein has been linked to maintenance of genomic integrity but the molecular basis of this connection is unknown. Here, we identify MMS19 as a member of the cytosolic iron-sulfur protein assembly (CIA) machinery. MMS19 functions as part of the CIA targeting complex that specifically interacts with and facilitates iron-sulfur cluster insertion into apoproteins involved in methionine biosynthesis, DNA replication, DNA repair and telomere maintenance. MMS19 thus serves as an adapter between early-acting CIA components and a subset of cellular iron-sulfur proteins. The function of MMS19 in maturation of crucial components of DNA metabolism may explain the sensitivity of MMS19 mutants to DNA damage and the presence of extended telomeres. PMID:22678362

  11. Cytochromes and iron sulfur proteins in sulfur metabolism of phototrophic bacteria

    NASA Technical Reports Server (NTRS)

    Fischer, U.

    1985-01-01

    Dissimilatory sulfur metabolism in phototrophic sulfur bacteria provides the bacteria with electrons for photosynthetic electron transport chain and, with energy. Assimilatory sulfate reduction is necessary for the biosynthesis of sulfur-containing cell components. Sulfide, thiosulfate, and elemental sulfur are the sulfur compounds most commonly used by phototrophic bacteria as electron donors for anoxygenic photosynthesis. Cytochromes or other electron transfer proteins, like high-potential-iron-sulfur protein (HIPIP) function as electron acceptors or donors for most enzymatic steps during the oxidation pathways of sulfide or thiosulfate. Yet, heme- or siroheme-containing proteins themselves undergo enzymatic activities in sulfur metabolism. Sirohemes comprise a porphyrin-like prosthetic group of sulfate reductase. eenzymatic reactions involve electron transfer. Electron donors or acceptors are necessary for each reaction. Cytochromes and iron sulfur problems, are able to transfer electrons.

  12. Leu1 plays a role in iron metabolism and is required for virulence in Cryptococcus neoformans.

    PubMed

    Do, Eunsoo; Hu, Guanggan; Caza, Mélissa; Oliveira, Debora; Kronstad, James W; Jung, Won Hee

    2015-02-01

    Amino acid biosynthetic pathways that are absent in mammals are considered an attractive target for antifungal therapy. Leucine biosynthesis is one such target pathway, consisting of a five-step conversion process starting from the valine precursor 2-keto-isovalerate. Isopropylmalate dehydrogenase (Leu1) is an Fe-S cluster protein that is required for leucine biosynthesis in the model fungus Saccharomyces cerevisiae. The human pathogenic fungus Cryptococcus neoformans possesses an ortholog of S. cerevisiae Leu1, and our previous transcriptome data showed that the expression of LEU1 is regulated by iron availability. In this study, we characterized the role of Leu1 in iron homeostasis and the virulence of C. neoformans. We found that deletion of LEU1 caused leucine auxotrophy and that Leu1 may play a role in the mitochondrial-cytoplasmic Fe-S cluster balance. Whereas cytoplasmic Fe-S protein levels were not affected, mitochondrial Fe-S proteins were up-regulated in the leu1 mutant, suggesting that Leu1 mainly influences mitochondrial iron metabolism. The leu1 mutant also displayed increased sensitivity to oxidative stress and cell wall/membrane disrupting agents, which may have been caused by mitochondrial dysfunction. Furthermore, the leu1 mutant was deficient in capsule formation and showed attenuated virulence in a mouse inhalation model of cryptococcosis. Overall, our results indicate that Leu1 plays a role in iron metabolism and is required for virulence in C. neoformans.

  13. Leu1 plays a role in iron metabolism and is required for virulence in Cryptococcus neoformans

    PubMed Central

    Do, Eunsoo; Hu, Guanggan; Caza, Mélissa; Oliveira, Debora; Kronstad, James W.; Jung, Won Hee

    2015-01-01

    Amino acid biosynthetic pathways that are absent in mammals are considered an attractive target for antifungal therapy. Leucine biosynthesis is one such target pathway, consisting of a five-step conversion process starting from the valine precursor 2-keto-isovalerate. Isopropylmalate dehydrogenase (Leu1) is an Fe-S cluster protein that is required for leucine biosynthesis in the model fungus Saccharomyces cerevisiae. The human pathogenic fungus Cryptococcus neoformans possesses an ortholog of S. cerevisiae Leu1, and our previous transcriptome data showed that the expression of LEU1 is regulated by iron availability. In this study, we characterized the role of Leu1 in iron homeostasis and the virulence of C. neoformans. We found that deletion of LEU1 caused leucine auxotrophy and that Leu1 may play a role in the mitochondrial-cytoplasmic Fe-S cluster balance. Whereas cytoplasmic Fe-S protein levels were not affected, mitochondrial Fe-S proteins were up- regulated in the leu1 mutant, suggesting that Leu1 mainly influences mitochondrial iron metabolism. The leu1 mutant also displayed increased sensitivity to oxidative stress and cell wall/membrane disrupting agents, which may have been caused by mitochondrial dysfunction. Furthermore, the leu1 mutant was deficient in capsule formation and showed attenuated virulence in a mouse inhalation model of cryptococcosis. Overall, our results indicate that Leu1 plays a role in iron metabolism and is required for virulence in C. neoformans. PMID:25554701

  14. Vitamin D, Iron Metabolism, and Diet in Alpinists During a 2-Week High-Altitude Climb.

    PubMed

    Kasprzak, Zbigniew; Śliwicka, Ewa; Hennig, Karol; Pilaczyńska-Szcześniak, Łucja; Huta-Osiecka, Anna; Nowak, Alicja

    2015-09-01

    A defensive mechanism against hypobaric hypoxia at high altitude is erythropoesis. Some authors point to the contribution of vitamin D to the regulation of this process. The aim of the present study was to assess the 25-hydroxycholecalciferol (25(OH)D) level and its associations with iron metabolic and inflammatory indices in participants of a 2-week mountaineering expedition. The study sample included 9 alpinists practicing recreational mountain climbing. Every 2 or 3 days they set up a different base between 3200 and 3616 m with the intention of climbing 4000 m peaks in the Mont Blanc massif. Before their departure for the mountains and 2 days after returning to the sea level anthropometric parameters, hematological parameters, serum levels of 25(OH)D and iron metabolic indices were measured in all the participants. The composition of the participants' diet was also evaluated. The comparative analysis showed a significant decrease in body mass, BMI values, total iron, and 25(OH)D concentrations (p<0.05). Also significant increases in unsaturated iron-binding capacity, hematocrit, and C-reactive protein concentrations (p<0.05) were found. It can be concluded that the 2-week climbing expedition contributed to the reduction of 25(OH)D levels and these changes were associated with modulation of immune processes. Moreover, the climbers' diet requires some serious modifications.

  15. Herbicide safeners: uses, limitations, metabolism, and mechanisms of action.

    PubMed

    Abu-Qare, Aqel W; Duncan, Harry J

    2002-09-01

    Several methods were examined to minimize crops injury caused by herbicides. Thus increase their selectivity. A selective herbicide is one that controls weeds at rates that do not injure the crop. Herbicides are selective in a particular crop within certain limits imposed by the herbicide, the plant, the application rate, the method and time of application, and environment conditions. Herbicide safeners are compounds of diverse chemical families. They are applied with herbicides to protect crops against their injury. Using chemical safeners offer practical, efficient and simple method of improving herbicide selectivity. This method has been applied successfully in cereal crops such as maize, rice and sorghum, against pre-emergence thiocarbamate and chloroacetanilide herbicides. Some reports indicate promising results for the development of safeners for post-emergence herbicides in broadleaved crops. Various hypotheses were proposed explaining mechanisms of action of herbicide safeners: interference with uptake and translocation of the herbicide, alteration in herbicide metabolism, and competition at site of action of the herbicide. Even though progress was made in the development of herbicide safeners and in understanding their mechanisms of action, more research is needed to elucidate clearly how these chemicals act and why their activity is restricted to particular crops and herbicides.

  16. Zebrafish in the sea of mineral (iron, zinc, and copper) metabolism.

    PubMed

    Zhao, Lu; Xia, Zhidan; Wang, Fudi

    2014-01-01

    Iron, copper, zinc, and eight other minerals are classified as essential trace elements because they present in minute in vivo quantities and are essential for life. Because either excess or insufficient levels of trace elements can be detrimental to life (causing human diseases such as iron-deficiency anemia, hemochromatosis, Menkes syndrome and Wilson's disease), the endogenous levels of trace minerals must be tightly regulated. Many studies have demonstrated the existence of systems that maintain trace element homeostasis, and these systems are highly conserved in multiple species ranging from yeast to mice. As a model for studying trace mineral metabolism, the zebrafish is indispensable to researchers. Several large-scale mutagenesis screens have been performed in zebrafish, and these screens led to the identification of a series of metal transporters and the generation of several mutagenesis lines, providing an in-depth functional analysis at the system level. Moreover, because of their developmental advantages, zebrafish have also been used in mineral metabolism-related chemical screens and toxicology studies. Here, we systematically review the major findings of trace element homeostasis studies using the zebrafish model, with a focus on iron, zinc, copper, selenium, manganese, and iodine. We also provide a homology analysis of trace mineral transporters in fish, mice and humans. Finally, we discuss the evidence that zebrafish is an ideal experimental tool for uncovering novel mechanisms of trace mineral metabolism and for improving approaches to treat mineral imbalance-related diseases.

  17. Zebrafish in the sea of mineral (iron, zinc, and copper) metabolism

    PubMed Central

    Zhao, Lu; Xia, Zhidan; Wang, Fudi

    2014-01-01

    Iron, copper, zinc, and eight other minerals are classified as essential trace elements because they present in minute in vivo quantities and are essential for life. Because either excess or insufficient levels of trace elements can be detrimental to life (causing human diseases such as iron-deficiency anemia, hemochromatosis, Menkes syndrome and Wilson's disease), the endogenous levels of trace minerals must be tightly regulated. Many studies have demonstrated the existence of systems that maintain trace element homeostasis, and these systems are highly conserved in multiple species ranging from yeast to mice. As a model for studying trace mineral metabolism, the zebrafish is indispensable to researchers. Several large-scale mutagenesis screens have been performed in zebrafish, and these screens led to the identification of a series of metal transporters and the generation of several mutagenesis lines, providing an in-depth functional analysis at the system level. Moreover, because of their developmental advantages, zebrafish have also been used in mineral metabolism-related chemical screens and toxicology studies. Here, we systematically review the major findings of trace element homeostasis studies using the zebrafish model, with a focus on iron, zinc, copper, selenium, manganese, and iodine. We also provide a homology analysis of trace mineral transporters in fish, mice and humans. Finally, we discuss the evidence that zebrafish is an ideal experimental tool for uncovering novel mechanisms of trace mineral metabolism and for improving approaches to treat mineral imbalance-related diseases. PMID:24639652

  18. Transcriptional Characterization of a Widely-Used Grapevine Rootstock Genotype under Different Iron-Limited Conditions.

    PubMed

    Vannozzi, Alessandro; Donnini, Silvia; Vigani, Gianpiero; Corso, Massimiliano; Valle, Giorgio; Vitulo, Nicola; Bonghi, Claudio; Zocchi, Graziano; Lucchin, Margherita

    2016-01-01

    Iron chlorosis is a serious deficiency that affects orchards and vineyards reducing quality and yield production. Chlorotic plants show abnormal photosynthesis and yellowing shoots. In grapevine iron uptake and homeostasis are most likely controlled by a mechanism known as "Strategy I," characteristic of non-graminaceous plants and based on a system of soil acidification, iron reduction and transporter-mediated uptake. Nowadays, grafting of varieties of economic interest on tolerant rootstocks is widely used practice against many biotic and abiotic stresses. Nevertheless, many interspecific rootstocks, and in particular those obtained by crossing exclusively non-vinifera genotypes, can show limited nutrient uptake and transport, in particular for what concerns iron. In the present study, 101.14, a commonly used rootstock characterized by susceptibility to iron chlorosis was subjected to both Fe-absence and Fe-limiting conditions. Grapevine plantlets were grown in control, Fe-deprived, and bicarbonate-supplemented hydroponic solutions. Whole transcriptome analyses, via mRNA-Seq, were performed on root apices of stressed and unstressed plants. Analysis of differentially expressed genes (DEGs) confirmed that Strategy I is the mechanism responsible for iron uptake in grapevine, since many orthologs genes to the Arabidopsis "ferrome" were differentially regulated in stressed plant. Molecular differences in the plant responses to Fe absence and presence of bicarbonate were also identified indicating the two treatments are able to induce response-mechanisms only partially overlapping. Finally, we measured the expression of a subset of genes differentially expressed in 101.14 (such as IRT1, FERRITIN1, bHLH38/39) or known to be fundamental in the "strategy I" mechanism (AHA2 and FRO2) also in a tolerant rootstock (M1) finding important differences which could be responsible for the different degrees of tolerance observed.

  19. Transcriptional Characterization of a Widely-Used Grapevine Rootstock Genotype under Different Iron-Limited Conditions

    PubMed Central

    Vannozzi, Alessandro; Donnini, Silvia; Vigani, Gianpiero; Corso, Massimiliano; Valle, Giorgio; Vitulo, Nicola; Bonghi, Claudio; Zocchi, Graziano; Lucchin, Margherita

    2017-01-01

    Iron chlorosis is a serious deficiency that affects orchards and vineyards reducing quality and yield production. Chlorotic plants show abnormal photosynthesis and yellowing shoots. In grapevine iron uptake and homeostasis are most likely controlled by a mechanism known as “Strategy I,” characteristic of non-graminaceous plants and based on a system of soil acidification, iron reduction and transporter-mediated uptake. Nowadays, grafting of varieties of economic interest on tolerant rootstocks is widely used practice against many biotic and abiotic stresses. Nevertheless, many interspecific rootstocks, and in particular those obtained by crossing exclusively non-vinifera genotypes, can show limited nutrient uptake and transport, in particular for what concerns iron. In the present study, 101.14, a commonly used rootstock characterized by susceptibility to iron chlorosis was subjected to both Fe-absence and Fe-limiting conditions. Grapevine plantlets were grown in control, Fe-deprived, and bicarbonate-supplemented hydroponic solutions. Whole transcriptome analyses, via mRNA-Seq, were performed on root apices of stressed and unstressed plants. Analysis of differentially expressed genes (DEGs) confirmed that Strategy I is the mechanism responsible for iron uptake in grapevine, since many orthologs genes to the Arabidopsis “ferrome” were differentially regulated in stressed plant. Molecular differences in the plant responses to Fe absence and presence of bicarbonate were also identified indicating the two treatments are able to induce response-mechanisms only partially overlapping. Finally, we measured the expression of a subset of genes differentially expressed in 101.14 (such as IRT1, FERRITIN1, bHLH38/39) or known to be fundamental in the “strategy I” mechanism (AHA2 and FRO2) also in a tolerant rootstock (M1) finding important differences which could be responsible for the different degrees of tolerance observed. PMID:28105035

  20. Fatigue limit prediction of ferritic-pearlitic ductile cast iron considering stress ratio and notch size

    NASA Astrophysics Data System (ADS)

    Deguchi, T.; Kim, H. J.; Ikeda, T.

    2017-05-01

    The mechanical behavior of ductile cast iron is governed by graphite particles and casting defects in the microstructures, which can significantly decrease the fatigue strength. In our previous study, the fatigue limit of ferritic-pearlitic ductile cast iron specimens with small defects ((\\sqrt{{area}}=80˜ 1500{{μ }}{{m}})) could successfully be predicted based on the \\sqrt{{area}} parameter model by using \\sqrt{{area}} as a geometrical parameter of defect as well as the tensile strength as a material parameter. In addition, the fatigue limit for larger defects could be predicted based on the conventional fracture mechanics approach. In this study, rotating bending and tension-compression fatigue tests with ferritic-pearlitic ductile cast iron containing circumferential sharp notches as well as smooth specimens were performed to investigate quantitatively the effects of defect. The notch depths ranged 10 ˜ 2500 μm and the notch root radii were 5 and 50 μm. The stress ratios were R = -1 and 0.1. The microscopic observation of crack propagation near fatigue limit revealed that the fatigue limit was determined by the threshold condition for propagation of a small crack emanating from graphite particles. The fatigue limit could be successfully predicted as a function of R using a method proposed in this study.

  1. Springs as Model Systems for Aquatic Ecosystems Ecology: Stoichiometry, Metabolism and Nutrient Limitation

    NASA Astrophysics Data System (ADS)

    Cohen, M. J.; Nifong, R. L.; Kurz, M. J.; Martin, J. B.; Cropper, W. P.; Korhnak, L. V.

    2013-12-01

    Springs have been called nature's chemostats, where low variation in discharge, temperature and chemistry creates a natural laboratory in which to address basic questions about aquatic ecosystems. Ecological stoichiometry posits that patterns of metabolism, trophic energy transfer and community structure arise in response to coupled elemental cycles. In this work we synthesize several recent studies in Florida's iconic springs to explore the overarching hypothesis that stoichiometry can be used to indicate the nutrient limitation status of autotrophs and ecosystem metabolism. Of foremost importance is that the chemically stable conditions observed in springs ensures that autotroph tissue elemental composition, which is thought to vary with environmental supply, is near steady state. Moreover, the elemental ratios of discharging water vary dramatically across our study springs (for example, molar N:P ranges from 0.4:1 to 400:1), subjecting the communities of autotrophs, which are largely conserved across systems, to dramatically different nutrient supply. At the scale of whole ecosystem metabolism, we show that C:N:P ratios are strongly conserved across a wide gradient of environmental supplies, counter to the prediction of stoichiometric plasticity. Moreover, the absence of a relationship between gross primary production and nutrient concentrations or stoichiometry suggests that metabolic homeostasis may be a diagnostic symptom of nutrient saturation. At the scale of individual autotrophs, both submerged vascular plants and filamentous algae, this finding is strongly reinforced, with remarkable within-species tissue C:N:P homeostasis over large gradients, and no statistically significant evidence that gradients in nutrient supply affect autotroph composition. Expanding the suite of elements for which contemporaneous environment and tissue measurements are available to include 19 metals and micronutrients revealed that, while plants were homeostatic across large N

  2. Transcriptional and Translational Regulatory Responses to Iron Limitation in the Globally Distributed Marine Bacterium Candidatus Pelagibacter ubique

    PubMed Central

    Smith, Daniel P.; Kitner, Joshua B.; Norbeck, Angela D.; Clauss, Therese R.; Lipton, Mary S.; Schwalbach, Michael S.; Steindler, Laura; Nicora, Carrie D.; Smith, Richard D.; Giovannoni, Stephen J.

    2010-01-01

    Iron is recognized as an important micronutrient that limits microbial plankton productivity over vast regions of the oceans. We investigated the gene expression responses of Candidatus Pelagibacter ubique cultures to iron limitation in natural seawater media supplemented with a siderophore to chelate iron. Microarray data indicated transcription of the periplasmic iron binding protein sfuC increased by 16-fold, and iron transporter subunits, iron-sulfur center assembly genes, and the putative ferroxidase rubrerythrin transcripts increased to a lesser extent. Quantitative peptide mass spectrometry revealed that sfuC protein abundance increased 27-fold, despite an average decrease of 59% across the global proteome. Thus, we propose sfuC as a marker gene for indicating iron limitation in marine metatranscriptomic and metaproteomic ecological surveys. The marked proteome reduction was not directly correlated to changes in the transcriptome, implicating post-transcriptional regulatory mechanisms as modulators of protein expression. Two RNA-binding proteins, CspE and CspL, correlated well with iron availability, suggesting that they may contribute to the observed differences between the transcriptome and proteome. We propose a model in which the RNA-binding activity of CspE and CspL selectively enables protein synthesis of the iron acquisition protein SfuC during transient growth-limiting episodes of iron scarcity. PMID:20463970

  3. Transcriptional and translational regulatory responses to iron limitation in the globally distributed marine bacterium Candidatus Pelagibacter ubique

    SciTech Connect

    Smith, Daniel P.; Kitner, J. B.; Norbeck, Angela D.; Clauss, Therese RW; Lipton, Mary S.; Schwalbach, M. S.; Steindler, L.; Nicora, Carrie D.; Smith, Richard D.; Giovannoni, Stephen J.

    2010-05-05

    Abstract Background: Iron is recognized as an important micronutrient that limits microbial plankton productivity over vast regions of the oceans. We investigated the gene expression responses of Candidatus Pelagibacter ubique cultures to iron limitation in natural seawater media supplemented with a siderophore to chelate iron. Methodology/Principal Findings: Microarray data indicated transcription of the periplasmic iron binding protein sfuC increased by 16-fold, and iron transporter subunits, iron-sulfur center assembly genes, and the putative ferroxidase rubrerythrin transcripts increased to a lesser extent. Quantitative peptide mass spectrometry revealed that sfuC protein abundance increased 27-fold, despite an average decrease of 59% across the global proteome. Two RNA-binding proteins, CspE and CspL, correlated well with iron availability, suggesting that they may contribute to the observed differences between the transcriptome and proteome. Conclusions/Significance: We propose sfuC as a marker gene for indicating iron limitation in marine metatranscriptomic and metaproteomic ecological surveys. The marked proteome reduction was not directly correlated to changes in the transcriptome, implicating post-transcriptional regulatory mechanisms as modulators of protein expression. We propose a model in which the RNA-binding activity of cspE and cspL selectively enables protein synthesis of the iron acquisition protein sfuC during transient growth-limiting episodes of iron scarcity.

  4. Dealing with iron metabolism in rice: from breeding for stress tolerance to biofortification.

    PubMed

    Santos, Railson Schreinert Dos; Araujo, Artur Teixeira de; Pegoraro, Camila; Oliveira, Antonio Costa de

    2017-03-16

    Iron is a well-known metal. Used by humankind since ancient times in many different ways, this element is present in all living organisms, where, unfortunately, it represents a two-way problem. Being an essential block in the composition of different proteins and metabolic pathways, iron is a vital component for animals and plants. That is why iron deficiency has a severe impact on the lives of different organisms, including humans, becoming a major concern, especially in developing countries where access to adequate nutrition is still difficult. On the other hand, this metal is also capable of causing damage when present in excess, becoming toxic to cells and affecting the whole organism. Because of its importance, iron absorption, transport and storage mechanisms have been extensively investigated in order to design alternatives that may solve this problem. As the understanding of the strategies that plants use to control iron homeostasis is an important step in the generation of improved plants that meet both human agricultural and nutritional needs, here we discuss some of the most important points about this topic.

  5. Effect of enhanced iron chelation therapy on glucose metabolism in patients with beta-thalassaemia major.

    PubMed

    Farmaki, Kalistheni; Angelopoulos, Nicholas; Anagnostopoulos, George; Gotsis, Efstathios; Rombopoulos, Grigorios; Tolis, George

    2006-08-01

    Recently introduced chelation regimens that combine deferoxamine (DFO) and deferiprone have been shown to have greater efficacy in promoting iron excretion than either chelator alone and have been associated with rapid reduction of the iron load in the heart and liver, and with reversal of cardiac dysfunction. It is unclear whether this combined therapy could be associated with a reduction in iron load or decline in the severity of iron-induced endocrinopathies. Starting in January 2001, 42 patients with beta-thalassaemia major, previously maintained on subcutaneous DFO only, were switched to combined treatment with DFO and deferiprone. The primary endpoint was to investigate the effects of this therapy on the glucose metabolism characteristics of this population. Combination therapy markedly decreased ferritin levels (638 +/- 1345 vs. 2991 +/- 2093 microg/l, P < 0.001). Glucose responses were improved at all times during an oral glucose tolerance test, particularly in patients in early stages of glucose intolerance. Glucose quantitative secretion also decreased significantly with combined therapy, while no significant change occurred in insulin levels in any group. Insulin secretion, according to the homeostasis assessment model, markedly increased in all groups, while overall reduction in insulin sensitivity did not reach statistical significance. This study showed that the combination of DFO and deferiprone was associated with an improvement in liver iron deposition and glucose intolerance.

  6. [Asbestos-stimulated changes in nitric oxide and iron metabolism in rats].

    PubMed

    Shandarenko, S H; Kishko, T O; Chumachenko, I M; Dmytrenko, M P

    2011-01-01

    Under intratracheal asbestos fibers installation it has been investigated NO synthesis in the lung and liver tissues of Wistar rats by EPR method. Asbestos A6-45, sifted through the sieve with size 0.1 mm, has been administrated in a dose of 5 mg/kg. To evaluate the NO synthesis EPR and NO-trap methods have been used. The amplitude of EPR signal "trap-NO" in the lung samples was 12, 16 and 14 times greater than in controls on the 3th, 6th and 10th days after asbestos installation and was corresponding to NO rate of about 2 mkmol/(g x h). In the liver samples of asbestos-stimulated animals the NO level contained in the non-heme iron nitrosyl complexes was about 2 mkmol/g. Thus, the asbestos fibers stimulate NO synthesis not only in the lung tissue, but also in other organs. The obtained data shows that under NO hyperproduction certain changes in iron metabolism take place, such as: the decrease of transferrin iron and the accumulation of ferric iron not bound with transferrin. The accumulation of ferric iron not shielded by proteins is one of the oxidative stress triggers.

  7. Impact of endogenous nitric oxide on microglial cell energy metabolism and labile iron pool

    PubMed Central

    Chénais, Benoît; Morjani, Hamid; Drapier, Jean-Claude

    2002-01-01

    Microglial activation is common in several neurodegenerative disorders. In the present study, we used the murine BV-2 microglial cell line stimulated with γ-interferon and lipopolysaccharide to gain new insights into the effects of endogenously produced NO on mitochondrial respiratory capacity, iron regulatory protein activity, and redox-active iron level. Using polarographic measurement of respiration of both intact and digitonin-permeabilized cells, and spectrophotometric determination of individual respiratory chain complex activity, we showed that in addition to the reversible inhibition of cytochrome-c oxidase, long-term endogenous NO production reduced complex I and complex II activities in an irreversible manner. As a consequence, the cellular ATP level was decreased in NO-producing cells, whereas ATPase activity was unaffected. We show that NO up-regulates RNA-binding of iron regulatory protein 1 in microglial cells, and strongly reduces the labile iron pool. Together these results point to a contribution of NO derived from inflammatory microglia to the misregulation of energy-producing reactions and iron metabolism, often associated with the pathogenesis of neurodegenerative disorders. PMID:12065670

  8. The habenula and iron metabolism in cerebral mouse models of multiple sclerosis

    PubMed Central

    Sands, Scott A.; Tsau, Sheila; LeVine, Steven M.

    2015-01-01

    Iron accumulates in the CNS of patients with multiple sclerosis, but our understanding of the mechanism accounting for this accumulation is unclear. Mouse models of cerebral experimental autoimmune encephalomyelitis (EAE) in C57BL/6 and SJL mice were used together with a histochemical stain for iron and immunohistochemical stains for transferrin receptor, synaptophysin, iron regulatory protein 1 (IRP1) and/or IRP2 to investigate the role of disease activity on CNS iron metabolism. The expression of transferrin receptor, but not IRP1 or IRP2, increased in the medial habenula, which is adjacent to the third ventricle, in response to both types of cerebral EAE. In the habenula, the elevated expression of transferrin receptor in C57BL/6 mice with cerebral EAE was generally restricted to the medial habenula while the expression in SJL mice with cerebral EAE was more diffusely expressed. Iron levels were increased in all regions of the habenula in C57BL/6 mice with cerebral EAE, and in the medial and medial lateral but not the lateral habenula in SJL mice with cerebral EAE. Synaptophysin, which has been observed previously in endocytic vesicles together with the transferrin receptor, was concentrated at the medial habenula, but its levels did not increase with disease in C57BL/6 mice with cerebral EAE. Our results support the model that the medial habenula responds to disease activity by upregulating transferrin receptor to facilitate the movement of iron into the brain from the third ventricle, raising the possibility that a similar mechanism accounts for iron accumulation in deep gray matter structures in patients with multiple sclerosis. PMID:26362814

  9. A comparative gene expression analysis of iron-limited cultures of Chaetoceros socialis and Pseudo-nitzschia arenysensis using newly developed iron assays

    NASA Astrophysics Data System (ADS)

    Abdala, Z. M.; Powell, K.; Cronin, D.; Chappell, D.

    2016-02-01

    A comparative gene expression analysis of iron-limited cultures of Chaetoceros socialis and Pseudo-nitzschia arenysensisusing newly developed iron assays Zuzanna M. Abdala, Kimberly Powell, Dylan P. Cronin, P. Dreux Chappell Diatoms, accounting for about 40% of the primary production in marine ecosystems, play a vital role in the dynamics of marine systems. Iron availability is understood to be a driving factor controlling productivity of many marine phytoplankton, including diatoms, as it functions as a cofactor for many proteins including several involved with photosynthetic processes. Previous work examining transcriptomes of diatoms of the Thalassiosira genus grown in controlled laboratory settings has identified genes whose expression can be used as sensitive markers of iron status. Data mining publically available diatom transcriptome data for these genes enables development of additional iron status assays for environmentally-relevant diatoms. For the present study, gene expression analysis of iron-limited laboratory cultures of Chaetoceros socialis and Pseudo-nitzschia arenysensis grown in continuous light was done using quantitative reverse transcriptase polymerase chain reaction (qRT-PCR). C. socialis and P. arenysensis serve as comparative models for analyzing gene expression in iron limitation in different ecological community assemblages. These data may ultimately assist to illuminate the function of iron in photosynthetic activity in diatoms.

  10. Iron pentacarbonyl detection limits in the cigarette smoke matrix using FT-IR spectroscopy

    NASA Astrophysics Data System (ADS)

    Parrish, Milton E.; Plunkett, Susan E.; Harward, Charles N.

    2005-11-01

    Endogenous metals present in tobacco from agricultural practices have been purported to generate metal carbonyls in cigarette smoke. Transition metal catalysts, such as iron oxide, have been investigated for the reduction of carbon monoxide (CO) in cigarette smoke. These studies motivated the development of an analytical method to determine if iron pentacarbonyl [Fe(CO) 5] is present in mainstream smoke from cigarette models having cigarette paper made with iron oxide. An FT-IR puff-by-puff method was developed and the detection limit was determined using two primary reference spectra from different sources to estimate the amount of Fe(CO) 5 present in a high-pressure steel cylinder of CO. We do not detect Fe(CO) 5 in a single 35 mL puff from reference cigarettes or from those cigarette models having cigarette paper made with iron oxide, with a 30-ppbV limit of detection (LOD). Also, it was shown that a filter containing activated carbon would remove Fe(CO) 5.

  11. Nutritional Immunity Triggers the Modulation of Iron Metabolism Genes in the Sub-Antarctic Notothenioid Eleginops maclovinus in Response to Piscirickettsia salmonis.

    PubMed

    Martínez, Danixa; Oyarzún, Ricardo; Pontigo, Juan Pablo; Romero, Alex; Yáñez, Alejandro J; Vargas-Chacoff, Luis

    2017-01-01

    Iron deprivation is a nutritional immunity mechanism through which fish can limit the amount of iron available to invading bacteria. The aim of this study was to evaluate the modulation of iron metabolism genes in the liver and brain of sub-Antarctic notothenioid Eleginops maclovinus challenged with Piscirickettsia salmonis. The specimens were inoculated with two P. salmonis strains: LF-89 (ATCC(®) VR-1361™) and Austral-005 (antibiotic resistant). Hepatic and brain samples were collected at intervals over a period of 35 days. Gene expression (by RT-qPCR) of proteins involved in iron storage, transport, and binding were statistically modulated in infected fish when compared with control counterparts. Specifically, the expression profiles of the transferrin and hemopexin genes in the liver, as well as the expression profiles of ferritin-M, ferritin-L, and transferrin in the brain, were similar for both experimental groups. Nevertheless, the remaining genes such as ferritin-H, ceruloplasmin, hepcidin, and haptoglobin presented tissue-specific expression profiles that varied in relation to the injected bacterial strain and sampling time-point. These results suggest that nutritional immunity could be an important immune defense mechanism for E. maclovinus against P. salmonis injection. This study provides relevant information for understanding iron metabolism of a sub-Antarctic notothenioid fish.

  12. Interference of quorum sensing in Pseudomonas syringae by bacterial epiphytes that limit iron availability.

    PubMed

    Dulla, Glenn F J; Krasileva, Ksenia V; Lindow, Steven E

    2010-06-01

    Leaf surfaces harbour bacterial epiphytes that are capable of influencing the quorum sensing (QS) system, density determination through detection of diffusible signal molecules, of the plant-pathogen Pseudomonas syringae pv. syringae (Pss) which controls expression of extracellular polysaccharide production, motility and other factors contributing to virulence to plants. Approximately 11% of the bacterial epiphytes recovered from a variety of plants produced a diffusible factor capable of inhibiting the QS system of Pss as indicated by suppression of ahlI. Blockage of QS by these interfering strains correlated strongly with their ability to limit iron availability to Pss. A direct relationship between the ability of isogenic Escherichia coli strains to sequester iron via their production of different siderophores and their ability to suppress QS in Pss was also observed. Quorum sensing induction was inversely related to iron availability in culture media supplemented with iron chelators or with FeCl(3). Co-inoculation of interfering strains with Pss onto leaves increased the number of resultant disease lesions over twofold compared with that on plants inoculated with Pss alone. Transposon-generated mutants of interfering strains in which QS inhibition was blocked did not increase disease when co-inoculated with Pss. Increased disease incidence was also not observed when a non-motile mutant of Pss was co-inoculated onto plants with QS interfering bacteria suggesting that these strains enhanced the motility of Pss in an iron-dependent manner, leading to an apparent increase in virulence of this pathogen. Considerable cross-talk mediated by iron scavenging apparently occurs on plants, thereby altering the behaviour of bacteria such as Pss that exhibit important QS-dependent traits in this habitat.

  13. Acetylcholinesterase-independent protective effects of huperzine A against iron overload-induced oxidative damage and aberrant iron metabolism signaling in rat cortical neurons

    PubMed Central

    Tao, Ling-xue; Huang, Xiao-tian; Chen, Yu-ting; Tang, Xi-can; Zhang, Hai-yan

    2016-01-01

    Aim: Iron dyshomeostasis is one of the primary causes of neuronal death in Alzheimer's disease (AD). Huperzine A (HupA), a natural inhibitor of acetylcholinesterase (AChE), is a licensed anti-AD drug in China and a nutraceutical in the United Sates. Here, we investigated the protective effects of HupA against iron overload-induced injury in neurons. Methods: Rat cortical neurons were treated with ferric ammonium citrate (FAC), and cell viability was assessed with MTT assays. Reactive oxygen species (ROS) assays and adenosine triphosphate (ATP) assays were performed to assess mitochondrial function. The labile iron pool (LIP) level, cytosolic-aconitase (c-aconitase) activity and iron uptake protein expression were measured to determine iron metabolism changes. The modified Ellman's method was used to evaluate AChE activity. Results: HupA significantly attenuated the iron overload-induced decrease in neuronal cell viability. This neuroprotective effect of HupA occurred concurrently with a decrease in ROS and an increase in ATP. Moreover, HupA treatment significantly blocked the upregulation of the LIP level and other aberrant iron metabolism changes induced by iron overload. Additionally, another specific AChE inhibitor, donepezil (Don), at a concentration that caused AChE inhibition equivalent to that of HupA negatively, influenced the aberrant changes in ROS, ATP or LIP that were induced by excessive iron. Conclusion: We provide the first demonstration of the protective effects of HupA against iron overload-induced neuronal damage. This beneficial role of HupA may be attributed to its attenuation of oxidative stress and mitochondrial dysfunction and elevation of LIP, and these effects are not associated with its AChE-inhibiting effect. PMID:27498774

  14. Presence of acute phase changes in zinc, iron, and copper metabolism in turkey embryos

    SciTech Connect

    Klasing, K.C.; Richards, M.P.; Darcey, S.E.; Laurin, D.E.

    1987-01-01

    Acute phase changes in trace mineral metabolism were examined in turkey embryos. An endotoxin injection resulted in increased concentrations of serum copper and liver zinc and decreased concentrations of serum zinc in embryos incubated either in ovo or ex ovo. Changes in zinc and copper metabolism occurred when endotoxin either was injected intramuscularly, into the amnionic fluid, or administered onto the chorioallantoic membrane. Unlike poults, embryos did not respond to an inflammatory challenge with decreased serum iron concentrations. Acute phase changes in embryo serum zinc and copper as well as liver zinc concentrations were similar to those in poults. Increased liver zinc concentrations were associated with increased zinc in metallothionein (MT). An injection of a crude interleukin 1 preparation into embryos resulted in similar increases in hepatic zinc and MT concentrations as an endotoxin injection, suggesting a role for this cytokine in mediating the acute phase changes in embryonic zinc metabolism.

  15. Daily regulation of serum and urinary hepcidin is not influenced by submaximal cycling exercise in humans with normal iron metabolism.

    PubMed

    Troadec, Marie-Bérengère; Lainé, Fabrice; Daniel, Vincent; Rochcongar, Pierre; Ropert, Martine; Cabillic, Florian; Perrin, Michèle; Morcet, Jeff; Loréal, Olivier; Olbina, Gordana; Westerman, Mark; Nemeth, Elizabeta; Ganz, Tomas; Brissot, Pierre

    2009-06-01

    Hepcidin and hemojuvelin (HJV) are two critical regulators of iron metabolism as indicated by the development of major iron overload associated to mutations in hepcidin and HJV genes. Hepcidin and HJV are highly expressed in liver and muscles, respectively. Intensive muscular exercise has been reported to modify serum iron parameters and to increase hepcidinuria. The present study aimed at evaluating the potential impact of low intensity muscle exercise on iron metabolism and on hepcidin, its key regulator. Fourteen normal volunteers underwent submaximal cycling-based exercise in a crossover design and various iron parameters, including serum and urinary hepcidin, were serially studied. The results demonstrated that submaximal ergocycle endurance exercise did not modulate hepcidin. This study also indicated that hepcidinuria did not show any daily variation whereas serum hepcidin did. The findings, by demonstrating that hepcidin concentrations are not influenced by submaximal cycling exercise, may have implications for hepcidin sampling in medical practice.

  16. Behavioral, biochemical, and genetic analysis of iron metabolism in high-intensity blood donors.

    PubMed

    Mast, Alan E; Foster, Tisha M; Pinder, Holly L; Beczkiewicz, Craig A; Bellissimo, Daniel B; Murphy, Anthony T; Kovacevic, Steve; Wroblewski, Victor J; Witcher, Derrick R

    2008-10-01

    Individuals donating whole blood 13 times in a 2-year period without development of iron deficiency anemia (superdonors) are a self-selected population that is deferred for low hematocrit (Hct) level less frequently than other donors. Iron metabolism was assessed in 138 superdonors through a questionnaire and measurement of Hct, serum ferritin, serum hepcidin, and serum growth differentiation factor 15 (GDF15). Genetic testing for HFE and JAK-2 mutations was also performed. Iron deficiency (ferritin level, <30 microg/L) is present in more than 60 percent of superdonors. Behaviors altering iron status included casual use of iron supplements in males, but not in females, and cigarette smoking that produced increased Hct associated with decreased ferritin. The striking biochemical characteristic of superdonors is greatly decreased serum hepcidin, consistent with their need to absorb maximal amounts of dietary iron to replace that lost from blood donation. GDF15 is normal in most superdonors, indicating that GDF15 overexpression arising from the expanded erythroid pool necessary to replace donated red cells is not the biochemical mechanism for the decreased serum hepcidin. Mutations in JAK-2 were not found, indicating that undiagnosed polycythemia vera is not a common cause for successful repeated blood donation by superdonors. Mutations in HFE associated with hemochromatosis were present in superdonors at the same frequency as the normal population. However, superdonors heterozygous for the H63D mutation in HFE had significantly decreased hepcidin : ferritin ratios demonstrating for the first time that the heterozygous state for HFE mutations is associated with alterations in hepcidin expression.

  17. Searching iron sensors in plants by exploring the link among 2'-OG-dependent dioxygenases, the iron deficiency response and metabolic adjustments occurring under iron deficiency.

    PubMed

    Vigani, Gianpiero; Morandini, Piero; Murgia, Irene

    2013-01-01

    Knowledge accumulated on the regulation of iron (Fe) homeostasis, its intracellular trafficking and transport across various cellular compartments and organs in plants; storage proteins, transporters and transcription factors involved in Fe metabolism have been analyzed in detail in recent years. However, the key sensor(s) of cellular plant "Fe status" triggering the long-distance shoot-root signaling and leading to the root Fe deficiency responses is (are) still unknown. Local Fe sensing is also a major task for roots, for adjusting the internal Fe requirements to external Fe availability: how such sensing is achieved and how it leads to metabolic adjustments in case of nutrient shortage, is mostly unknown. Two proteins belonging to the 2'-OG-dependent dioxygenases family accumulate several folds in Fe-deficient Arabidopsis roots. Such proteins require Fe(II) as enzymatic cofactor; one of their subgroups, the HIF-P4H (hypoxia-inducible factor-prolyl 4-hydroxylase), is an effective oxygen sensor in animal cells. We envisage here the possibility that some members of the 2'-OG dioxygenase family may be involved in the Fe deficiency response and in the metabolic adjustments to Fe deficiency or even in sensing Fe, in plant cells.

  18. Searching iron sensors in plants by exploring the link among 2′-OG-dependent dioxygenases, the iron deficiency response and metabolic adjustments occurring under iron deficiency

    PubMed Central

    Vigani, Gianpiero; Morandini, Piero; Murgia, Irene

    2013-01-01

    Knowledge accumulated on the regulation of iron (Fe) homeostasis, its intracellular trafficking and transport across various cellular compartments and organs in plants; storage proteins, transporters and transcription factors involved in Fe metabolism have been analyzed in detail in recent years. However, the key sensor(s) of cellular plant “Fe status” triggering the long-distance shoot–root signaling and leading to the root Fe deficiency responses is (are) still unknown. Local Fe sensing is also a major task for roots, for adjusting the internal Fe requirements to external Fe availability: how such sensing is achieved and how it leads to metabolic adjustments in case of nutrient shortage, is mostly unknown. Two proteins belonging to the 2′-OG-dependent dioxygenases family accumulate several folds in Fe-deficient Arabidopsis roots. Such proteins require Fe(II) as enzymatic cofactor; one of their subgroups, the HIF-P4H (hypoxia-inducible factor-prolyl 4-hydroxylase), is an effective oxygen sensor in animal cells. We envisage here the possibility that some members of the 2′-OG dioxygenase family may be involved in the Fe deficiency response and in the metabolic adjustments to Fe deficiency or even in sensing Fe, in plant cells. PMID:23755060

  19. Pf4 bacteriophage produced by Pseudomonas aeruginosa inhibits Aspergillus fumigatus metabolism via iron sequestration.

    PubMed

    Penner, Jack C; Ferreira, Jose A G; Secor, Patrick R; Sweere, Johanna M; Birukova, Maria K; Joubert, Lydia-Marie; Haagensen, Janus A J; Garcia, Omar; Malkovskiy, Andrey V; Kaber, Gernot; Nazik, Hasan; Manasherob, Robert; Spormann, Alfred M; Clemons, Karl V; Stevens, David A; Bollyky, Paul L

    2016-09-01

    Pseudomonas aeruginosa (Pa) and Aspergillus fumigatus (Af) are major human pathogens known to interact in a variety of disease settings, including airway infections in cystic fibrosis. We recently reported that clinical CF isolates of Pa inhibit the formation and growth of Af biofilms. Here, we report that the bacteriophage Pf4, produced by Pa, can inhibit the metabolic activity of Af biofilms. This phage-mediated inhibition was dose dependent, ablated by phage denaturation, and was more pronounced against preformed Af biofilm rather than biofilm formation. In contrast, planktonic conidial growth was unaffected. Two other phages, Pf1 and fd, did not inhibit Af, nor did supernatant from a Pa strain incapable of producing Pf4. Pf4, but not Pf1, attaches to Af hyphae in an avid and prolonged manner, suggesting that Pf4-mediated inhibition of Af may occur at the biofilm surface. We show that Pf4 binds iron, thus denying Af a crucial resource. Consistent with this, the inhibition of Af metabolism by Pf4 could be overcome with supplemental ferric iron, with preformed biofilm more resistant to reversal. To our knowledge, this is the first report of a bacterium producing a phage that inhibits the growth of a fungus and the first description of a phage behaving as an iron chelator in a biological system.

  20. Metabolic Strategies in Energy-Limited Microbial Communities in the Anoxic Subsurface (Frasassi Cave System, Italy)

    NASA Astrophysics Data System (ADS)

    McCauley, R. L.; Jones, D. S.; Schaperdoth, I.; Steinberg, L.; Macalady, J. L.

    2010-12-01

    Two major sources of energy, light and chemical potential, are available to microorganisms. However, energy is not always abundant and is often a limiting factor in microbial survival and replication. The anoxic, terrestrial subsurface offers a unique opportunity to study microorganisms and their potentially novel metabolic strategies that are relevant for understanding biogeochemistry and biosignatures as related to the non-photosynthetic, energy-limited environments on the modern and ancient Earth and elsewhere in the solar system. Geochemical data collected in a remote stratified lake 600 m below ground surface in the sulfidic Frasassi cave system (Italy) suggest that little redox energy is available for life, consistent with low signal from domain-specific FISH probes. The carbon isotope signatures of biofilms (-33‰) and DIC (-9‰) in the anoxic water suggest in situ production by lithoautotrophs using RuBisCO. 16S rDNA libraries constructed from the biofilm are dominated by diverse sulfate reducing bacteria. The remaining bacterial and archaeal clones affiliate with more than 11 major uncultivated or novel prokaryotic lineages. Diverse dsrAB gene sequences are consistent with high sulfate concentrations and undetectable or extremely low oxygen, nitrate, and iron concentrations. However, the electron donor for sulfate reduction is unclear. Methane is detectable in the anoxic water although no 16S rDNA sequences associated with known methanogens or anaerobic methane oxidizers were retrieved. mcrA gene sequences retrieved from the biofilm by cloning are not related to cultivated methanogens or to known anaerobic methane oxidizers. Non-purgable organic carbon (NPOC) is below detection limits (i.e. <42 μM acetate) suggesting that alternative electron donors or novel metabolisms may be important. A sample collected by cave divers in October 2009 was pyrosequenced at the Pennsylvania State University Genomics Core Facility using Titanium chemistry (454 Life

  1. Accumulation and metabolism of iron-dextran by hepatocytes, Kupffer cells and endothelial cells in the neonatal pig liver.

    PubMed

    Caperna, T J; Failla, M L; Steele, N C; Richards, M P

    1987-02-01

    Treatment of newborn pigs with supplemental iron is a common procedure utilized to prevent neonatal anemia. The aim of this study was to investigate the hepatic distribution and intracellular metabolism of iron-dextran, a widely used colloidal-iron-carbohydrate preparation. Piglets were injected intramuscularly with iron-dextran (50 mg Fe/kg body wt) at 1 d of age. Hepatocytes and sinusoidal cells (Kupffer cells and endothelial cells) were isolated from iron-treated and control (uninjected) piglets at 2, 6 and 11 d of age. The concentrations of iron, copper and zinc in isolated cells were determined by atomic-absorption spectroscopy. In addition, the quantities of ferritin-protein and ferritin-iron were measured by immunoelectrophoresis and ion-exchange chromatography, respectively. At 2 d of age, the concentration (microgram/mg cell protein) of iron was 5-, 62- and 54-fold higher in hepatocytes, Kupffer cells and endothelial cells, respectively, isolated from iron-treated piglets than from control piglets. Hepatocytes, Kupffer cells and endothelial cells accumulated ferritin in response to iron-dextran treatment. Higher concentrations of ferritin-protein and ferritin-iron were present in Kupffer cells and endothelial cells than in hepatocytes at all times after treatment with iron-dextran. The percentage of cellular iron that was associated with ferritin, however, was greater in hepatocytes than in sinusoidal cells. Iron accumulated by all three liver cell types was mobilized to extrahepatic sites. Slight alterations in zinc and copper status of liver cells were evident at 11 d of age as a result of iron treatment.

  2. Two Sinorhizobium meliloti glutaredoxins regulate iron metabolism and symbiotic bacteroid differentiation.

    PubMed

    Benyamina, Sofiane M; Baldacci-Cresp, Fabien; Couturier, Jérémy; Chibani, Kamel; Hopkins, Julie; Bekki, Abdelkader; de Lajudie, Philippe; Rouhier, Nicolas; Jacquot, Jean-Pierre; Alloing, Geneviève; Puppo, Alain; Frendo, Pierre

    2013-03-01

    Legumes interact symbiotically with bacteria of the Rhizobiaceae to form nitrogen-fixing root nodules. We investigated the contribution of the three glutaredoxin (Grx)-encoding genes present in the Sinorhizobium meliloti genome to this symbiosis. SmGRX1 (CGYC active site) and SmGRX3 (CPYG) recombinant proteins displayed deglutathionylation activity in the 2-hydroethyldisulfide assay, whereas SmGRX2 (CGFS) did not. Mutation of SmGRX3 did not affect S. meliloti growth or symbiotic capacities. In contrast, SmGRX1 and SmGRX2 mutations decreased the growth of free-living bacteria and the nitrogen fixation capacity of bacteroids. Mutation of SmGRX1 led to nodule abortion and an absence of bacteroid differentiation, whereas SmGRX2 mutation decreased nodule development without modifying bacteroid development. The higher sensitivity of the Smgrx1 mutant strain as compared with wild-type strain to oxidative stress was associated with larger amounts of glutathionylated proteins. The Smgrx2 mutant strain displayed significantly lower levels of activity than the wild type for two iron-sulfur-containing enzymes, aconitase and succinate dehydrogenase. This lower level of activity could be associated with deregulation of the transcriptional activity of the RirA iron regulator and higher intracellular iron content. Thus, two S. meliloti Grx proteins are essential for symbiotic nitrogen fixation, playing independent roles in bacterial differentiation and the regulation of iron metabolism.

  3. Abnormal Brain Iron Metabolism in Irp2 Deficient Mice Is Associated with Mild Neurological and Behavioral Impairments

    PubMed Central

    Zumbrennen-Bullough, Kimberly B.; Becker, Lore; Garrett, Lillian; Hölter, Sabine M.; Calzada-Wack, Julia; Mossbrugger, Ilona; Quintanilla-Fend, Leticia; Racz, Ildiko; Rathkolb, Birgit; Klopstock, Thomas; Wurst, Wolfgang; Zimmer, Andreas; Wolf, Eckhard; Fuchs, Helmut; Gailus-Durner, Valerie; de Angelis, Martin Hrabě; Romney, Steven J.; Leibold, Elizabeth A.

    2014-01-01

    Iron Regulatory Protein 2 (Irp2, Ireb2) is a central regulator of cellular iron homeostasis in vertebrates. Two global knockout mouse models have been generated to explore the role of Irp2 in regulating iron metabolism. While both mouse models show that loss of Irp2 results in microcytic anemia and altered body iron distribution, discrepant results have drawn into question the role of Irp2 in regulating brain iron metabolism. One model shows that aged Irp2 deficient mice develop adult-onset progressive neurodegeneration that is associated with axonal degeneration and loss of Purkinje cells in the central nervous system. These mice show iron deposition in white matter tracts and oligodendrocyte soma throughout the brain. A contrasting model of global Irp2 deficiency shows no overt or pathological signs of neurodegeneration or brain iron accumulation, and display only mild motor coordination and balance deficits when challenged by specific tests. Explanations for conflicting findings in the severity of the clinical phenotype, brain iron accumulation and neuronal degeneration remain unclear. Here, we describe an additional mouse model of global Irp2 deficiency. Our aged Irp2−/− mice show marked iron deposition in white matter and in oligodendrocytes while iron content is significantly reduced in neurons. Ferritin and transferrin receptor 1 (TfR1, Tfrc), expression are increased and decreased, respectively, in the brain from Irp2−/− mice. These mice show impairments in locomotion, exploration, motor coordination/balance and nociception when assessed by neurological and behavioral tests, but lack overt signs of neurodegenerative disease. Ultrastructural studies of specific brain regions show no evidence of neurodegeneration. Our data suggest that Irp2 deficiency dysregulates brain iron metabolism causing cellular dysfunction that ultimately leads to mild neurological, behavioral and nociceptive impairments. PMID:24896637

  4. Effects of dietary manganese and iron on manganese and iron metabolism during infancy

    SciTech Connect

    Kiehl, H.; Loennerdal, B. )

    1991-03-15

    To derive a better understanding of the metabolism of Mn during infancy, infant formulas with different levels of Mn and Fe were labeled with {sup 54}Mn and {sup 59}Fe and administered orally to suckling rats: control low-Fe formula; control with 100-times Mn; and control with 100-times Fe. Another group received 200 {mu}g MnCl{sub 2} daily during infancy. 12 hr post-dosing, the pattern of {sup 54}Mn distribution in the tissues paralleled that of {sup 59}Fe. An excess of either mineral decreased overall retention but led to higher recoveries of both elements in the proximal intestine and liver. Conversely, these recoveries in pups given Mn from birth were lower than in controls. Analysis of the cytosolic fractions from intestine and liver using FPLC gel filtration demonstrated the impact of the mineral loads on protein profiles. In all cases except the high-Mn dose, dietary manipulations resulted in greater relative levels of a high molecular weight protein with MW similar to ferritin. The high-Mn formula seemed to induce in the hepatocyte a lower MW protein with which most of the {sup 54}Mn and {sup 59}Fe was associated. These results suggest a possible role of Mn as a regulator in the synthesis of cytosolic proteins of the enterocyte and hepatocyte in infants.

  5. Anaerobic Sulfur Metabolism Coupled to Dissimilatory Iron Reduction in the Extremophile Acidithiobacillus ferrooxidans

    PubMed Central

    Osorio, Héctor; Mangold, Stefanie; Denis, Yann; Ñancucheo, Ivan; Esparza, Mario; Johnson, D. Barrie; Bonnefoy, Violaine; Dopson, Mark

    2013-01-01

    Gene transcription (microarrays) and protein levels (proteomics) were compared in cultures of the acidophilic chemolithotroph Acidithiobacillus ferrooxidans grown on elemental sulfur as the electron donor under aerobic and anaerobic conditions, using either molecular oxygen or ferric iron as the electron acceptor, respectively. No evidence supporting the role of either tetrathionate hydrolase or arsenic reductase in mediating the transfer of electrons to ferric iron (as suggested by previous studies) was obtained. In addition, no novel ferric iron reductase was identified. However, data suggested that sulfur was disproportionated under anaerobic conditions, forming hydrogen sulfide via sulfur reductase and sulfate via heterodisulfide reductase and ATP sulfurylase. Supporting physiological evidence for H2S production came from the observation that soluble Cu2+ included in anaerobically incubated cultures was precipitated (seemingly as CuS). Since H2S reduces ferric iron to ferrous in acidic medium, its production under anaerobic conditions indicates that anaerobic iron reduction is mediated, at least in part, by an indirect mechanism. Evidence was obtained for an alternative model implicating the transfer of electrons from S0 to Fe3+ via a respiratory chain that includes a bc1 complex and a cytochrome c. Central carbon pathways were upregulated under aerobic conditions, correlating with higher growth rates, while many Calvin-Benson-Bassham cycle components were upregulated during anaerobic growth, probably as a result of more limited access to carbon dioxide. These results are important for understanding the role of A. ferrooxidans in environmental biogeochemical metal cycling and in industrial bioleaching operations. PMID:23354702

  6. THE LATTICE PARAMETERS AND SOLUBILITY LIMITS OF ALPHA IRON AS AFFECTED BY SOME BINARY TRANSITION-ELEMENT ADDITIONS.

    DTIC Science & Technology

    The lattice parameters of alpha iron with binary additions of all the transition metals, except technetium, have been accurately determined on solid...samples. No direct correlation with solute size is observed, but an effect of electron configuration is noted. The solubility limits of alpha iron with

  7. Effects of Iron Limitation on the Degradation of Toluene by Pseudomonas Strains Carrying the TOL (pWWO) Plasmid

    PubMed Central

    Dinkla, Inez J. T.; Gabor, Esther M.; Janssen, Dick B.

    2001-01-01

    Most aerobic biodegradation pathways for hydrocarbons involve iron-containing oxygenases. In iron-limited environments, such as the rhizosphere, this may influence the rate of degradation of hydrocarbon pollutants. We investigated the effects of iron limitation on the degradation of toluene by Pseudomonas putida mt2 and the transconjugant rhizosphere bacterium P. putida WCS358(pWWO), both of which contain the pWWO (TOL) plasmid that harbors the genes for toluene degradation. The results of continuous-culture experiments showed that the activity of the upper-pathway toluene monooxygenase decreased but that the activity of benzyl alcohol dehydrogenase was not affected under iron-limited conditions. In contrast, the activities of three meta-pathway (lower-pathway) enzymes were all found to be reduced when iron concentrations were decreased. Additional experiments in which citrate was used as a growth substrate and the pathways were induced with the gratuitous inducer o-xylene showed that expression of the TOL genes increased the iron requirement in both strains. Growth yields were reduced and substrate affinities decreased under iron-limited conditions, suggesting that iron availability can be an important parameter in the oxidative breakdown of hydrocarbons. PMID:11472911

  8. Iron in Child Obesity. Relationships with Inflammation and Metabolic Risk Factors

    PubMed Central

    Bouglé, Dominique; Brouard, Jacques

    2013-01-01

    Iron (Fe) sequestration is described in overweight and in its associated metabolic complications, i.e., metabolic syndrome (MetS) and non-alcoholic liver fatty disease (NAFLD); however, the interactions between Fe, obesity and inflammation make it difficult to recognize the specific role of each of them in the risk of obesity-induced metabolic diseases. Even the usual surrogate marker of Fe stores, ferritin, is influenced by inflammation; therefore, in obese subjects inflammation parameters must be measured together with those of Fe metabolism. This cross-sectional study in obese youth (502 patients; 57% girls): 11.4 ± 3.0 years old (x ± SD); BMI z score 5.5 ± 2.3), multivariate regression analysis showed associations between Fe storage assessed by serum ferritin with risk factors for MetS and NAFLD, assessed by transaminase levels, which were independent of overweight and the acute phase protein fibrinogen. Further studies incorporating the measurement of complementary parameters of Fe metabolism could improve the comprehension of mechanisms involved. PMID:23783556

  9. Iron Limitation of a Springtime Bacterial and Phytoplankton Community in the Ross Sea: Implications for Vitamin B12 Nutrition

    PubMed Central

    Bertrand, Erin M.; Saito, Mak A.; Lee, Peter A.; Dunbar, Robert B.; Sedwick, Peter N.; DiTullio, Giacomo R.

    2011-01-01

    The Ross Sea is home to some of the largest phytoplankton blooms in the Southern Ocean. Primary production in this system has previously been shown to be iron limited in the summer and periodically iron and vitamin B12 colimited. In this study, we examined trace metal limitation of biological activity in the Ross Sea in the austral spring and considered possible implications for vitamin B12 nutrition. Bottle incubation experiments demonstrated that iron limited phytoplankton growth in the austral spring while B12, cobalt, and zinc did not. This is the first demonstration of iron limitation in a Phaeocystis antarctica-dominated, early season Ross Sea phytoplankton community. The lack of B12 limitation in this location is consistent with previous Ross Sea studies in the austral summer, wherein vitamin additions did not stimulate P. antarctica growth and B12 was limiting only when bacterial abundance was low. Bottle incubation experiments and a bacterial regrowth experiment also revealed that iron addition directly enhanced bacterial growth. B12 uptake measurements in natural water samples and in an iron fertilized bottle incubation demonstrated that bacteria serve not only as a source for vitamin B12, but also as a significant sink, and that iron additions enhanced B12 uptake rates in phytoplankton but not bacteria. Additionally, vitamin uptake rates did not become saturated upon the addition of up to 95 pM B12. A rapid B12 uptake rate was observed after 13 min, which then decreased to a slower constant uptake rate over the next 52 h. Results from this study highlight the importance of iron availability in limiting early season Ross Sea phytoplankton growth and suggest that rates of vitamin B12 production and consumption may be impacted by iron availability. PMID:21886638

  10. Iron limitation of a springtime bacterial and phytoplankton community in the ross sea: implications for vitamin b(12) nutrition.

    PubMed

    Bertrand, Erin M; Saito, Mak A; Lee, Peter A; Dunbar, Robert B; Sedwick, Peter N; Ditullio, Giacomo R

    2011-01-01

    The Ross Sea is home to some of the largest phytoplankton blooms in the Southern Ocean. Primary production in this system has previously been shown to be iron limited in the summer and periodically iron and vitamin B(12) colimited. In this study, we examined trace metal limitation of biological activity in the Ross Sea in the austral spring and considered possible implications for vitamin B(12) nutrition. Bottle incubation experiments demonstrated that iron limited phytoplankton growth in the austral spring while B(12), cobalt, and zinc did not. This is the first demonstration of iron limitation in a Phaeocystis antarctica-dominated, early season Ross Sea phytoplankton community. The lack of B(12) limitation in this location is consistent with previous Ross Sea studies in the austral summer, wherein vitamin additions did not stimulate P. antarctica growth and B(12) was limiting only when bacterial abundance was low. Bottle incubation experiments and a bacterial regrowth experiment also revealed that iron addition directly enhanced bacterial growth. B(12) uptake measurements in natural water samples and in an iron fertilized bottle incubation demonstrated that bacteria serve not only as a source for vitamin B(12), but also as a significant sink, and that iron additions enhanced B(12) uptake rates in phytoplankton but not bacteria. Additionally, vitamin uptake rates did not become saturated upon the addition of up to 95 pM B(12). A rapid B(12) uptake rate was observed after 13 min, which then decreased to a slower constant uptake rate over the next 52 h. Results from this study highlight the importance of iron availability in limiting early season Ross Sea phytoplankton growth and suggest that rates of vitamin B(12) production and consumption may be impacted by iron availability.

  11. Elevated Carbon Dioxide Improves Plant Iron Nutrition through Enhancing the Iron-Deficiency-Induced Responses under Iron-Limited Conditions in Tomato1[OA

    PubMed Central

    Jin, Chong Wei; Du, Shao Ting; Chen, Wei Wei; Li, Gui Xin; Zhang, Yong Song; Zheng, Shao Jian

    2009-01-01

    The increases in atmospheric carbon dioxide (CO2) concentrations can enhance plant growth and change their nutrient demands. We report that when tomato (Lycopersicon esculentum ‘Zheza 809’) plants were grown in iron (Fe)-limited medium (with hydrous ferric iron oxide) and elevated CO2 (800 μL L−1), their biomass and root-to-shoot ratio were greater than plants grown in ambient CO2 (350 μL L−1). Furthermore, the associated increase in Fe concentrations in the shoots and roots alleviated Fe-deficiency-induced chlorosis. Despite the improved nutrient status of plants grown in Fe-limited medium under elevated CO2, the Fe-deficiency-induced responses in roots, including ferric chelate reductase activity, proton secretion, subapical root hair development, and the expression of FER, FRO1, and IRT genes, were all greater than plants grown in the ambient CO2. The biomass of plants grown in Fe-sufficient medium was also increased by the elevated CO2 treatment, but changes in tissue Fe concentrations and Fe deficiency responses were not observed. These results suggest that the improved Fe nutrition and induction of Fe-deficient-induced responses in plants grown in Fe-limited medium under elevated CO2 are caused by interactions between elevated CO2 and Fe deprivation. Elevated CO2 also increased the nitric oxide (NO) levels in roots, but treatment with the NO scavenger cPTIO inhibited ferric chelate reductase activity and prevented the accumulation of LeFRO1, LeIRT1, and FER transcripts in roots of the Fe-limited plants. These results implicate some involvement of NO in enhancing Fe-deficiency-induced responses when Fe limitation and elevated CO2 occur together. We propose that the combination of elevated CO2 and Fe limitation induces morphological, physiological, and molecular responses that enhance the capacity for plants to access and utilize Fe from sparingly soluble sources, such as Fe(III)-oxide. PMID:19329565

  12. Prion Protein (PrP) Knock-Out Mice Show Altered Iron Metabolism: A Functional Role for PrP in Iron Uptake and Transport

    PubMed Central

    Singh, Ajay; Kong, Qingzhong; Luo, Xiu; Petersen, Robert B.; Meyerson, Howard; Singh, Neena

    2009-01-01

    Despite overwhelming evidence implicating the prion protein (PrP) in prion disease pathogenesis, the normal function of this cell surface glycoprotein remains unclear. In previous reports we demonstrated that PrP mediates cellular iron uptake and transport, and aggregation of PrP to the disease causing PrP-scrapie (PrPSc) form results in imbalance of iron homeostasis in prion disease affected human and animal brains. Here, we show that selective deletion of PrP in transgenic mice (PrPKO) alters systemic iron homeostasis as reflected in hematological parameters and levels of total iron and iron regulatory proteins in the plasma, liver, spleen, and brain of PrPKO mice relative to matched wild type controls. Introduction of radiolabeled iron (59FeCl3) to Wt and PrPKO mice by gastric gavage reveals inefficient transport of 59Fe from the duodenum to the blood stream, an early abortive spike of erythropoiesis in the long bones and spleen, and eventual decreased 59Fe content in red blood cells and all major organs of PrPKO mice relative to Wt controls. The iron deficient phenotype of PrPKO mice is reversed by expressing Wt PrP in the PrPKO background, demonstrating a functional role for PrP in iron uptake and transport. Since iron is required for essential metabolic processes and is also potentially toxic if mismanaged, these results suggest that loss of normal function of PrP due to aggregation to the PrPSc form induces imbalance of brain iron homeostasis, resulting in disease associated neurotoxicity. PMID:19568430

  13. [Effect of dinitrosyl iron complexes on erythrocyte energy metabolism under thermal trauma conditions].

    PubMed

    Martusevich, A K; Solov'eva, A G; Peretiagin, S P; Vanin, A F

    2014-01-01

    The effect of dinitrosyl iron complexes (DNIC) on the energy metabolism of erythrocytes under combined thermal trauma conditions has been studied on a group of 30 Wistar rats, which was divided into 3 groups: intact (n = 10), control (n = 10), and main (n = 10). Combined thermal trauma (skin burn + thermoinhalation damage) was modeled in animals of the control and main groups. Rats of control group received infusions of sodium chloride solution (n = 10) every day. Rats of the main group obtained infusions of DNIC solution in sodium chloride. Rat blood samples were characterized by the activity of lactate dehydrogenase in direct and reverse reaction, lactate level, and coefficients of the substrate provision and energy reactions balance. It was stated, that DNIC clearly normalized the energy metabolism of erythrocytes beginning with the third day after thermal trauma onset.

  14. The effects of maternal iron deficiency on infant fibroblast growth factor-23 and mineral metabolism

    PubMed Central

    Braithwaite, V.S.; Prentice, A.; Darboe, M.K.; Prentice, A.M.; Moore, S.E.

    2016-01-01

    Fibroblast growth factor-23 (FGF23), a phosphate(Phos)-regulating hormone, is abnormally elevated in hypophosphataemic syndromes and an elevated FGF23 is a predictor of mortality in kidney disease. Recent findings suggest iron deficiency as a potential mediator of FGF23 expression and murine studies have shown in utero effects of maternal iron deficiency on offspring FGF23 and phosphate metabolism. Our aim was to investigate the impact of maternal iron status on infant FGF23 and mineral metabolites over the first 2 years of life. Infants born to mothers with normal (NIn = 25,) and low (LIn = 25) iron status during pregnancy, from a mother-infant trial (ISRCTN49285450) in rural Gambia, West Africa, had blood and plasma samples analysed at 12, 24, 52, 78 and 104 weeks (wk) of age. Circulating intact-FGF23 (I-FGF23), Phos, total alkaline phosphatase (TALP) and haemoglobin (Hb) decreased and estimated glomerular filtration rate increased over time [all P ≤ 0.0001)]. C-terminal-FGF23 (C-FGF23) and TALP were significantly higher in LI compared with NI, from 52 wk for C-FGF23 [Beta coefficient (SE) 18.1 (0.04) %, P = 0.04] and from 24 wk for TALP [44.7 (29.6) U/L, P = 0.04]. Infant Hb was the strongest negative predictor of C-FGF23 concentration [− 21% (4%) RU/mL, P ≤ 0.0001], Phos was the strongest positive predictor of I-FGF23 [32.0(3.9) pg/mL, P ≤ 0.0001] and I-FGF23 did not predict C-FGF23 over time [− 0.5% (0.5%), P = 0.3]. In conclusion, this study suggests that poor maternal iron status is associated with a higher infant C-FGF23 and TALP but similar I-FGF23 concentrations in infants and young children. These findings further highlight the likely public health importance of preventing iron deficiency during pregnancy. Whether or not children who are born to iron deficient mothers have persistently high concentrations of these metabolites and are more likely to be at risk of impaired bone development and pre-disposed to rickets

  15. Lipocalin 2 bolsters innate and adaptive immune responses to blood-stage malaria infection by reinforcing host iron metabolism.

    PubMed

    Zhao, Hong; Konishi, Aki; Fujita, Yukiko; Yagi, Masanori; Ohata, Keiichi; Aoshi, Taiki; Itagaki, Sawako; Sato, Shintaro; Narita, Hirotaka; Abdelgelil, Noha H; Inoue, Megumi; Culleton, Richard; Kaneko, Osamu; Nakagawa, Atsushi; Horii, Toshihiro; Akira, Shizuo; Ishii, Ken J; Coban, Cevayir

    2012-11-15

    Plasmodium parasites multiply within host erythrocytes, which contain high levels of iron, and parasite egress from these cells results in iron release and host anemia. Although Plasmodium requires host iron for replication, how host iron homeostasis and responses to these fluxes affect Plasmodium infection are incompletely understood. We determined that Lipocalin 2 (Lcn2), a host protein that sequesters iron, is abundantly secreted during human (P. vivax) and mouse (P. yoeliiNL) blood-stage malaria infections and is essential to control P. yoeliiNL parasitemia, anemia, and host survival. During infection, Lcn2 bolsters both host macrophage function and granulocyte recruitment and limits reticulocytosis, or the expansion of immature erythrocytes, which are the preferred target cell of P. yoeliiNL. Additionally, a chronic iron imbalance due to Lcn2 deficiency results in impaired adaptive immune responses against Plasmodium parasites. Thus, Lcn2 exerts antiparasitic effects by maintaining iron homeostasis and promoting innate and adaptive immune responses.

  16. Iron-Restricted Diet Affects Brain Ferritin Levels, Dopamine Metabolism and Cellular Prion Protein in a Region-Specific Manner.

    PubMed

    Pino, Jessica M V; da Luz, Marcio H M; Antunes, Hanna K M; Giampá, Sara Q de Campos; Martins, Vilma R; Lee, Kil S

    2017-01-01

    Iron is an essential micronutrient for several physiological functions, including the regulation of dopaminergic neurotransmission. On the other hand, both iron, and dopamine can affect the folding and aggregation of proteins related with neurodegenerative diseases, such as cellular prion protein (PrP(C)) and α-synuclein, suggesting that deregulation of iron homeostasis and the consequential disturbance of dopamine metabolism can be a risk factor for conformational diseases. These proteins, in turn, are known to participate in the regulation of iron and dopamine metabolism. In this study, we evaluated the effects of dietary iron restriction on brain ferritin levels, dopamine metabolism, and the expression levels of PrP(C) and α-synuclein. To achieve this goal, C57BL/6 mice were fed with iron restricted diet (IR) or with normal diet (CTL) for 1 month. IR reduced iron and ferritin levels in liver. Ferritin reduction was also observed in the hippocampus. However, in the striatum of IR group, ferritin level was increased, suggesting that under iron-deficient condition, each brain area might acquire distinct capacity to store iron. Increased lipid peroxidation was observed only in hippocampus of IR group, where ferritin level was reduced. IR also generated discrete results regarding dopamine metabolism of distinct brain regions: in striatum, the level of dopamine metabolites (DOPAC and HVA) was reduced; in prefrontal cortex, only HVA was increased along with the enhanced MAO-A activity; in hippocampus, no alterations were observed. PrP(C) levels were increased only in the striatum of IR group, where ferritin level was also increased. PrP(C) is known to play roles in iron uptake. Thus, the increase of PrP(C) in striatum of IR group might be related to the increased ferritin level. α-synuclein was not altered in any regions. Abnormal accumulation of ferritin, increased MAO-A activity or lipid peroxidation are molecular features observed in several neurological

  17. Iron-Restricted Diet Affects Brain Ferritin Levels, Dopamine Metabolism and Cellular Prion Protein in a Region-Specific Manner

    PubMed Central

    Pino, Jessica M. V.; da Luz, Marcio H. M.; Antunes, Hanna K. M.; Giampá, Sara Q. de Campos; Martins, Vilma R.; Lee, Kil S.

    2017-01-01

    Iron is an essential micronutrient for several physiological functions, including the regulation of dopaminergic neurotransmission. On the other hand, both iron, and dopamine can affect the folding and aggregation of proteins related with neurodegenerative diseases, such as cellular prion protein (PrPC) and α-synuclein, suggesting that deregulation of iron homeostasis and the consequential disturbance of dopamine metabolism can be a risk factor for conformational diseases. These proteins, in turn, are known to participate in the regulation of iron and dopamine metabolism. In this study, we evaluated the effects of dietary iron restriction on brain ferritin levels, dopamine metabolism, and the expression levels of PrPC and α-synuclein. To achieve this goal, C57BL/6 mice were fed with iron restricted diet (IR) or with normal diet (CTL) for 1 month. IR reduced iron and ferritin levels in liver. Ferritin reduction was also observed in the hippocampus. However, in the striatum of IR group, ferritin level was increased, suggesting that under iron-deficient condition, each brain area might acquire distinct capacity to store iron. Increased lipid peroxidation was observed only in hippocampus of IR group, where ferritin level was reduced. IR also generated discrete results regarding dopamine metabolism of distinct brain regions: in striatum, the level of dopamine metabolites (DOPAC and HVA) was reduced; in prefrontal cortex, only HVA was increased along with the enhanced MAO-A activity; in hippocampus, no alterations were observed. PrPC levels were increased only in the striatum of IR group, where ferritin level was also increased. PrPC is known to play roles in iron uptake. Thus, the increase of PrPC in striatum of IR group might be related to the increased ferritin level. α-synuclein was not altered in any regions. Abnormal accumulation of ferritin, increased MAO-A activity or lipid peroxidation are molecular features observed in several neurological disorders. Our

  18. Iron and aluminium oxides containing industrial wastes as adsorbents of heavy metals: Application possibilities and limitations.

    PubMed

    Jacukowicz-Sobala, Irena; Ociński, Daniel; Kociołek-Balawejder, Elżbieta

    2015-07-01

    Industrial wastes with a high iron or aluminium oxide content are produced in huge quantities as by-products of water treatment (water treatment residuals), bauxite processing (red mud) and hard and brown coal burning in power plants (fly ash). Although they vary in their composition, the wastes have one thing in common--a high content of amorphous iron and/or aluminium oxides with a large specific surface area, whereby this group of wastes shows very good adsorbability towards heavy metals, arsenates, selenates, etc. But their physical form makes their utilisation quite difficult, since it is not easy to separate the spent sorbent from the solution and high bed hydraulic resistances occur in dynamic regime processes. Nevertheless, because of the potential benefits of utilising the wastes in industrial effluent treatment, this issue attracts much attention today. This study describes in detail the waste generation processes, the chemical structure of the wastes, their physicochemical properties, and the mechanisms of fixing heavy metals and semimetals on the surface of iron and aluminium oxides. Typical compositions of wastes generated in selected industrial plants are given. A detailed survey of the literature on the adsorption applications of the wastes, including methods of their thermal and chemical activation, as well as regeneration of the spent sorbents, is presented. The existing and potential ways of modifying the physical form of the discussed group of wastes, making it possible to overcome the basic limitation on their practical use, are discussed. © The Author(s) 2015.

  19. Gravitational collapse of a rotating iron stellar core: The limiting case of transparency to neutrino emission

    NASA Astrophysics Data System (ADS)

    Imshennik, V. S.; Molokanov, V. O.

    2010-10-01

    A quasi-one-dimensional hydrodynamic model for the collapse of a rotating iron stellar core is used to determine the neutrino spectra in the limiting case of total transparency to neutrino emission (without any deposition effect). The derived spectra allow the previously constructed spectra used to theoretically estimate the number of events in the LSD underground neutrino detector from SN 1987A to be refined. At typical iron stellar core parameters, including those that characterize the core rotation specified in the initial conditions of the model, this number has turned out to be 1.6, which is close in order of magnitude to its experimental value of 5. Here, we compare in detail these results by assuming that the transparency of the collapsing iron core itself could be attributable to the development of its three-dimensional dynamical instability—the subject of future theoretical studies. The physical formulation of the problem coincides closely with the collapse model proposed in our previous paper, where the above number of events turned out to be 0.5. We have confirmed the previously published results with regard to the neutrino spectra, including the significant superiority of electron neutrinos over electron antineutrinos in them. The hydrostatically equilibrium configuration (a rotating collapsar) obtained in our model calculation is discussed in comparison with self-similar solutions that are close in physical formulation of the problem. This result seems a nontrivial consequence of the included rotation effects that hinder nonstop collapse established in the mentioned self-similar solutions.

  20. Iron limitation of microbial phosphorus acquisition in the tropical North Atlantic

    NASA Astrophysics Data System (ADS)

    Browning, Thomas; Achterberg, Eric; Yong, Jaw Chuen; Rapp, Insa; Utermann, Caroline; Engel, Anja; Moore, Mark

    2017-04-01

    Growth-limitation of marine phytoplankton by fixed nitrogen (N) has been demonstrated for most of the low-latitude oceans; however, in the (sub)tropical North Atlantic enhanced N2 fixation leads to secondary/(co-)limitation by phosphorus (P). The dissolved organic P pool is rarely fully depleted in the modern ocean and potentially represents a substantial additional P source. Microbes can use a variety of alkaline phosphatase enzymes to access P from a major fraction of this pool. In contrast to the relatively well studied PhoA family of alkaline phosphatases that utilize zinc (Zn) as a cofactor, the recent discovery of iron (Fe) as a cofactor in the more widespread PhoX[1] and PhoD[2] enzymes imply potential for a complex, biochemically-dependant interplay between oceanic Zn, Fe and P cycles. Here we demonstrate enhanced natural community alkaline phosphatase activity (APA) following Fe amendment within the low Zn and moderately low Fe western tropical North Atlantic. In contrast, beneath the Saharan dust plume in the Eastern Atlantic no APA response to trace metal addition was observed. This is the first demonstration of intermittent Fe limitation of microbial P acquisition, providing an additional facet in the argument for Fe control of the coupling between oceanic N and P cycles. 1. Yong, S. C. et al. A complex iron-calcium cofactor catalyzing phosphotransfer chemistry. Science 345, 1170-3 (2014). 2. Rodriguez, F. et al. Crystal structure of the Bacillus subtilis phosphodiesterase PhoD reveals an iron and calcium-containing active site. J. Biol. Chem. 289, 30889-30899 (2014).

  1. Redox Balance in Lactobacillus reuteri DSM20016: Roles of Iron-Dependent Alcohol Dehydrogenases in Glucose/ Glycerol Metabolism.

    PubMed

    Chen, Lu; Bromberger, Paul David; Nieuwenhuiys, Gavin; Hatti-Kaul, Rajni

    2016-01-01

    Lactobacillus reuteri, a heterofermentative bacterium, metabolizes glycerol via a Pdu (propanediol-utilization) pathway involving dehydration to 3-hydroxypropionaldehyde (3-HPA) followed by reduction to 1,3-propandiol (1,3-PDO) with concomitant generation of an oxidized cofactor, NAD+ that is utilized to maintain cofactor balance required for glucose metabolism and even for oxidation of 3-HPA by a Pdu oxidative branch to 3-hydroxypropionic acid (3-HP). The Pdu pathway is operative inside Pdu microcompartment that encapsulates different enzymes and cofactors involved in metabolizing glycerol or 1,2-propanediol, and protects the cells from the toxic effect of the aldehyde intermediate. Since L. reuteri excretes high amounts of 3-HPA outside the microcompartment, the organism is likely to have alternative alcohol dehydrogenase(s) in the cytoplasm for transformation of the aldehyde. In this study, diversity of alcohol dehydrogenases in Lactobacillus species was investigated with a focus on L. reuteri. Nine ADH enzymes were found in L. reuteri DSM20016, out of which 3 (PduQ, ADH6 and ADH7) belong to the group of iron-dependent enzymes that are known to transform aldehydes/ketones to alcohols. L. reuteri mutants were generated in which the three ADHs were deleted individually. The lagging growth phenotype of these deletion mutants revealed that limited NAD+/NADH recycling could be restricting their growth in the absence of ADHs. Notably, it was demonstrated that PduQ is more active in generating NAD+ during glycerol metabolism within the microcompartment by resting cells, while ADH7 functions to balance NAD+/NADH by converting 3-HPA to 1,3-PDO outside the microcompartment in the growing cells. Moreover, evaluation of ADH6 deletion mutant showed strong decrease in ethanol level, supporting the role of this bifuctional alcohol/aldehyde dehydrogenase in ethanol production. To the best of our knowledge, this is the first report revealing both internal and external recycling

  2. Statistical analysis of iron geochemical data suggests limited late Proterozoic oxygenation

    NASA Astrophysics Data System (ADS)

    Sperling, Erik A.; Wolock, Charles J.; Morgan, Alex S.; Gill, Benjamin C.; Kunzmann, Marcus; Halverson, Galen P.; MacDonald, Francis A.; Knoll, Andrew H.; Johnston, David T.

    2015-07-01

    Sedimentary rocks deposited across the Proterozoic-Phanerozoic transition record extreme climate fluctuations, a potential rise in atmospheric oxygen or re-organization of the seafloor redox landscape, and the initial diversification of animals. It is widely assumed that the inferred redox change facilitated the observed trends in biodiversity. Establishing this palaeoenvironmental context, however, requires that changes in marine redox structure be tracked by means of geochemical proxies and translated into estimates of atmospheric oxygen. Iron-based proxies are among the most effective tools for tracking the redox chemistry of ancient oceans. These proxies are inherently local, but have global implications when analysed collectively and statistically. Here we analyse about 4,700 iron-speciation measurements from shales 2,300 to 360 million years old. Our statistical analyses suggest that subsurface water masses in mid-Proterozoic oceans were predominantly anoxic and ferruginous (depleted in dissolved oxygen and iron-bearing), but with a tendency towards euxinia (sulfide-bearing) that is not observed in the Neoproterozoic era. Analyses further indicate that early animals did not experience appreciable benthic sulfide stress. Finally, unlike proxies based on redox-sensitive trace-metal abundances, iron geochemical data do not show a statistically significant change in oxygen content through the Ediacaran and Cambrian periods, sharply constraining the magnitude of the end-Proterozoic oxygen increase. Indeed, this re-analysis of trace-metal data is consistent with oxygenation continuing well into the Palaeozoic era. Therefore, if changing redox conditions facilitated animal diversification, it did so through a limited rise in oxygen past critical functional and ecological thresholds, as is seen in modern oxygen minimum zone benthic animal communities.

  3. Statistical analysis of iron geochemical data suggests limited late Proterozoic oxygenation.

    PubMed

    Sperling, Erik A; Wolock, Charles J; Morgan, Alex S; Gill, Benjamin C; Kunzmann, Marcus; Halverson, Galen P; Macdonald, Francis A; Knoll, Andrew H; Johnston, David T

    2015-07-23

    Sedimentary rocks deposited across the Proterozoic-Phanerozoic transition record extreme climate fluctuations, a potential rise in atmospheric oxygen or re-organization of the seafloor redox landscape, and the initial diversification of animals. It is widely assumed that the inferred redox change facilitated the observed trends in biodiversity. Establishing this palaeoenvironmental context, however, requires that changes in marine redox structure be tracked by means of geochemical proxies and translated into estimates of atmospheric oxygen. Iron-based proxies are among the most effective tools for tracking the redox chemistry of ancient oceans. These proxies are inherently local, but have global implications when analysed collectively and statistically. Here we analyse about 4,700 iron-speciation measurements from shales 2,300 to 360 million years old. Our statistical analyses suggest that subsurface water masses in mid-Proterozoic oceans were predominantly anoxic and ferruginous (depleted in dissolved oxygen and iron-bearing), but with a tendency towards euxinia (sulfide-bearing) that is not observed in the Neoproterozoic era. Analyses further indicate that early animals did not experience appreciable benthic sulfide stress. Finally, unlike proxies based on redox-sensitive trace-metal abundances, iron geochemical data do not show a statistically significant change in oxygen content through the Ediacaran and Cambrian periods, sharply constraining the magnitude of the end-Proterozoic oxygen increase. Indeed, this re-analysis of trace-metal data is consistent with oxygenation continuing well into the Palaeozoic era. Therefore, if changing redox conditions facilitated animal diversification, it did so through a limited rise in oxygen past critical functional and ecological thresholds, as is seen in modern oxygen minimum zone benthic animal communities.

  4. Alterations of systemic and muscle iron metabolism in human subjects treated with low-dose recombinant erythropoietin.

    PubMed

    Robach, Paul; Recalcati, Stefania; Girelli, Domenico; Gelfi, Cecilia; Aachmann-Andersen, Niels J; Thomsen, Jonas J; Norgaard, Anne M; Alberghini, Alessandra; Campostrini, Natascia; Castagna, Annalisa; Viganò, Agnese; Santambrogio, Paolo; Kempf, Tibor; Wollert, Kai C; Moutereau, Stéphane; Lundby, Carsten; Cairo, Gaetano

    2009-06-25

    The high iron demand associated with enhanced erythropoiesis during high-altitude hypoxia leads to skeletal muscle iron mobilization and decrease in myoglobin protein levels. To investigate the effect of enhanced erythropoiesis on systemic and muscle iron metabolism under nonhypoxic conditions, 8 healthy volunteers were treated with recombinant erythropoietin (rhEpo) for 1 month. As expected, the treatment efficiently increased erythropoiesis and stimulated bone marrow iron use. It was also associated with a prompt and considerable decrease in urinary hepcidin and a slight transient increase in GDF-15. The increased iron use and reduced hepcidin levels suggested increased iron mobilization, but the treatment was associated with increased muscle iron and L ferritin levels. The muscle expression of transferrin receptor and ferroportin was up-regulated by rhEpo administration, whereas no appreciable change in myoglobin levels was observed, which suggests unaltered muscle oxygen homeostasis. In conclusion, under rhEpo stimulation, the changes in the expression of muscle iron proteins indicate the occurrence of skeletal muscle iron accumulation despite the remarkable hepcidin suppression that may be mediated by several factors, such as rhEpo or decreased transferrin saturation or both.

  5. Effect of S-allylcysteine, a sulphur containing amino acid on iron metabolism in streptozotocin induced diabetic rats.

    PubMed

    Saravanan, Ganapathy; Ponmurugan, Ponnusamy; Begum, Mustapha Shabana

    2013-04-01

    It is suggested that iron may play a role in the pathogenesis of diabetes. Iron is not only chaperoned through its essential functional pathways, but it also causes damage to biological systems by catalyzing the production of reactive oxygen species. So, the parenchymal tissues of several organs are subject to cell injury and functional insufficiency due to excess deposition of iron. The present study investigated the effects of S-allylcysteine (SAC), a sulphur containing amino acid derived from garlic on the changes in iron metabolism induced by oxidative stress in tissues, as well as on serum biochemical parameters of streptozotocin (STZ)-induced diabetic rats. SAC was administered orally for 45days to control and experimental diabetic rats. The effects of SAC on glucose, insulin, serum iron, ferritin, transferrin, serum bilirubin, heart heme oxygenase activity (HO) and δ-aminolevulinicacid dehydratase activity (δ-ALA-D) in liver and kidneys were studied. The levels of glucose, iron, ferritin, bilirubin and HO in liver were increased significantly (p<0.05) whereas the levels of insulin, transferrin and δ-ALA-D in tissues were decreased in diabetic rats. Administration of SAC to diabetic rats showed a decrease in blood glucose, iron, ferritin, bilirubin and HO. In addition, the levels of insulin, transferrin and δ-ALA-D activity in tissues were increased in SAC treated diabetic rats. These findings suggest that S-allylcysteine could have a protective effect against alterations in oxidative stress induced iron metabolism in the diabetic state which was evidenced by the capacity of this natural antioxidant to modulate parameters of iron metabolism. Copyright © 2012 Elsevier GmbH. All rights reserved.

  6. A proteomic analysis of the iron response of Photobacterium damselae subsp. damselae reveals metabolic adaptations to iron levels changes and novel potential virulence factors.

    PubMed

    Puentes, Beatriz; Balado, Miguel; Bermúdez-Crespo, José; Osorio, Carlos R; Lemos, Manuel L

    2017-03-01

    Photobacterium damselae subsp. damselae (Pdd) is a marine bacterium that can infect numerous species of marine fish as well as other species including humans. Low iron availability is one of the signs that bacterial pathogens can detect in order to begin colonizing their host, and the reduction of iron levels is a nonspecific host defense strategy that prevents bacterial proliferation. In this work a proteomic approach was used to study the gene expression adaptations of a Pdd strain in response to iron availability. A comparative analysis of induced proteins in both high- and low-iron conditions showed profound cellular metabolic adaptations that result, for instance, in amino acid requirement. It also provided important information about the changes that occur in the energetic metabolism induced by the surrounding iron levels, allowing for the identification of novel potential virulence factors. Among others, genes involved in the synthesis and transport of a vibrioferrin-like siderophore were identified for the first time. In addition to plasmid pPHDD1-encoded Dly and HlyA hemolysins, a pPHDD1-borne operon, which may encode a transferrin receptor, was also found. This operon identification suggests that this virulence plasmid could encode so-far unknown additional virulence factors other than hemolysins. Copyright © 2017 Elsevier B.V. All rights reserved.

  7. Iron-limitation and high light stress on phytoplankton populations from the Australian Sub-Antarctic Zone (SAZ)

    NASA Astrophysics Data System (ADS)

    Petrou, Katherina; Hassler, Christel S.; Doblin, Martina A.; Shelly, Kirsten; Schoemann, Véronique; van den Enden, Rick; Wright, Simon; Ralph, Peter J.

    2011-11-01

    The high nutrient low chlorophyll (HNLC) surface waters of the Southern Ocean are characterised by high concentrations of nitrate and phosphate, low concentrations of dissolved iron and deep vertical mixing. Future climate scenarios predict increased surface temperatures and ocean stratification in the region. These changes to vertical mixing will result in a slowdown of nutrient supply to surface waters and an increase in the integrated irradiance in the upper mixed layer. To investigate the influence of iron-limitation and high irradiance on phytoplankton growth and physiology, a 6-day shipboard incubation experiment was conducted during the Sub-Antarctic Zone Sensitivity to Environmental Change (SAZ Sense) voyage using phytoplankton populations from the upper mixed layer in the north-eastern SAZ region. Iron-limitation was induced with an organic siderophore and was compared with a 1 nM iron-enriched incubation and an unamended treatment (under silicate replete conditions). As expected, iron enrichment led to dominance by large diatoms and enhanced photosynthetic performance, while the iron-limited community showed a decline in total chl a and photochemical efficiency. Under the added stress of high light, the iron-limited community was able to cope with the shift from in situ (<150 μmol photons m -2 s -1) to incubation (mean=765 μmol photons m -2 s -1) irradiance by increasing the proportion of photoprotective pigments and diverting excess light energy via energy-dependent quenching ( qE). The responses to iron-limitation under high light showed that the phytoplankton community was able to acclimate to these conditions, but exhibited an overall decline in photosynthetic activity. Data presented here suggest the community shifts, in particular the decrease in diatoms, and the decline in photosynthetic performance of phytoplankton under low iron-high irradiance conditions has the potential to impact future ocean productivity and biogeochemical cycling.

  8. Proanthocyanidin Protects Human Embryo Hepatocytes from Fluoride-Induced Oxidative Stress by Regulating Iron Metabolism.

    PubMed

    Niu, Qiang; Mu, Lati; Li, Shugang; Xu, Shangzhi; Ma, Ruling; Guo, Shuxia

    2016-02-01

    To investigate whether grape seed proanthocyanidin extract (GSPE) antagonizes fluoride-induced oxidative injury by regulating iron metabolism, human embryo hepatic cells (L-02) were incubated with sodium fluoride (NaF, 80 mg/L) and/or GSPE (100 μmol/L) for 24 h. Results showed the glutathione peroxidase (GSH-Px) content, superoxide dismutase (SOD) activity, and total antioxidant capacity (T-AOC) level of the NaF group were significantly lower than that of the control group (P < 0.05), while malondialdehyde (MDA) content increased in the NaF group compared with the control group (P < 0.05). Moreover, the indexes mentioned above showed opposite changes in the NaF + GSPE group. In addition, iron content significantly increased in the NaF group compared to the control group(P < 0.05) and significantly decreased in the NaF + GSPE group compared to the NaF group (P < 0.05). Furthermore, hepcidin (coded by HAMP) messenger RNA (mRNA) expression significantly increased in the NaF group compared to the control group(P < 0.05) and significantly decreased in the NaF + GSPE group compared to the NaF group (P < 0.05). Ferroportin 1 (coded by FPN1) mRNA expression significantly decreased in the NaF group compared to the control group (P < 0.05) and significantly increased in the NaF + GSPE group compared to the NaF group (P < 0.05). These results indicate that GSPE provides significant cellular protection against oxidative stress induced by excessive fluoride via the iron metabolism regulation.

  9. Diurnal variations in iron concentrations and expression of genes involved in iron absorption and metabolism in pigs.

    PubMed

    Zhang, Yiming; Wan, Dan; Zhou, Xihong; Long, Ciming; Wu, Xin; Li, Lan; He, Liuqin; Huang, Pan; Chen, Shuai; Tan, Bie; Yin, Yulong

    2017-09-02

    Diurnal variations in serum iron levels have been well documented in clinical studies, and serum iron is an important diagnostic index for iron-deficiency anemia. However, the underlying mechanism of dynamic iron regulation in response to the circadian rhythm is still unclear. In this study, we investigated daily variations in iron status in the plasma and liver of pigs. The transcripts encoding key factors involved in iron uptake and homeostasis were evaluated. The results showed that iron levels in the plasma and liver exhibited diurnal rhythms. Diurnal variations were also observed in transcript levels of divalent metal transporter 1 (DMT1), membrane-associated ferric reductase 1 (DCYTB), and transferrin receptor (TfR) in the duodenum and jejunum, as well as hepcidin (HAMP) and TfR in the liver. Moreover, the results showed a network in which diurnal variations in systemic iron levels were tightly regulated by hepcidin and Tf/TfR via DCYTB and DMT1. These findings provide new insights into circadian iron homeostasis regulation. The diurnal variations in serum iron levels may also have pathophysiological implications for clinical diagnostics related to iron deficiency anemia in pigs. Copyright © 2017 Elsevier Inc. All rights reserved.

  10. Effects of exercise on hepcidin response and iron metabolism during recovery.

    PubMed

    Peeling, Peter; Dawson, Brian; Goodman, Carmel; Landers, Grant; Wiegerinck, Erwin T; Swinkels, Dorine W; Trinder, Debbie

    2009-12-01

    Urinary hepcidin, inflammation, and iron metabolism were examined during the 24 hr after exercise. Eight moderately trained athletes (6 men, 2 women) completed a 60-min running trial (15-min warm-up at 75-80% HR(peak) + 45 min at 85-90% HR(peak)) and a 60-min trial of seated rest in a randomized, crossover design. Venous blood and urine samples were collected pretrial, immediately posttrial, and at 3, 6, and 24 hr posttrial. Samples were analyzed for interleukin-6 (IL-6), C-reactive protein (CRP), serum iron, serum ferritin, and urinary hepcidin. The immediate postrun levels of IL-6 and 24-hr postrun levels of CRP were significantly increased from baseline (6.9 and 2.6 times greater, respectively) and when compared with the rest trial (p < or = .05). Hepcidin levels in the run trial after 3, 6, and 24 hr of recovery were significantly greater (1.7-3.1 times) than the pre- and immediate postrun levels (p < or = .05). This outcome was consistent in all participants, despite marked variation in the magnitude of rise. In addition, the 3-hr postrun levels of hepcidin were significantly greater than at 3 hr in the rest trial (3.0 times greater, p < or = .05). Hepcidin levels continued to increase at 6 hr postrun but failed to significantly differ from the rest trial (p = .071), possibly because of diurnal influence. Finally, serum iron levels were significantly increased immediately postrun (1.3 times, p < or = .05). The authors concluded that high-intensity exercise was responsible for a significant increase in hepcidin levels subsequent to a significant increase in IL-6 and serum iron.

  11. Iron Status and Metabolic Syndrome in Patients with Non-Alcoholic Fatty Liver Disease

    PubMed Central

    Ghamarchehreh, Mohammad Ebrahim; Jonaidi-Jafari, Nematollah; Bigdeli, Mohammad; Khedmat, Hossein; Saburi, Amin

    2016-01-01

    BACKGROUND A hypothesis has been presented about the role of serum iron, ferritin and transferrin saturation among patients with non-alcoholic fatty liver disease (NAFLD) and resistance to insulin (metabolic syndrome [MetS]), but there is much controversy. This study aimed at investigating the level of serum iron and demographic characteristics in patients with NAFLD with or without MetS. METHODS A case-control study was conducted on patients with elevated liver enzymes referring to Baqiyatallah clinic, Tehran, Iran during 2010-2011. After ruling out other causes of increased aminotransferases and approving the diagnosis of NAFLD, the patients were divided into two groups of with or without MetS. Then, the individuals’ demographic, sonographic, and laboratory characteristics were recorded. RESULTS This research included 299 patients suffering from NAFLD who were divided into MetS (n=143; 47.8%) and non-MetS (n=156; 52.2%) groups. The age, systolic and diastolic blood pressure, body mass index, waist/hip ratio, glucose tolerance test, serum insulin, C. peptide, triglyceride, and HB A1c were different between MetS and non-MetS groups (p<0.05). There was no significant difference in serum iron and ferritin levels between the two groups, however, a significant correlation was found between serum ferritin and alanine transaminase (p=0.005) and also aspartate aminotransferase (p=0.032). CONCLUSION Our findings did not show a significant relationship between iron, in free or storage form, and the presence of MetS among patients with NAFLD, but serum ferritin can correlate with hepatocytes injuries indicated by raised aminotransferases. Nevertheless, to clarify this relationship further molecular, genomic, and histopathological studies are required. PMID:26933479

  12. An energetic model for oxygen-limited metabolism

    SciTech Connect

    Beronio, P.B. Jr. . Amoco Research Center); Tsao, G.T. . Lab. of Renewable Resources Engineering)

    1993-12-01

    Microbial production of 2,3-butanediol by Klebsiella oxytoca occurs under conditions of an oxygen limitation. The extent to which substrate is oxidized to 2,3-butanediol and its coproducts, (acetic acid, acetoin, and ethanol) and the relative flow rates of substrate to energetic and biosynthetic pathways are controlled by the degree of oxygen limitation. Two energetic relationships which describe the response to an oxygen limitation have been derived. The first relationship describes the coupling between growth and energy production observed under oxygen-limited conditions. This allows calculation of energetic parameters and modeling of the cell mass and substrate profiles in terms of the degree of oxygen limitation only. The second relationship describes the average degree of oxidation and the rate of the end-product flow. The model has been tested with both batch and continuous culture. During these kinetic studies, two phases of growth have been observed: energy-coupled growth, which was described above; and, energy-uncoupled growth, which arises when the degree of oxygen limitation reaches a critical value. Optimal culture performance with respect to 2,3-butanediol productivity occurs during energy-coupled growth.

  13. Abnormal iron metabolism and oxidative stress in mice expressing a mutant form of the ferritin light polypeptide gene

    PubMed Central

    Barbeito, Ana G.; Garringer, Holly J.; Baraibar, Martin A.; Gao, Xiaoying; Arredondo, Miguel; Núñez, Marco T.; Smith, Mark A.; Ghetti, Bernardino; Vidal, Ruben

    2009-01-01

    Insertional mutations in exon 4 of the ferritin light chain (FTL) gene are associated with hereditary ferritinopathy (HF) or neuroferritinopathy, an autosomal dominant neurodegenerative disease characterized by progressive impairment of motor and cognitive functions. To determine the pathogenic mechanisms by which mutations in FTL lead to neurodegeneration, we investigated iron metabolism and markers of oxidative stress in the brain of transgenic (Tg) mice that express the mutant human FTL498-499InsTC cDNA. Compared with wild-type mice, brain extracts from Tg (FTL-Tg) mice showed an increase in the cytoplasmic levels of both FTL and ferritin heavy chain polypeptides, a decrease in the protein and mRNA levels of transferrin receptor-1, and a significant increase in iron levels. Transgenic mice also showed the presence of markers for lipid peroxidation, protein carbonyls, and nitrone–protein adducts in the brain. However, gene expression analysis of iron management proteins in the liver of Tg mice indicates that the FTL-Tg mouse liver is iron deficient. Our data suggest that disruption of iron metabolism in the brain has a primary role in the process of neurodegeneration in HF and that the pathogenesis of HF is likely to result from a combination of reduction in iron storage function and enhanced toxicity associated with iron-induced ferritin aggregates in the brain. PMID:19519778

  14. Tumor-initiating cells of breast and prostate origin show alterations in the expression of genes related to iron metabolism

    PubMed Central

    Tomkova, Veronika; Korenkova, Vlasta; Langerova, Lucie; Simonova, Ekaterina; Zjablovskaja, Polina; Alberich-Jorda, Meritxell; Neuzil, Jiri; Truksa, Jaroslav

    2017-01-01

    The importance of iron in the growth and progression of tumors has been widely documented. In this report, we show that tumor-initiating cells (TICs), represented by spheres derived from the MCF7 cell line, exhibit higher intracellular labile iron pool, mitochondrial iron accumulation and are more susceptible to iron chelation. TICs also show activation of the IRP/IRE system, leading to higher iron uptake and decrease in iron storage, suggesting that level of properly assembled cytosolic iron-sulfur clusters (FeS) is reduced. This finding is confirmed by lower enzymatic activity of aconitase and FeS cluster biogenesis enzymes, as well as lower levels of reduced glutathione, implying reduced FeS clusters synthesis/utilization in TICs. Importantly, we have identified specific gene signature related to iron metabolism consisting of genes regulating iron uptake, mitochondrial FeS cluster biogenesis and hypoxic response (ABCB10, ACO1, CYBRD1, EPAS1, GLRX5, HEPH, HFE, IREB2, QSOX1 and TFRC). Principal component analysis based on this signature is able to distinguish TICs from cancer cells in vitro and also Leukemia-initiating cells (LICs) from non-LICs in the mouse model of acute promyelocytic leukemia (APL). Majority of the described changes were also recapitulated in an alternative model represented by MCF7 cells resistant to tamoxifen (TAMR) that exhibit features of TICs. Our findings point to the critical importance of redox balance and iron metabolism-related genes and proteins in the context of cancer and TICs that could be potentially used for cancer diagnostics or therapy. PMID:28031527

  15. Quantitative proteomic view on secreted, cell surface-associated, and cytoplasmic proteins of the methicillin-resistant human pathogen Staphylococcus aureus under iron-limited conditions.

    PubMed

    Hempel, Kristina; Herbst, Florian-Alexander; Moche, Martin; Hecker, Michael; Becher, Dörte

    2011-04-01

    Staphylococcus aureus is capable of colonizing and infecting humans by its arsenal of surface-exposed and secreted proteins. Iron-limited conditions in mammalian body fluids serve as a major environmental signal to bacteria to express virulence determinants. Here we present a comprehensive, gel-free, and GeLC-MS/MS-based quantitative proteome profiling of S. aureus under this infection-relevant situation. (14)N(15)N metabolic labeling and three complementing approaches were combined for relative quantitative analyses of surface-associated proteins. The surface-exposed and secreted proteome profiling approaches comprise trypsin shaving, biotinylation, and precipitation of the supernatant. By analysis of the outer subproteomic and cytoplasmic protein fraction, 1210 proteins could be identified including 221 surface-associated proteins. Thus, access was enabled to 70% of the predicted cell wall-associated proteins, 80% of the predicted sortase substrates, two/thirds of lipoproteins and more than 50% of secreted and cytoplasmic proteins. For iron-deficiency, 158 surface-associated proteins were quantified. Twenty-nine proteins were found in altered amounts showing particularly surface-exposed proteins strongly induced, such as the iron-regulated surface determinant proteins IsdA, IsdB, IsdC and IsdD as well as lipid-anchored iron compound-binding proteins. The work presents a crucial subject for understanding S. aureus pathophysiology by the use of methods that allow quantitative surface proteome profiling.

  16. Impaired growth under iron-limiting conditions associated with the acquisition of colistin resistance in Acinetobacter baumannii.

    PubMed

    López-Rojas, Rafael; García-Quintanilla, Meritxell; Labrador-Herrera, Gema; Pachón, Jerónimo; McConnell, Michael J

    2016-06-01

    Acquisition of colistin resistance in Acinetobacter baumannii has been associated with reduced bacterial fitness and virulence, although the mechanisms underlying this fitness loss have not been well characterised. In this study, the role played by environmental iron levels on the growth and survival of colistin-resistant strains of A. baumannii was assessed. Growth assays with the colistin-susceptible ATCC 19606 strain and its colistin-resistant derivative RC64 [colistin minimum inhibitory concentration (MIC) of 64 mg/L] demonstrated that the strains grew similarly in rich laboratory medium (Mueller-Hinton broth), whereas RC64 demonstrated impaired growth compared with ATCC 19606 in human serum (>100-fold at 24 h). Compared with RC64, ATCC 19606 grew in the presence of higher concentrations of the iron-specific chelator 2,2'-bipyridine and grew more readily under iron-limiting conditions in solid and liquid media. In addition, iron supplementation of human serum increased the growth of RC64 compared with unsupplemented human serum to a greater extent than ATCC 19606. The ability of 11 colistin-resistant clinical isolates with mutations in the pmrB gene to grow in iron-replete and iron-limiting conditions was assessed, demonstrating that eight of the strains showed reduced growth under iron limitation. Individual mutations in the pmrB gene did not directly correlate with a decreased capacity for growth under iron limitation, suggesting that mutations in pmrB may not directly produce this phenotype. Together these results indicate that acquisition of colistin resistance in A. baumannii can be associated with a decreased ability to grow in low-iron environments.

  17. Mouse Handling Limits the Impact of Stress on Metabolic Endpoints

    PubMed Central

    Ghosal, Sriparna; Nunley, Amanda; Mahbod, Parinaz; Lewis, Alfor G.; Smith, Eric P.; Tong, Jenny; D’Alessio, David A.; Herman, James P.

    2015-01-01

    Studies focused on end-points that are confounded by stress are best performed under minimally stressful conditions. The objective of this study was to demonstrate the impact of handling designed to reduce animal stress on measurements of glucose tolerance. A cohort of mice (CD1.C57BL/6) naïve to any specific handling were subjected to either a previously described “cup” handling method, or a “tail-picked” method in which the animals were picked up by the tail (as is common for metabolic studies). Following training, an elevated plus maze (EPM) test was performed followed by measurement of blood glucose and plasma corticosterone. A second cohort (CD1.C57BL/6) was rendered obese by exposure to a high fat diet, handled with either the tail-picked or cup method and subjected to an intraperitoneal glucose tolerance test. A third cohort of C57BL/6 mice was exposed to a cup regimen that included a component of massage and was subjected to tests of anxiety-like behavior, glucose homeostasis, and corticosterone secretion. We found that the cup mice showed reduced anxiety-like behaviors in the EPM coupled with a reduction in blood glucose levels compared to mice handled by the tail-picked method. Additionally, cup mice on the high fat diet exhibited improved glucose tolerance compared to tail-picked controls. Finally, we found that the cup/massage group showed lower glucose levels following an overnight fast, and decreased anxiety-like behaviors associated with lower stress-induced plasma corticosterone concentration compared to tail-picked controls. These data demonstrate that application of handling methods that reduce anxiety-like behaviors in mice mitigates the confounding contribution of stress to interpretation of metabolic endpoints (such as glucose tolerance). PMID:26079207

  18. Mouse handling limits the impact of stress on metabolic endpoints.

    PubMed

    Ghosal, Sriparna; Nunley, Amanda; Mahbod, Parinaz; Lewis, Alfor G; Smith, Eric P; Tong, Jenny; D'Alessio, David A; Herman, James P

    2015-10-15

    Studies focused on end-points that are confounded by stress are best performed under minimally stressful conditions. The objective of this study was to demonstrate the impact of handling designed to reduce animal stress on measurements of glucose tolerance. A cohort of mice (CD1.C57BL/6) naïve to any specific handling was subjected to either a previously described "cup" handling method, or a "tail-picked" method in which the animals were picked up by the tail (as is common for metabolic studies). Following training, an elevated plus maze (EPM) test was performed followed by measurement of blood glucose and plasma corticosterone. A second cohort (CD1.C57BL/6) was rendered obese by exposure to a high fat diet, handled with either the tail-picked or cup method and subjected to an intraperitoneal glucose tolerance test. A third cohort of C57BL/6 mice was exposed to a cup regimen that included a component of massage and was subjected to tests of anxiety-like behavior, glucose homeostasis, and corticosterone secretion. We found that the cup mice showed reduced anxiety-like behaviors in the EPM coupled with a reduction in blood glucose levels compared to mice handled by the tail-picked method. Additionally, cup mice on the high fat diet exhibited improved glucose tolerance compared to tail-picked controls. Finally, we found that the cup/massage group showed lower glucose levels following an overnight fast, and decreased anxiety-like behaviors associated with lower stress-induced plasma corticosterone concentration compared to tail-picked controls. These data demonstrate that application of handling methods that reduce anxiety-like behaviors in mice mitigates the confounding contribution of stress to interpretation of metabolic endpoints (such as glucose tolerance). Copyright © 2015 Elsevier Inc. All rights reserved.

  19. The Effect of the Hemochromatosis (HFE) Genotype on Lead Load and Iron Metabolism among Lead Smelter Workers

    PubMed Central

    Fan, Guangqin; Du, Guihua; Li, Huijun; Lin, Fen; Sun, Ziyong; Yang, Wei; Feng, Chang; Zhu, Gaochun; Li, Yanshu; Chen, Ying; Jiao, Huan; Zhou, Fankun

    2014-01-01

    Background Both an excess of toxic lead (Pb) and an essential iron disorder have been implicated in many diseases and public health problems. Iron metabolism genes, such as the hemochromatosis (HFE) gene, have been reported to be modifiers for lead absorption and storage. However, the HFE gene studies among the Asian population with occupationally high lead exposure are lacking. Objectives To explore the modifying effects of the HFE genotype (wild-type, H63D variant and C282Y variant) on the Pb load and iron metabolism among Asian Pb-workers with high occupational exposure. Methods Seven hundred and seventy-one employees from a lead smelter manufacturing company were tested to determine their Pb intoxication parameters, iron metabolic indexes and identify the HFE genotype. Descriptive and multivariate analyses were conducted. Results Forty-five H63D variant carriers and no C282Y variant carrier were found among the 771 subjects. Compared with subjects with the wild-type genotype, H63D variant carriers had higher blood lead levels, even after controlling for factors such as age, sex, marriage, education, smoking and lead exposure levels. Multivariate analyses also showed that the H63D genotype modifies the associations between the blood lead levels and the body iron burden/transferrin. Conclusions No C282Y variant was found in this Asian population. The H63D genotype modified the association between the lead and iron metabolism such that increased blood lead is associated with a higher body iron content or a lower transferrin in the H63D variant. It is indicated that H63D variant carriers may be a potentially highly vulnerable sub-population if they are exposed to high lead levels occupationally. PMID:24988074

  20. In Absence of the Cellular Prion Protein, Alterations in Copper Metabolism and Copper-Dependent Oxidase Activity Affect Iron Distribution

    PubMed Central

    Gasperini, Lisa; Meneghetti, Elisa; Legname, Giuseppe; Benetti, Federico

    2016-01-01

    Essential elements as copper and iron modulate a wide range of physiological functions. Their metabolism is strictly regulated by cellular pathways, since dysregulation of metal homeostasis is responsible for many detrimental effects. Neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease and prion diseases are characterized by alterations of metal ions. These neurodegenerative maladies involve proteins that bind metals and mediate their metabolism through not well-defined mechanisms. Prion protein, for instance, interacts with divalent cations via multiple metal-binding sites and it modulates several metal-dependent physiological functions, such as S-nitrosylation of NMDA receptors. In this work we focused on the effect of prion protein absence on copper and iron metabolism during development and adulthood. In particular, we investigated copper and iron functional values in serum and several organs such as liver, spleen, total brain and isolated hippocampus. Our results show that iron content is diminished in prion protein-null mouse serum, while it accumulates in liver and spleen. Our data suggest that these alterations can be due to impairments in copper-dependent cerulopalsmin activity which is known to affect iron mobilization. In prion protein-null mouse total brain and hippocampus, metal ion content shows a fluctuating trend, suggesting the presence of homeostatic compensatory mechanisms. However, copper and iron functional values are likely altered also in these two organs, as indicated by the modulation of metal-binding protein expression levels. Altogether, these results reveal that the absence of the cellular prion protein impairs copper metabolism and copper-dependent oxidase activity, with ensuing alteration of iron mobilization from cellular storage compartments. PMID:27729845

  1. In Absence of the Cellular Prion Protein, Alterations in Copper Metabolism and Copper-Dependent Oxidase Activity Affect Iron Distribution.

    PubMed

    Gasperini, Lisa; Meneghetti, Elisa; Legname, Giuseppe; Benetti, Federico

    2016-01-01

    Essential elements as copper and iron modulate a wide range of physiological functions. Their metabolism is strictly regulated by cellular pathways, since dysregulation of metal homeostasis is responsible for many detrimental effects. Neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease and prion diseases are characterized by alterations of metal ions. These neurodegenerative maladies involve proteins that bind metals and mediate their metabolism through not well-defined mechanisms. Prion protein, for instance, interacts with divalent cations via multiple metal-binding sites and it modulates several metal-dependent physiological functions, such as S-nitrosylation of NMDA receptors. In this work we focused on the effect of prion protein absence on copper and iron metabolism during development and adulthood. In particular, we investigated copper and iron functional values in serum and several organs such as liver, spleen, total brain and isolated hippocampus. Our results show that iron content is diminished in prion protein-null mouse serum, while it accumulates in liver and spleen. Our data suggest that these alterations can be due to impairments in copper-dependent cerulopalsmin activity which is known to affect iron mobilization. In prion protein-null mouse total brain and hippocampus, metal ion content shows a fluctuating trend, suggesting the presence of homeostatic compensatory mechanisms. However, copper and iron functional values are likely altered also in these two organs, as indicated by the modulation of metal-binding protein expression levels. Altogether, these results reveal that the absence of the cellular prion protein impairs copper metabolism and copper-dependent oxidase activity, with ensuing alteration of iron mobilization from cellular storage compartments.

  2. Hepcidin and iron metabolism in non-diabetic obese and type 2 diabetic rats.

    PubMed

    Chen, Yue; Yin, Hui-qing; Liu, Hao-ling; Xiu, Lei; Peng, Xiao-yu

    2015-12-01

    The aim of this study was to investigate the changes of iron levels and hepatic regulatory molecules expression involved in iron metabolism in non-diabetic obese/type 2 diabetic rat models. Male Wistar rats were divided into 3 groups: control group, non-diabetic obese group and type 2 diabetic group (n=20 each). The rats were evaluated physiologically and biochemically. The hepatic histopathological changes were observed using haematoxylin and eosin (HE) staining. The mRNA expression patterns of hepcidin, interleukin-6 (IL-6), hypoxia-inducible factor (HIF) and ferroportin (Fpn) in the rat liver in control group, non-diabetic obese group and type 2 diabetic group were analyzed by real-time RT-PCR. The protein expression patterns of hepcidin in liver of each group were further analyzed by immunohistochemistry and Western blotting. As compared with control group, the ferritin in non-diabetic obese group and type 2 diabetic group was increased significantly (P<0.001). However, there was no significant difference in soluble transferring receptor (sTfR):ferritin ratio among the three groups (P>0.05). The real-time RT-PCR, immunohistochemistry and Western blotting results all revealed that the expression levels of hepcidin in non-diabetic obese group and type 2 diabetic group were elevated significantly as compared with those in control group (P<0.001). The expression levels of hepcidin mRNA between non-diabetic obese group and type 2 diabetic group showed no significant difference (P>0.05). However, the protein expression levels of hepcidin in type 2 diabetic group were significantly higher than those in non-diabetic obese group (P<0.05). Compared to control group, the expression levels of IL-6 mRNA in non-diabetic obese group and type 2 diabetic group were increased significantly and the expression levels of Fpn mRNA decreased (P<0.05). However, the expression levels of HIF mRNA had no significant difference among three groups. It is suggested that iron metabolism is

  3. Initial Characterization of Carbon Metabolism in Iron Oxidizing Microbial Communities of Acidic Hot Springs in Norris Geyser Basin, Yellowstone National Park

    NASA Astrophysics Data System (ADS)

    Kreuzer, H. W.; Jennings, R. D.; Whitmore, L.; Inskeep, W. P.; Moran, J.

    2012-12-01

    Norris Geyser Basin in Yellowstone National Park is home to several acidic, sulfidic hot springs. Visual inspection of the springs reveals distinct geochemical regions starting with a sulfur deposition zone followed by a transition to iron oxide deposition downstream. The microbial communities in the iron oxidation zones are dominated by Archaea, including several members that appear to define previously unrecognized taxa. Abiotic iron oxidation rates are very slow at these temperatures (typically ~ 65-70 oC) and pH's (typically ~3). Therefore, the relatively rapid iron oxide deposition rate strongly suggests the process is microbially mediated, and an organism previously isolated from these springs, Metallosphaera yellowstonensis, has been shown to oxide iron in culture. M. yellowstonensis has been observed in the all microbial communities analyzed in the iron oxidizing zones of these springs, though metagenomic profiling suggests it constitutes only ~20% of the community membership. When we began our studies of C flow in the iron-oxidizing community, no C source had been demonstrated. Observed potential carbon sources in the springs include dissolved inorganic carbon, dissolved organic carbon, and methane, as well as random inputs of heterotrophic carbon in the forms of insect carcasses, pine needles, and animal scat. The temperatures in the iron oxidation zones are above the photosynthetic upper temperature limit, thus precluding photosynthetic-based autotrophy within the community itself. We are employing geochemical and stable isotope techniques to assess carbon inventories in the system. We have demonstrated that M. yellowstonensis as well as excised samples of iron oxide mat communities can fix CO2, and our estimated isotopic fractionation factor is consistent with the 3-hydroxypropionate 4-hydroxybutyrate pathway. Genes of this pathway have been identified in the M. yellowstonensis genome. We have tentatively identified small amounts of organic compounds

  4. Molecular evidence of iron limitation and availability in the global diazotroph Trichodesmium

    PubMed Central

    Chappell, Phoebe Dreux; Moffett, James W; Hynes, Annette M; Webb, Eric A

    2012-01-01

    The activity of the N2-fixing cyanobacterial genus Trichodesmium is critical to the global nitrogen (N) and carbon (C) cycles. Although iron (Fe) has been shown to be an important element limiting the growth and N2 fixation of Trichodesmium, there have been no specific data demonstrating the in situ affect of Fe on Trichodesmium. We surveyed Trichodesmium populations from the Atlantic and Pacific Oceans for Fe limitation using a novel quantitative reverse transcriptase-PCR (qRT-PCR) method monitoring the expression of an Fe limitation-induced gene, isiB. Here we report the first molecular evidence of in situ Fe limitation of Trichodesmium N2 fixation, which was evident in samples from the Pacific Ocean, whereas limitation appeared minimal to nonexistent in Atlantic Ocean samples. As our method is Trichodesmium clade specific, we were also able to determine that representatives from the Trichodesmium tenue clade were the most biologically active group of Trichodesmium in the majority of our samples, which speaks to their dominance in open ocean regimes. Furthermore, comparisons of our field expression and chemical data with laboratory studies suggest that the majority of dissolved Fe in the open ocean is available to Trichodesmium colonies regardless of Fe complexation. PMID:22402399

  5. Evidence for a metabolic limitation of survival in hypothermic hamsters.

    NASA Technical Reports Server (NTRS)

    Prewitt, R. L.; Anderson, G. L.; Musacchia, X. J.

    1972-01-01

    The underlying factors limiting survival in the hypothermic state are studied. Hamsters of both sexes, clipped and unclipped, were inducted into profound hypothermia by the helium cold method until they reached a temperature between 7 and 10 C. It appears that the primary cause of death is failure of respiration due to the depletion of carbohydrate energy supplies and may explain why survival time in hypothermia is shorter than the normal hibernation time of the hamster.

  6. The Regulation of Iron Absorption and Homeostasis

    PubMed Central

    Wallace, Daniel F

    2016-01-01

    Iron is an essential element in biology, required for numerous cellular processes. Either too much or too little iron can be detrimental, and organisms have developed mechanisms for balancing iron within safe limits. In mammals there are no controlled mechanisms for the excretion of excess iron, hence body iron homeostasis is regulated at the sites of absorption, utilisation and recycling. This review will discuss the discoveries that have been made in the past 20 years into advancing our understanding of iron homeostasis and its regulation. The study of iron-associated disorders, such as the iron overload condition hereditary haemochromatosis and various forms of anaemia have been instrumental in increasing our knowledge in this area, as have cellular and animal model studies. The liver has emerged as the major site of systemic iron regulation, being the location where the iron regulatory hormone hepcidin is produced. Hepcidin is a negative regulator of iron absorption and recycling, achieving this by binding to the only known cellular iron exporter ferroportin and causing its internalisation and degradation, thereby reducing iron efflux from target cells and reducing serum iron levels. Much of the research in the iron metabolism field has focussed on the regulation of hepcidin and its interaction with ferroportin. The advances in this area have greatly increased our knowledge of iron metabolism and its regulation and have led to the development of novel diagnostics and therapeutics for iron-associated disorders. PMID:28303071

  7. Arabidopsis plastidial folylpolyglutamate synthetase is required for nitrogen metabolism under nitrate-limited condition in darkness.

    PubMed

    Meng, Hongyan; Xu, Bosi; Zhang, Chunyi; Jiang, Ling

    2017-01-08

    Folates play an important role in plant metabolism. Here we report a T-DNA insertion mutant (atdfb-3) of the plastidial folylpolyglutamate synthetase gene (AtDFB) was defective in folate metabolism and nitrogen metabolism under nitrate-limited conditions in darkness. Exogenous applied 5-formyl-tetrahydrofolate (5-F-THF) completely restored nitrogen content, soluble protein, total amino acids, individual amino acids including Glu, Gln, Asp, Asn, Pro, Arg and Met, nitrate, and endogenous 5-F-THF in atdfb-3 to the wild-type level. At the same time the application of 5-F-THF partially restored the content of Ser and nitrite in the mutant. Taken together, these results indicated that intact folate metabolism was necessary for nitrogen metabolism in Arabidopsis thaliana under nitrate-limited condition in darkness, providing novel insights into function of folate. Copyright © 2016 Elsevier Inc. All rights reserved.

  8. Vishweshwaraiah Iron Steel Limited (VISL) fire disasters following steel converter blast, 30 July 2003.

    PubMed

    Kumar, Pramod

    2010-02-01

    A fire disaster occurred in Vishweshwaraiah Iron Steel Limited (VISL), Bhadravathi, India on 30 July 2003. The steel converter containing 24,000 kg of liquid metal (pig iron) at very high temperature exploded. A total of 30 workers became victims. Seven persons died on the spot. Twenty-three victims were transferred to the VISL hospital; of these, six were transferred to the burns unit of the Kasturba Hospital, Manipal (180 km from VISL). All six treated at the burns unit suffered 3-65% total body surface area (TBSA) burn, two had external injuries and two had eye involvement. Out of the six patients admitted at the burns unit, two expired (one due to refractory shock and another due to pulmonary embolism). Out of four survivors, one underwent tangential excision; another underwent operation for removal of foreign body from both soles and the remaining two were managed conservatively. Of the four survivors, two who had eye injuries, one developed minute corneal opacities within 2 months. The total duration of hospital stay of survivors at the burns unit varied from 8 to 43 days. All the victims were counselled by VISL psychiatrists before resuming their duties. Except the one who developed mixed anxiety-depression disorder, all survivors returned to work. The article describes the mechanism of the incident, injuries sustained and suggestions in relation to future safety measures.

  9. Wilson's disease patient with iron metabolism discharge barriers: A case report

    PubMed Central

    Cai, Guoen; Huang, Xinming; Ye, Qinyong; Xiong, Wenting; Duan, Qing

    2017-01-01

    Wilson's disease (WD) is an autosomal genetic disease. In the present study, the patient was a 35-year-old woman who exhibited drinking bucking (bulbar paralysis) and dysphagia for a period of nine years. Genetic analysis of the patient identified the Thr935Met and Pro992Leu mutations, which lead to copper metabolism discharge barriers. Moreover, magnetic resonance imaging revealed a susceptibility-weighted imaging (SWI) hyperintense area in the bilateral substantia nigra and lenticular nuclei. These SWI observations indicated that ‘mineral deposits’ were present. The present case demonstrates that the SWI hyperintense area in the bilateral lenticular nuclei, substantia nigra and red nucleus combined with the patient's symptoms indicated that there is a possibility to diagnose WD when it is not detected by genetic analysis. In addition, it demonstrates that systemic mineral removal treatment (including manganese, iron and copper) may be successful for the initial treatment of WD. PMID:28123513

  10. The capacity of Porphyromonas gingivalis to multiply under iron-limiting conditions correlates with its pathogenicity in an animal model.

    PubMed

    Grenier, D; Goulet, V; Mayrand, D

    2001-07-01

    Isolates of Porphyromonas gingivalis have various abilities to induce infections in an animal model. The hypothesis of this study was that pathogenic strains of P. gingivalis could multiply under iron-limiting conditions, while non-pathogenic strains could not. Three pathogenic strains (W50, W83, and ATCC 49417) grew to a final optical density (660 nm) > 2 in horse serum, while the growth of the 3 non-pathogenic strains (ATCC 33277, LB13D-2, and HW24D-1) was negligible. When an excess of hemin or ferric chloride was added to the serum, significant growth of the non-pathogenic strains occurred. Under iron-limiting conditions, the pathogenic strains of P. gingivalis had a much lower requirement for human iron-loaded transferrin and hemin than the non-pathogenic strains. Proteolytic degradation of transferrin, which may be associated with the release of iron, was not markedly different for pathogenic and non-pathogenic strains. In addition, no relationship could be established between the level of 55Fe uptake from 55Fe-transferrin and the pathogenicity of strains. Our study provided evidence that the ability of P. gingivalis to multiply in vitro under iron-limiting conditions may be correlated with its ability to induce infections in an animal model. Isolates of P. gingivalis possessing a low requirement for iron are likely to have a higher potential for initiating periodontal infections.

  11. Iron metabolism in African American women in the second and third trimesters of high-risk pregnancies

    USDA-ARS?s Scientific Manuscript database

    Objective: To examine iron metabolism during the second and third trimesters in African American women with high-risk pregnancies. Design: Longitudinal pilot study. Setting: Large, university-based, urban Midwestern U.S. medical center. Participants: Convenience sample of 32 African American wome...

  12. Evidence for a conserved system for iron metabolism in the mitochondria of Saccharomyces cerevisiae.

    PubMed

    Schilke, B; Voisine, C; Beinert, H; Craig, E

    1999-08-31

    nifU of nitrogen-fixing bacteria is involved in the synthesis of the Fe-S cluster of nitrogenase. In a synthetic lethal screen with the mitochondrial heat shock protein (HSP)70, SSQ1, we identified a gene of Saccharomyces cerevisiae, NFU1, which encodes a protein with sequence identity to the C-terminal domain of NifU. Two other yeast genes were found to encode proteins related to the N-terminal domain of bacterial NifU. They have been designated ISU1 and ISU2. Isu1, Isu2, and Nfu1 are located in the mitochondrial matrix. ISU genes of yeast carry out an essential function, because a Deltaisu1Deltaisu2 strain is inviable. Growth of Deltanfu1Delta isu1 cells is significantly compromised, allowing assessment of the physiological roles of Nfu and Isu proteins. Mitochondria from Deltanfu1Deltaisu1 cells have decreased activity of several respiratory enzymes that contain Fe-S clusters. As a result, Deltanfu1Deltaisu1 cells grow poorly on carbon sources requiring respiration. Deltanfu1Deltaisu1 cells also accumulate abnormally high levels of iron in their mitochondria, similar to Deltassq1 cells, indicating a role for these proteins in iron metabolism. We suggest that NFU1 and ISU1 gene products play a role in iron homeostasis, perhaps in assembly, insertion, and/or repair of mitochondrial Fe-S clusters. The conservation of these protein domains in many organisms suggests that this role has been conserved throughout evolution.

  13. Evidence for a conserved system for iron metabolism in the mitochondria of Saccharomyces cerevisiae

    PubMed Central

    Schilke, Brenda; Voisine, Cindy; Beinert, Helmut; Craig, Elizabeth

    1999-01-01

    nifU of nitrogen-fixing bacteria is involved in the synthesis of the Fe–S cluster of nitrogenase. In a synthetic lethal screen with the mitochondrial heat shock protein (HSP)70, SSQ1, we identified a gene of Saccharomyces cerevisiae, NFU1, which encodes a protein with sequence identity to the C-terminal domain of NifU. Two other yeast genes were found to encode proteins related to the N-terminal domain of bacterial NifU. They have been designated ISU1 and ISU2. Isu1, Isu2, and Nfu1 are located in the mitochondrial matrix. ISU genes of yeast carry out an essential function, because a Δisu1Δisu2 strain is inviable. Growth of Δnfu1Δ isu1 cells is significantly compromised, allowing assessment of the physiological roles of Nfu and Isu proteins. Mitochondria from Δnfu1Δisu1 cells have decreased activity of several respiratory enzymes that contain Fe–S clusters. As a result, Δnfu1Δisu1 cells grow poorly on carbon sources requiring respiration. Δnfu1Δisu1 cells also accumulate abnormally high levels of iron in their mitochondria, similar to Δssq1 cells, indicating a role for these proteins in iron metabolism. We suggest that NFU1 and ISU1 gene products play a role in iron homeostasis, perhaps in assembly, insertion, and/or repair of mitochondrial Fe–S clusters. The conservation of these protein domains in many organisms suggests that this role has been conserved throughout evolution. PMID:10468587

  14. Genetic indicators of iron limitation in wild populations of Thalassiosira oceanica from the northeast Pacific Ocean

    PubMed Central

    Chappell, P Dreux; Whitney, LeAnn P; Wallace, Joselynn R; Darer, Adam I; Jean-Charles, Samua; Jenkins, Bethany D

    2015-01-01

    Assessing the iron (Fe) nutritional status of natural diatom populations has proven challenging as physiological and molecular responses can differ in diatoms of the same genus. We evaluated expression of genes encoding flavodoxin (FLDA1) and an Fe-starvation induced protein (ISIP3) as indicators of Fe limitation in the marine diatom Thalassiosira oceanica. The specificity of the response to Fe limitation was tested in cultures grown under Fe- and macronutrient-deficient conditions, as well as throughout the diurnal light cycle. Both genes showed a robust and specific response to Fe limitation in laboratory cultures and were detected in small volume samples collected from the northeast Pacific, demonstrating the sensitivity of this method. Overall, FLDA1 and ISIP3 expression was inversely related to Fe concentrations and offered insight into the Fe nutritional health of T. oceanica in the field. As T. oceanica is a species tolerant to low Fe, indications of Fe limitation in T. oceanica populations may serve as a proxy for severe Fe stress in the overall diatom community. At two shallow coastal locations, FLD1A and ISIP3 expression revealed Fe stress in areas where dissolved Fe concentrations were high, demonstrating that this approach may be powerful for identifying regions where Fe supply may not be biologically available. PMID:25333460

  15. Knocking down mitochondrial iron transporter (MIT) reprograms primary and secondary metabolism in rice plants.

    PubMed

    Vigani, Gianpiero; Bashir, Khurram; Ishimaru, Yasuhiro; Lehmann, Martin; Casiraghi, Fabio Marco; Nakanishi, Hiromi; Seki, Motoaki; Geigenberger, Peter; Zocchi, Graziano; Nishizawa, Naoko K

    2016-03-01

    Iron (Fe) is an essential micronutrient for plant growth and development, and its reduced bioavailability strongly impairs mitochondrial functionality. In this work, the metabolic adjustment in the rice (Oryza sativa) mitochondrial Fe transporter knockdown mutant (mit-2) was analysed. Biochemical characterization of purified mitochondria from rice roots showed alteration in the respiratory chain of mit-2 compared with wild-type (WT) plants. In particular, proteins belonging to the type II alternative NAD(P)H dehydrogenases accumulated strongly in mit-2 plants, indicating that alternative pathways were activated to keep the respiratory chain working. Additionally, large-scale changes in the transcriptome and metabolome were observed in mit-2 rice plants. In particular, a strong alteration (up-/down-regulation) in the expression of genes encoding enzymes of both primary and secondary metabolism was found in mutant plants. This was reflected by changes in the metabolic profiles in both roots and shoots of mit-2 plants. Significant alterations in the levels of amino acids belonging to the aspartic acid-related pathways (aspartic acid, lysine, and threonine in roots, and aspartic acid and ornithine in shoots) were found that are strictly connected to the Krebs cycle. Furthermore, some metabolites (e.g. pyruvic acid, fumaric acid, ornithine, and oligosaccharides of the raffinose family) accumulated only in the shoot of mit-2 plants, indicating possible hypoxic responses. These findings suggest that the induction of local Fe deficiency in the mitochondrial compartment of mit-2 plants differentially affects the transcript as well as the metabolic profiles in root and shoot tissues. © The Author 2015. Published by Oxford University Press on behalf of the Society for Experimental Biology.

  16. Knocking down mitochondrial iron transporter (MIT) reprograms primary and secondary metabolism in rice plants

    PubMed Central

    Vigani, Gianpiero; Bashir, Khurram; Ishimaru, Yasuhiro; Lehmann, Martin; Casiraghi, Fabio Marco; Nakanishi, Hiromi; Seki, Motoaki; Geigenberger, Peter; Zocchi, Graziano; Nishizawa, Naoko K.

    2016-01-01

    Iron (Fe) is an essential micronutrient for plant growth and development, and its reduced bioavailability strongly impairs mitochondrial functionality. In this work, the metabolic adjustment in the rice (Oryza sativa) mitochondrial Fe transporter knockdown mutant (mit-2) was analysed. Biochemical characterization of purified mitochondria from rice roots showed alteration in the respiratory chain of mit-2 compared with wild-type (WT) plants. In particular, proteins belonging to the type II alternative NAD(P)H dehydrogenases accumulated strongly in mit-2 plants, indicating that alternative pathways were activated to keep the respiratory chain working. Additionally, large-scale changes in the transcriptome and metabolome were observed in mit-2 rice plants. In particular, a strong alteration (up-/down-regulation) in the expression of genes encoding enzymes of both primary and secondary metabolism was found in mutant plants. This was reflected by changes in the metabolic profiles in both roots and shoots of mit-2 plants. Significant alterations in the levels of amino acids belonging to the aspartic acid-related pathways (aspartic acid, lysine, and threonine in roots, and aspartic acid and ornithine in shoots) were found that are strictly connected to the Krebs cycle. Furthermore, some metabolites (e.g. pyruvic acid, fumaric acid, ornithine, and oligosaccharides of the raffinose family) accumulated only in the shoot of mit-2 plants, indicating possible hypoxic responses. These findings suggest that the induction of local Fe deficiency in the mitochondrial compartment of mit-2 plants differentially affects the transcript as well as the metabolic profiles in root and shoot tissues. PMID:26685186

  17. Discovering the role of mitochondria in the iron deficiency-induced metabolic responses of plants.

    PubMed

    Vigani, Gianpiero

    2012-01-01

    In plants, iron (Fe) deficiency-induced chlorosis is a major problem, affecting both yield and quality of crops. Plants have evolved multifaceted strategies, such as reductase activity, proton extrusion, and specialised storage proteins, to mobilise Fe from the environment and distribute it within the plant. Because of its fundamental role in plant productivity, several issues concerning Fe homeostasis in plants are currently intensively studied. The activation of Fe uptake reactions requires an overall adaptation of the primary metabolism because these activities need the constant supply of energetic substrates (i.e., NADPH and ATP). Several studies concerning the metabolism of Fe-deficient plants have been conducted, but research focused on mitochondrial implications in adaptive responses to nutritional stress has only begun in recent years. Mitochondria are the energetic centre of the root cell, and they are strongly affected by Fe deficiency. Nevertheless, they display a high level of functional flexibility, which allows them to maintain the viability of the cell. Mitochondria represent a crucial target of studies on plant homeostasis, and it might be of interest to concentrate future research on understanding how mitochondria orchestrate the reprogramming of root cell metabolism under Fe deficiency. In this review, I summarise what it is known about the effect of Fe deficiency on mitochondrial metabolism and morphology. Moreover, I present a detailed view of the possible roles of mitochondria in the development of plant responses to Fe deficiency, integrating old findings with new and discussing new hypotheses for future investigations. Copyright © 2011 Elsevier GmbH. All rights reserved.

  18. Bioactive food components, cancer cell growth limitation and reversal of glycolytic metabolism.

    PubMed

    Keijer, Jaap; Bekkenkamp-Grovenstein, Melissa; Venema, Dini; Dommels, Yvonne E M

    2011-06-01

    Cancer cells are resistant to apoptosis and show a shift in energy production from mitochondrial oxidative phosphorylation to cytosolic glycolysis. Apoptosis resistance and metabolic reprogramming are linked in many cancer cells and both processes center on mitochondria. Clearly, mutated cancer cells escape surveillance and turn into selfish cells. However, many of the mechanisms that operate cellular metabolic control still function in cancer cells. This review describes the metabolic importance of glucose and glutamine, glycolytic enzymes, oxygen, growth cofactors and mitochondria and focuses on the potential role of bioactive food components, including micronutrients. The role of B- and A-vitamin cofactors in (mitochondrial) metabolism is highlighted and the cancer protective potential of omega-3 fatty acids and several polyphenols is discussed in relation to metabolic reprogramming, including the mechanisms that may be involved. Furthermore, it is shown that cancer cell growth reduction by limiting the growth cofactor folic acid seems to be associated with reversal of metabolic reprogramming. Altogether, reversal of metabolic reprogramming may be an attractive strategy to increase susceptibility to apoptotic surveillance. Food bioactive components that affect various aspects of metabolism may be important tools to reverse glycolytic to oxidative metabolism and enhance sensitivity to apoptosis. The success of such a strategy may depend on several actors, acting in concert. Growth cofactors may be one of these, which call for careful (re)evaluation of their function in normal and in cancer metabolism.

  19. Evolution of metabolic rate in a parasitic wasp: the role of limitation in intrinsic resources.

    PubMed

    Moiroux, Joffrey; Giron, David; Vernon, Philippe; van Baaren, Joan; van Alphen, Jacques J M

    2012-07-01

    Metabolic rate, a physiological trait closely related to fitness traits, is expected to evolve in response to two main environmental variables: (1) climate, low metabolic rates being found in dry and hot regions when comparing populations originating from different climates in a common garden experiment and (2) resource limitations, low metabolic rates being selected when resources are limited. The main goal of this study was to investigate if differences in intrinsic resource limitations may have disrupted the expected evolution of metabolic rate in response to climate in a parasitic wasp. We compared CO(2) production of females from 4 populations of a Drosophila parasitoid, Leptopilina boulardi, as an estimate of their metabolic rate. Two populations from a hot and dry area able to synthesise lipids de novo at adult stage were compared with two populations originating from a mild and humid climate where no lipid accumulation during adult life was observed. These last females are thus more limited in lipids than the first ones. We observed that a high metabolic rate has been selected in hot and dry environments, contrarily to the results of a great majority of studies. We suggest that lipogenesis occurring there may have allowed the selection of a higher metabolic rate, as females are less limited in energetic resources than females from the mild environment. A high metabolic rate may have been selected there as it partly compensates for the long distances that females have to cross to find laying opportunities in distant orchards. We suggest that intrinsic resources should be integrated when investigating geographical variations in metabolism as this factor may disrupt evolution in response to climate.

  20. A high fat diet does not affect the iron bioavailability in Wistar rats fed with chia and increases gene expression of iron metabolism proteins.

    PubMed

    da Silva, Bárbara Pereira; Matyelka, Jéssika Camila da Silva; Moreira, Maria Eliza de Castro; Toledo, Renata Celi Lopes; Della Lucia, Ceres Mattos; Pinheiro-Sant'Ana, Helena Maria; Martino, Hércia Stampini Duarte

    2016-12-07

    This study evaluated the effect of chia on the iron bioavailability and gene expression of proteins involved in iron metabolism in animals fed with a high fat diet and a standard diet. Four experimental groups were tested (n = 8): standard diet + ferrous sulfate (SD + FS), standard diet + chia (SD + C), high fat diet + ferrous sulfate (HFD + FS), high fat diet + chia (HFD + C). The hemoglobin gain, hemoglobin regeneration efficiency, biological relative value of HRE, serum ferritin and transferrin, liver iron concentration and gene expression of proteins were evaluated. The SD + C group showed lower transferrin expression when compared to the control group. The control group showed serum transferrin concentration higher than the other groups. Serum ferritin and liver iron concentration did not differ among the animals that received chia ferritin and hephaestin expression was lower in experimental groups when compared with the control group. The peroxisome proliferator activated receptor expression was higher in animals fed with SD + C than in the control group. The expression of duodenal cytochrome B and divalent metal transporter 1 in the HFD + C group was higher and ferroportin was lower in the groups containing chia. Animals fed with chia showed similar iron bioavailability compared to animals fed with ferrous sulfate.

  1. Effects of Radiation and Dietary Iron on Expression of Genes and Proteins Involved in Drug Metabolism

    NASA Technical Reports Server (NTRS)

    Faust, K. M.; Wotring, V. E.

    2014-01-01

    Liver function, especially the rate of metabolic enzyme activities, determines the concentration of circulating drugs and the duration of their efficacy. Most pharmaceuticals are metabolized by the liver, and clinically-used medication doses are given with normal liver function in mind. A drug overdose can result in the case of a liver that is damaged and removing pharmaceuticals from the circulation at a rate slower than normal. Alternatively, if liver function is elevated and removing drugs from the system more quickly than usual, it would be as if too little drug had been given for effective treatment. Because of the importance of the liver in drug metabolism, we want to understand any effects of spaceflight on the enzymes of the liver. Dietary factors and exposure to radiation are aspects of spaceflight that are potential oxidative stressors and both can be modeled in ground experiments. In this experiment, we examined the effects of high dietary iron and low dose gamma radiation (individually and combined) on the gene expression of enzymes involved in drug metabolism, redox homeostasis, and DNA repair. METHODS All procedures were approved by the JSC Animal Care and Use Committee. Male Sprague-Dawley rats were divided into 4 groups (n=8); control, high Fe diet (650 mg iron/kg), radiation (fractionated 3 Gy exposure from a Cs- 137 source) and combined high Fe diet + radiation exposure. Animals were euthanized 24h after the last treatment of radiation; livers were removed immediately and flash -frozen in liquid nitrogen. Expression of genes thought to be involved in redox homeostasis, drug metabolism and DNA damage repair was measured by RT-qPCR. Where possible, protein expression of the same genes was measured by western blotting. All data are expressed as % change in expression normalized to reference gene expression; comparisons were then made of each treatment group to the sham exposed/ normal diet control group. Data was considered significant at p< 0

  2. Co-limitation of diatoms by iron and silicic acid in the equatorial Pacific

    NASA Astrophysics Data System (ADS)

    Brzezinski, Mark A.; Baines, Stephen B.; Balch, William M.; Beucher, Charlotte P.; Chai, Fei; Dugdale, Richard C.; Krause, Jeffrey W.; Landry, Michael R.; Marchi, Albert; Measures, Chris I.; Nelson, David M.; Parker, Alexander E.; Poulton, Alex J.; Selph, Karen E.; Strutton, Peter G.; Taylor, Andrew G.; Twining, Benjamin S.

    2011-03-01

    The relative roles of silicon (Si) and iron (Fe) as limiting nutrients in the eastern equatorial Pacific (EEP) were examined in a series of nine microcosm experiments conducted over two years between 110°W and 140°W longitude. Si and Fe additions had consistently different but synergistic effects on macronutrient use, phytoplankton biomass and phytoplankton community structure. Silicon addition increased silicic acid use and biogenic silica production, but had no significant effect on the use of inorganic nitrogen or orthophosphate, chlorophyll accumulation, particulate inorganic (PIC) carbon accumulation, or plankton community composition relative to controls. That result, together with observations that Si addition increased the cellular Si content of the numerically dominant diatom by ˜50%, indicates that the main effect of Si was to regulate diatom silicification. Like the effect of Si, Fe addition increased the rate of silicic acid use and biogenic silica production and had no effect on PIC production. Unlike the effect of Si, Fe addition also enhanced rates of organic matter production, had no effect on cellular Si content of diatoms, and resulted in the growth of initially rare, large (>40 μm) diatoms relative to controls, indicating that Fe limitation acts mainly through its effects on growth rate and phytoplankton community composition. A pennate diatom of the genus Pseudo-nitzschia dominated the diatom assemblage in situ, grew readily in the controls and did not show a strong growth response to either Fe or Si addition suggesting that its growth was regulated by other factors such as grazing or light. Addition of germanium, an inhibitor of diatom cell division, eliminated the effects of Fe on macronutrient use, biogenic silica production and chlorophyll accumulation and phytoplankton community composition, consistent with a predominantly diatom response to Fe addition. The lack of a response of PIC production to Fe suggests that coccolithophores were

  3. Transcriptional response of Leptospira interrogans to iron limitation and characterization of a PerR homolog

    USDA-ARS?s Scientific Manuscript database

    Leptospira interrogans is the causative agent of leptospirosis, a zoonosis of global significance. Iron is essential for growth of most bacterial species. Since availability of iron is low in the host, pathogens have evolved complex iron acquisition mechanisms to survive and establish infection. In ...

  4. An update on iron physiology

    PubMed Central

    Muñoz, Manuel; Villar, Isabel; García-Erce, José Antonio

    2009-01-01

    Iron is an essential micronutrient, as it is required for adequate erythropoietic function, oxidative metabolism and cellular immune responses. Although the absorption of dietary iron (1-2 mg/d) is regulated tightly, it is just balanced with losses. Therefore, internal turnover of iron is essential to meet the requirements for erythropoiesis (20-30 mg/d). Increased iron requirements, limited external supply, and increased blood loss may lead to iron deficiency (ID) and iron-deficiency anemia. Hepcidin, which is made primarily in hepatocytes in response to liver iron levels, inflammation, hypoxia and anemia, is the main iron regulatory hormone. Once secreted into the circulation, hepcidin binds ferroportin on enterocytes and macrophages, which triggers its internalization and lysosomal degradation. Thus, in chronic inflammation, the excess of hepcidin decreases iron absorption and prevents iron recycling, which results in hypoferremia and iron-restricted erythropoiesis, despite normal iron stores (functional ID), and anemia of chronic disease (ACD), which can evolve to ACD plus true ID (ACD + ID). In contrast, low hepcidin expression may lead to iron overload, and vice versa. Laboratory tests provide evidence of iron depletion in the body, or reflect iron-deficient red cell production. The appropriate combination of these laboratory tests help to establish a correct diagnosis of ID status and anemia. PMID:19787824

  5. Biogenesis and functions of mammalian iron-sulfur proteins in the regulation of iron homeostasis and pivotal metabolic pathways.

    PubMed

    Rouault, Tracey A; Maio, Nunziata

    2017-08-04

    Fe-S cofactors are composed of iron and inorganic sulfur in various stoichiometries. A complex assembly pathway conducts their initial synthesis and subsequent binding to recipient proteins. In this minireview, we discuss how discovery of the role of the mammalian cytosolic aconitase, known as iron regulatory protein 1 (IRP1), led to the characterization of the function of its Fe-S cluster in sensing and regulating cellular iron homeostasis. Moreover, we present an overview of recent studies that have provided insights into the mechanism of Fe-S cluster transfer to recipient Fe-S proteins. © 2017 by The American Society for Biochemistry and Molecular Biology, Inc.

  6. Higher iron pearl millet (Pennisetum glaucum L.) provides more absorbable iron that is limited by increased polyphenolic content

    USDA-ARS?s Scientific Manuscript database

    Background: Our objective was to compare the capacity of iron (Fe) biofortified and standard pearl millet (Pennisetum glaucum L.) to deliver Fe for hemoglobin (Hb) synthesis. Pearl millet is the most widely grown type of millet. It is common primarily in West Africa and the Indian subcontinent, and ...

  7. Drosophila mitoferrin is essential for male fertility: evidence for a role of mitochondrial iron metabolism during spermatogenesis

    PubMed Central

    2010-01-01

    Background Mammals and Drosophila melanogaster share some striking similarities in spermatogenesis. Mitochondria in spermatids undergo dramatic morphological changes and syncytial spermatids are stripped from their cytoplasm and then individually wrapped by single membranes in an individualization process. In mammalian and fruit fly testis, components of the mitochondrial iron metabolism are expressed, but so far their function during spermatogenesis is unknown. Here we investigate the role of Drosophila mitoferrin (dmfrn), which is a mitochondrial carrier protein with an established role in the mitochondrial iron metabolism, during spermatogenesis. Results We found that P-element insertions into the 5'-untranslated region of the dmfrn gene cause recessive male sterility, which was rescued by a fluorescently tagged transgenic dmfrn genomic construct (dmfrnvenus). Testes of mutant homozygous dmfrnSH115 flies were either small with unorganized content or contained some partially elongated spermatids, or testes were of normal size but lacked mature sperm. Testis squashes indicated that spermatid elongation was defective and electron micrographs showed mitochondrial defects in elongated spermatids and indicated failed individualization. Using a LacZ reporter and the dmfrnvenus transgene, we found that dmfrn expression in testes was highest in spermatids, coinciding with the stages that showed defects in the mutants. Dmfrn-venus protein accumulated in mitochondrial derivatives of spermatids, where it remained until most of it was stripped off during individualization and disposed of in waste bags. Male sterility in flies with the hypomorph alleles dmfrnBG00456 and dmfrnEY01302 over the deletion Df(3R)ED6277 was increased by dietary iron chelation and suppressed by iron supplementation of the food, while male sterility of dmfrnSH115/Df(3R)ED6277 flies was not affected by food iron levels. Conclusions In this work, we show that mutations in the Drosophila mitoferrin gene

  8. Cooperation of two mRNA-binding proteins drives metabolic adaptation to iron deficiency

    PubMed Central

    Puig, Sergi; Vergara, Sandra V.; Thiele, Dennis J.

    2008-01-01

    Summary Iron (Fe) is an essential co-factor for a wide range of cellular processes. We have previously demonstrated that during Fe-deficiency yeast Cth2 is expressed and promotes degradation of a battery of mRNAs leading to reprogramming of Fe-dependent metabolism and Fe-storage. We report that the Cth2-homologous protein, Cth1, is transiently expressed during Fe-deprivation and participates in the response to Fe-deficiency through the degradation of mRNAs primarily involved in mitochondrially-localized activities including respiration and amino acid biosynthesis. In parallel, wild type but not cth1Δ cth2Δ cells accumulate mRNAs encoding proteins that function in glucose import and storage and store high levels of glycogen. In addition, Fe-deficiency leads to Snf1 phosphorylation, a member of the AMP-activated protein kinase family required for the cellular response to glucose starvation. These studies demonstrate a metabolic reprogramming as a consequence of Fe-starvation that is dependent on the coordinated activities of two mRNA-binding proteins. PMID:18522836

  9. Temporal development of the barley leaf metabolic response to Pi limitation.

    PubMed

    Alexova, Ralitza; Nelson, Clark J; Millar, A Harvey

    2016-12-20

    The response of plants to Pi limitation involves interplay between root uptake of Pi , adjustment of resource allocation to different plant organs, and increased metabolic Pi use efficiency. To identify potentially novel, early-responding, metabolic hallmarks of Pi limitation in crop plants, we studied the metabolic response of barley leaves over the first 7 days of Pi stress, and the relationship of primary metabolites with leaf Pi levels and leaf biomass. The abundance of leaf Pi , Tyr, and shikimate were significantly different between low Pi and control plants 1 h after transfer of the plants to low Pi . Combining these data with (15) N metabolic labeling, we show that over the first 48 hours of Pi limitation metabolic flux through the N assimilation and aromatic amino acid pathways is increased. We propose that together with a shift in amino acid metabolism in the chloroplast a transient restoration of the energetic and redox state of the leaf is achieved. Correlation analysis of metabolite abundances revealed a central role for major amino acids in Pi stress, appearing to modulate partitioning of soluble sugars between amino acid and carboxylate synthesis, thereby limiting leaf biomass accumulation when external Pi is low.

  10. Volume dependence of the Grüneisen parameter and maximum compression limit for iron

    NASA Astrophysics Data System (ADS)

    Shanker, J.; Singh, B. P.; Baghel, H. K.

    2007-01-01

    Relationships for the volume dependence of the Grüneisen parameter γ have been used to discuss the behaviour of solids in the limit of infinite pressure ( P→∞). The model recently developed by Burakovsky and Preston (J. Phys. Chem. Solids 65 (2004) 1581) yields γ∞, q∞ and λ∞, the values of Grüneisen parameter γ and its logarithmic volume derivatives q and λ at P→∞, which are found to have fixed values, same for all the solids studied. On the other hand, the thermodynamics of solids at P→∞ formulated by Stacey (Geophys. J. Int. 143 (2000) 621) reveals that γ∞ and pressure derivative of bulk modulus are different for different materials. The empirical formulation for the volume dependence of γ used by Stacey and Davis (Phys. Earth Planet. Intr. 142 (2004) 137) has been shown to be approximately equivalent to the relationship proposed earlier by Al’tshuler et al. (J. Appl. Mech. Tech. Phys. 28 (1987) 129). The shock-pressure data for iron have been used to discuss the maximum compression limit for iron and to emphasize the invalidity of our recent criterion based on the lattice potential energy (Physica B 364 (2005) 186). The Burakovsky-Preston model based on the Thomas-Fermi approximation ( γ∞=1/2 and =5/3) has been found to be more consistent with the shock-compression data. The constraints γ∞>2/3 and >5/3 developed by Stacey are not in agreement with the strong shock compression limit reported for several materials. It is shown here that the Slater formula for γ which was found by Stacey to assume the status of an identity at P→∞ and used by him to derive the constraints for γ∞ and , is invalid when =5/3 It is also pointed out that γ∞=1/2 is to be preferred over γ∞=2/3 because of the thermodynamic constraint >1+ γ∞ developed by Stacey.

  11. Application of circuit simulation method for differential modeling of TIM-2 iron uptake and metabolism in mouse kidney cells.

    PubMed

    Xie, Zhijian; Harrison, Scott H; Torti, Suzy V; Torti, Frank M; Han, Jian

    2013-01-01

    Circuit simulation is a powerful methodology to generate differential mathematical models. Due to its highly accurate modeling capability, circuit simulation can be used to investigate interactions between the parts and processes of a cellular system. Circuit simulation has become a core technology for the field of electrical engineering, but its application in biology has not yet been fully realized. As a case study for evaluating the more advanced features of a circuit simulation tool called Advanced Design System (ADS), we collected and modeled laboratory data for iron metabolism in mouse kidney cells for a H ferritin (HFt) receptor, T cell immunoglobulin and mucin domain-2 (TIM-2). The internal controlling parameters of TIM-2 associated iron metabolism were extracted and the ratios of iron movement among cellular compartments were quantified by ADS. The differential model processed by circuit simulation demonstrated a capability to identify variables and predict outcomes that could not be readily measured by in vitro experiments. For example, an initial rate of uptake of iron-loaded HFt (Fe-HFt) was 2.17 pmol per million cells. TIM-2 binding probability with Fe-HFt was 16.6%. An average of 8.5 min was required for the complex of TIM-2 and Fe-HFt to form an endosome. The endosome containing HFt lasted roughly 2 h. At the end of endocytosis, about 28% HFt remained intact and the rest was degraded. Iron released from degraded HFt was in the labile iron pool (LIP) and stimulated the generation of endogenous HFt for new storage. Both experimental data and the model showed that TIM-2 was not involved in the process of iron export. The extracted internal controlling parameters successfully captured the complexity of TIM-2 pathway and the use of circuit simulation-based modeling across a wider range of cellular systems is the next step for validating the significance and utility of this method.

  12. Haematological and iron-related parameters in male and female athletes according to different metabolic energy demands.

    PubMed

    Milic, Radoje; Martinovic, Jelena; Dopsaj, Milivoj; Dopsaj, Violeta

    2011-03-01

    We investigated the iron-related haematological parameters in both male and female athletes participating in different sporting disciplines necessitating different metabolic energy demands. A total of 873 athletes (514 males, mean age: 22.08 ± 4.95 years and 359 females, mean age: 21.38 ± 3.88 years) were divided according to gender and to the predominant energy system required for participation in sport (aerobic, anaerobic or mixed) and haematological and iron-related parameters were measured. For both male and female athletes, significant differences related to the predominant energy system were found at a general level: male (Wilks' λ = 0.798, F = 3.047, p < 0.001) and female (Wilks' λ = 0.762, F = 2.591, p < 0.001). According to the ferritin cutoff value of 35 μg/L, whole body iron and sTfR significantly differed in all three groups of male and female athletes (p < 0.001). The percentage of hypochromic erythrocytes in male athletes was significantly higher only in those who required an anaerobic energy source (p < 0.001), whilst in the females hypochromic erythrocytes (p < 0.001) and haemoglobin (anaerobic, p = 0.042; mixed, p = 0.006) were significantly different only in anaerobic and mixed energy source athletes. According to the ferritin cutoff value of 22 μg/L, in females, whole body iron, sTfR and hypochromic erythrocytes were significantly higher in all three groups of athletes than those below the aforementioned cutoff value (p < 0.001). We conclude that the predominant energy system required for participation in sport affects haematological parameters. sTfR and body iron proved to be reliable parameters for monitoring the dynamics of iron metabolism and could contribute to successful iron-deficiency prevention.

  13. Redox Balance in Lactobacillus reuteri DSM20016: Roles of Iron-Dependent Alcohol Dehydrogenases in Glucose/ Glycerol Metabolism

    PubMed Central

    Bromberger, Paul David; Nieuwenhuiys, Gavin; Hatti-Kaul, Rajni

    2016-01-01

    Lactobacillus reuteri, a heterofermentative bacterium, metabolizes glycerol via a Pdu (propanediol-utilization) pathway involving dehydration to 3-hydroxypropionaldehyde (3-HPA) followed by reduction to 1,3-propandiol (1,3-PDO) with concomitant generation of an oxidized cofactor, NAD+ that is utilized to maintain cofactor balance required for glucose metabolism and even for oxidation of 3-HPA by a Pdu oxidative branch to 3-hydroxypropionic acid (3-HP). The Pdu pathway is operative inside Pdu microcompartment that encapsulates different enzymes and cofactors involved in metabolizing glycerol or 1,2-propanediol, and protects the cells from the toxic effect of the aldehyde intermediate. Since L. reuteri excretes high amounts of 3-HPA outside the microcompartment, the organism is likely to have alternative alcohol dehydrogenase(s) in the cytoplasm for transformation of the aldehyde. In this study, diversity of alcohol dehydrogenases in Lactobacillus species was investigated with a focus on L. reuteri. Nine ADH enzymes were found in L. reuteri DSM20016, out of which 3 (PduQ, ADH6 and ADH7) belong to the group of iron-dependent enzymes that are known to transform aldehydes/ketones to alcohols. L. reuteri mutants were generated in which the three ADHs were deleted individually. The lagging growth phenotype of these deletion mutants revealed that limited NAD+/NADH recycling could be restricting their growth in the absence of ADHs. Notably, it was demonstrated that PduQ is more active in generating NAD+ during glycerol metabolism within the microcompartment by resting cells, while ADH7 functions to balance NAD+/NADH by converting 3-HPA to 1,3-PDO outside the microcompartment in the growing cells. Moreover, evaluation of ADH6 deletion mutant showed strong decrease in ethanol level, supporting the role of this bifuctional alcohol/aldehyde dehydrogenase in ethanol production. To the best of our knowledge, this is the first report revealing both internal and external recycling

  14. Structure-substitution limit correlation study on Cr{sup 3+} substituted polycrystalline yttrium iron garnet

    SciTech Connect

    Modi, K. B.; Saija, K. G.; Sharma, P. U.; Lakhani, V. K.; Vasoya, N. H.; Pathak, T. K.; Zankat, K. B.

    2016-05-06

    Polycrystalline samples of Cr{sup 3+} - substituted yttrium iron garnet (Y{sub 3}Fe{sub 5}O{sub 12}) system with general chemical formula, Y{sub 3}Fe{sub 5-x}Cr{sub x}O{sub 12}, x = 0.0, 0.2, 0.4 and 0.6 were synthesized by double sintering ceramic technique and characterized by X-ray powder diffractometry. The Rietveld fitted X-ray diffraction patterns analysis revealed mono phase formation for x = 0.0 - 0.4 compositions while x = 0.6 composition possesses mixed phase character. The observed substitution limit has been discussed in the light of ionic size of substituent, electrostatic energy, electronic configuration and synthesis parameters. These observations strongly suggest that the electronic configuration of Cr{sup 3+}, which is favorable to the formation of d2sp3 (octahedral) type bonds, must be important. In the case of Cr{sup 3+}, the substitution does not appear to proceed well for x much greater than 0.5, this limitation probably is a consequence of the strong preference of a smaller ion Cr{sup 3+}, for a larger octahedral site which quickly leads to a condition not comparable with the requirement of the structure. The distribution of cations, mean ionic radii and theoretical lattice constant values have been determined.

  15. Brain Iron Metabolism and early brain injury following subarachnoid hemorrhage: iCeFISH-pilot (CSF iron in SAH)

    PubMed Central

    Selim, Magdy; Cotleur, Anne; Hussain, M. Shazam; Toth, Gabor; Provencio, J. Javier

    2015-01-01

    Objectives To explore the relationship between levels of non-protein bound iron in cerebrospinal fluid and the development of early brain injury in patients with aneurysmal SAH. Design Prospective observational cohort pilot study. Setting Neurointensive care unit of an academic, tertiary medical center Patients Patients admitted with aneurysmal subarachnoid hemorrhage Hunt and Hess grades 2 to 4 requiring ventriculostomy insertion as part of their clinical management. Interventions None. Measurements and main results Samples of cerebrospinal fluid (CSF) were obtained on days 1, 3, and 5. A fluorometric assay that relies on an oxidation sensitive probe was used to measure unbound iron, and levels of iron-handling proteins were measured by means of enzyme-linked immunosorbent assays. We prospectively collected and recorded demographic, clinical, and radiological data. A total of 12 patients were included in this analysis. Median Hunt and Hess score on admission was 3.5 (IQR: 1) and median modified Fisher scale score was 4 (IQR: 1). Seven of 12 patients (58%) developed delayed cerebral ischemia (DCI). Day 5 non-transferrin bound iron (NTBI) (7.88±1 vs. 3.58± 0.8, p= 0.02) and mean NTBI (7.39± 0.4 vs. 3.34±0.4 p= 0.03) were significantly higher in patients who developed DCI. Mean and day 3 levels of redox-active iron correlated with development of angiographic vasospasm in logistic regression analysis (p= 0.02); while mean redox-active iron and lower levels of ceruloplasmin on days 3, 5 and peak were correlated with development of deep cerebral infarcts. Conclusions our preliminary data indicate a causal relationship between unbound iron and brain injury following SAH and suggest a possible protective role for ceruloplasmin in this setting, particularly in the prevention of cerebral ischemia. Further studies are needed to validate these findings and to probe their clinical significance. PMID:24710655

  16. Determining host metabolic limitations on viral replication via integrated modeling and experimental perturbation.

    PubMed

    Birch, Elsa W; Ruggero, Nicholas A; Covert, Markus W

    2012-01-01

    Viral replication relies on host metabolic machinery and precursors to produce large numbers of progeny - often very rapidly. A fundamental example is the infection of Escherichia coli by bacteriophage T7. The resource draw imposed by viral replication represents a significant and complex perturbation to the extensive and interconnected network of host metabolic pathways. To better understand this system, we have integrated a set of structured ordinary differential equations quantifying T7 replication and an E. coli flux balance analysis metabolic model. Further, we present here an integrated simulation algorithm enforcing mutual constraint by the models across the entire duration of phage replication. This method enables quantitative dynamic prediction of virion production given only specification of host nutritional environment, and predictions compare favorably to experimental measurements of phage replication in multiple environments. The level of detail of our computational predictions facilitates exploration of the dynamic changes in host metabolic fluxes that result from viral resource consumption, as well as analysis of the limiting processes dictating maximum viral progeny production. For example, although it is commonly assumed that viral infection dynamics are predominantly limited by the amount of protein synthesis machinery in the host, our results suggest that in many cases metabolic limitation is at least as strict. Taken together, these results emphasize the importance of considering viral infections in the context of host metabolism.

  17. Determining Host Metabolic Limitations on Viral Replication via Integrated Modeling and Experimental Perturbation

    PubMed Central

    Birch, Elsa W.; Ruggero, Nicholas A.; Covert, Markus W.

    2012-01-01

    Viral replication relies on host metabolic machinery and precursors to produce large numbers of progeny - often very rapidly. A fundamental example is the infection of Escherichia coli by bacteriophage T7. The resource draw imposed by viral replication represents a significant and complex perturbation to the extensive and interconnected network of host metabolic pathways. To better understand this system, we have integrated a set of structured ordinary differential equations quantifying T7 replication and an E. coli flux balance analysis metabolic model. Further, we present here an integrated simulation algorithm enforcing mutual constraint by the models across the entire duration of phage replication. This method enables quantitative dynamic prediction of virion production given only specification of host nutritional environment, and predictions compare favorably to experimental measurements of phage replication in multiple environments. The level of detail of our computational predictions facilitates exploration of the dynamic changes in host metabolic fluxes that result from viral resource consumption, as well as analysis of the limiting processes dictating maximum viral progeny production. For example, although it is commonly assumed that viral infection dynamics are predominantly limited by the amount of protein synthesis machinery in the host, our results suggest that in many cases metabolic limitation is at least as strict. Taken together, these results emphasize the importance of considering viral infections in the context of host metabolism. PMID:23093930

  18. Relationship between Serum Levels of Body Iron Parameters and Insulin Resistance and Metabolic Syndrome in Korean Children

    PubMed Central

    Lee, Hye-Ja; Jang, Han Byul; Park, Ji Eun; Park, Kyung-Hee; Kang, Jae Heon; Park, Sang Ick; Song, Jihyun

    2014-01-01

    Objectives An increase in serum ferritin and levels of the cleaved soluble form of transferrin receptor (sTfR) are related to several metabolic conditions. We evaluated the relationship between body iron status indicators, including ferritin and sTfR, and insulin resistance and metabolic syndrome (MetS) in Korean children. Methods A cross-sectional study was conducted on 1350 children in Korea. Anthropometrical parameters; lipid profiles; levels of glucose, insulin, and leptin; and iron status indicators, including sTfR, serum ferritin, serum iron, total iron-binding capacity (TIBC), and transferrin saturation (TS), were analyzed. Results Although serum sTfR levels were significantly higher in boys than in girls (2.20 vs. 2.06 mg/L, p < 0.0001), serum iron and TS were higher in girls than in boys (101.38 vs. 95.77 mg/L, p = 0.027 and 30.15 vs. 28.91%, p = 0.04, respectively). Waist circumference (WC) and leptin were most significantly associated with body iron indicators when adjusted for age and sex. After adjusting for age, sex, and WC, sTfR levels showed the strongest positive association with leptin levels (p = 0.0001). Children in the highest tertile for homeostasis model assessment-insulin resistance (HOMA-IR) had higher TIBC (p = 0.0005) and lower serum iron (p = 0.0341), and the lowest TS (p < 0.0001) after adjustment for confounders. Children with higher sTfR were most significantly associated with risk of MetS compared with those lower sTfR (p = 0.0077). Conclusion The associations of serum levels of iron metabolism markers with leptin levels, HOMA-IR, and MetS suggest that iron-related factors may involve insulin resistance and MetS. PMID:25379371

  19. Limited Influence of Oxygen on the Evolution of Chemical Diversity in Metabolic Networks

    PubMed Central

    Takemoto, Kazuhiro; Yoshitake, Ikumi

    2013-01-01

    Oxygen is thought to promote species and biomolecule diversity. Previous studies have suggested that oxygen expands metabolic networks by acquiring metabolites with different chemical properties (higher hydrophobicity, for example). However, such conclusions are typically based on biased evaluation, and are therefore non-conclusive. Thus, we re-investigated the effect of oxygen on metabolic evolution using a phylogenetic comparative method and metadata analysis to reduce the bias as much as possible. Notably, we found no difference in metabolic network expansion between aerobes and anaerobes when evaluating phylogenetic relationships. Furthermore, we showed that previous studies have overestimated or underestimated the degrees of differences in the chemical properties (e.g., hydrophobicity) between oxic and anoxic metabolites in metabolic networks of unicellular organisms; however, such overestimation was not observed when considering the metabolic networks of multicellular organisms. These findings indicate that the contribution of oxygen to increased chemical diversity in metabolic networks is lower than previously thought; rather, phylogenetic signals and cell-cell communication result in increased chemical diversity. However, this conclusion does not contradict the effect of oxygen on metabolic evolution; instead, it provides a deeper understanding of how oxygen contributes to metabolic evolution despite several limitations in data analysis methods. PMID:24958261

  20. Influence of Lead on Repetitive Behavior and Dopamine Metabolism in a Mouse Model of Iron Overload

    PubMed Central

    Kueon, Chojin; Kim, Jonghan

    2014-01-01

    Exposures to lead (Pb) are associated with neurological problems including psychiatric disorders and impaired learning and memory. Pb can be absorbed by iron transporters, which are up-regulated in hereditary hemochromatosis, an iron overload disorder in which increased iron deposition in various parenchymal organs promote metal-induced oxidative damage. While dysfunction in HFE (High Fe) gene is the major cause of hemochromatosis, the transport and toxicity of Pb in Hfe-related hemochromatosis are largely unknown. To elucidate the relationship between HFE gene dysfunction and Pb absorption, H67D knock-in Hfe-mutant and wild-type mice were given drinking water containing Pb 1.6 mg/ml ad libitum for 6 weeks and examined for behavioral phenotypes using the nestlet-shredding and marble-burying tests. Latency to nestlet-shredding in Pb-treated wild-type mice was prolonged compared with non-exposed wild-types (p < 0.001), whereas Pb exposure did not alter shredding latency in Hfe-mutant mice. In the marble-burying test, Hfe-mutant mice showed an increased number of marbles buried compared with wild-type mice (p = 0.002), indicating more repetitive behavior upon Hfe mutation. Importantly, Pb-exposed wild-type mice buried more marbles than non-exposed wild-types, whereas the number of marbles buried by Hfe-mutant mice did not change whether or not exposed to Pb. These results suggest that Hfe mutation could normalize Pb-induced behavioral alteration. To explore the mechanism of repetitive behavior caused by Pb, western blot analysis was conducted for proteins involved in brain dopamine metabolism. The levels of tyrosine hydroxylase and dopamine transporter increased upon Pb exposure in both genotypes, whereas Hfe-mutant mice displayed down-regulation of the dopamine transporter and dopamine D1 receptor with D2 receptor elevated. Taken together, our data support the idea that both Pb exposure and Hfe mutation increase repetitive behavior in mice and further suggest that

  1. Iron as a Cofactor That Limits the Promotion of Cyanobacteria in Lakes Across a Tropic Gradient

    NASA Astrophysics Data System (ADS)

    Sorichetti, R. J.; Creed, I. F.; Trick, C. G.

    2014-12-01

    The frequency and intensity of cyanobacterial blooms (cyanoblooms) is increasing globally. While cyanoblooms in eutrophic (nutrient-rich) freshwater lakes are expected to persist and worsen with climate change projections, many of the "new" cyanobloom reports pertain to oligotrophic (nutrient-poor) freshwater lakes with no prior history of cyanobloom occurrence. Under the pressures of a changing climate, there exists a critical research need to revisit existing conceptual models and identify cyanobloom regulating factors currently unaccounted for. Iron (Fe) is required in nearly all pathways of cyanobacterial macronutrient use, though its precise role in regulating cyanobacterial biomass across the lake trophic gradient is not fully understood. The hypotheses tested were: (1) cyanobacteria will predominate in lakes when bioavailable Fe concentration is low, and (2) cyanobacteria overcome this Fe limitation in all lakes using the siderophore-based Fe acquisition strategy to scavenge Fe providing a competitive advantage over other phytoplankton. These hypotheses were tested using natural lakes across an oligo-meso-eutrophic gradient across Canada. In all lakes sampled, the relative cyanobacterial biomass was highest at low predicted Fe bioavailability (< 1.0 × 10-19 mol L-1). Within this range of low bioavailable Fe, iron-binding organic ligands were measured. Concentrations of ligands with reactive hydroxamate moieties were positively correlated to cyanobacterial biomass in both the oligotrophic (r2 = 0.77, p < 0.001) and eutrophic (r2 = 0.81, p < 0.001) lakes suggesting a possible low-Fe mediated cellular origin, siderophores. Fe-binding ligands with catecholate-type binding sites were detected in all lakes, although lack of a relationship with cyanobacterial biomass and a significant relationship with dissolved organic carbon (DOC) in oligotrophic (r2 = 0.65, p < 0.001) and eutrophic (r2 = 0.65, p < 0.001) lakes may indicate an allochthonous source that is not

  2. Iron limitation modulates ocean acidification effects on southern ocean phytoplankton communities.

    PubMed

    Hoppe, Clara J M; Hassler, Christel S; Payne, Christopher D; Tortell, Philippe D; Rost, Björn; Trimborn, Scarlett

    2013-01-01

    The potential interactive effects of iron (Fe) limitation and Ocean Acidification in the Southern Ocean (SO) are largely unknown. Here we present results of a long-term incubation experiment investigating the combined effects of CO2 and Fe availability on natural phytoplankton assemblages from the Weddell Sea, Antarctica. Active Chl a fluorescence measurements revealed that we successfully cultured phytoplankton under both Fe-depleted and Fe-enriched conditions. Fe treatments had significant effects on photosynthetic efficiency (Fv/Fm; 0.3 for Fe-depleted and 0.5 for Fe-enriched conditions), non-photochemical quenching (NPQ), and relative electron transport rates (rETR). pCO2 treatments significantly affected NPQ and rETR, but had no effect on Fv/Fm. Under Fe limitation, increased pCO2 had no influence on C fixation whereas under Fe enrichment, primary production increased with increasing pCO2 levels. These CO2-dependent changes in productivity under Fe-enriched conditions were accompanied by a pronounced taxonomic shift from weakly to heavily silicified diatoms (i.e. from Pseudo-nitzschia sp. to Fragilariopsis sp.). Under Fe-depleted conditions, this functional shift was absent and thinly silicified species dominated all pCO2 treatments (Pseudo-nitzschia sp. and Synedropsis sp. for low and high pCO2, respectively). Our results suggest that Ocean Acidification could increase primary productivity and the abundance of heavily silicified, fast sinking diatoms in Fe-enriched areas, both potentially leading to a stimulation of the biological pump. Over much of the SO, however, Fe limitation could restrict this possible CO2 fertilization effect.

  3. Specific hemosiderin deposition in spleen induced by a low dose of cisplatin: altered iron metabolism and its implication as an acute hemosiderin formation model.

    PubMed

    Wang, Yingze; Juan, L V; Ma, Xiaowei; Wang, Dongliang; Ma, Huili; Chang, Yanzhong; Nie, Guangjun; Jia, Lee; Duan, Xianglin; Liang, Xing-Jie

    2010-07-01

    Cisplatin is one of the commonly-used chemotherapeutic drugs to efficiently treat malignant tumors in clinic, however, the adverse effects of cisplatin such as nephrotoxicity, neurotoxicity, and hemolytic uremic syndrome are often observed at its clinical doses (approximately 60 mg/m(2)), which limit its broader application. In earlier studies, little attention was paid to the subtle changes in the architecture of lymphatic organs after low doses of cisplatin treatment. This paper reviews current understanding of cisplatin-induced erythrocyte injury, and presents our latest finding that a low dose of cisplatin (3.6 mg/m(2)/day, 14 days) could induce specific hemosiderin deposition in spleen of both normal and hepatoma-22 (H22) inoculated Balb/C mice. This dose of cisplatin significantly inhibited H22-induced acute ascites development. No significant toxicity was induced by this dose of cisplatin to tissues except for hemosiderin accumulation in the spleen of both normal and H22 tumor-bearing mice. Increased splenic iron content and erythrocyte injury were observed after treatment with the low dose of cisplatin. The mRNA levels of ferroportin (FPN1) and ferritin were upregulated by 25 and 5-fold in spleen, respectively. Overexpression of FPN1 and ferritin protein were also been observed at protein levels by Western blotting analysis. In addition, the mRNA expression of hepcidin was also increased, suggesting blockage of iron recycling through FPN1 in spleen with cisplatin treatment. In conclusion, cisplatin treatment damages the erythrocytes which accumulate in the red pulp of spleen with defective recycling of FPN1 and ferritin protein. Hepcidin inhibits the function of FPN1 as iron-exporter leading to iron overloaded inside ferritins of splenic cells, which are stained with abnormal hemosiderin accumulation. These results demonstrate that cisplatin-caused hemosiderin deposition in spleen provides a valuable clue for understanding the molecular basis of toxicity of

  4. Specific Hemosiderin Deposition in Spleen Induced by a Low Dose of Cisplatin: Altered Iron Metabolism and Its Implication as an Acute Hemosiderin Formation Model

    PubMed Central

    Wang, Yingze; Juan, LV; Ma, Xiaowei; Wang, Dongliang; Ma, Huili; Chang, Yanzhong; Nie, Guangjun; Jia, Lee; Duan, Xianglin; Liang, Xing-Jie

    2010-01-01

    Cisplatin is one of the commonly-used chemotherapeutic drugs to efficiently treat malignant tumors in clinic, however, the adverse effects of cisplatin such as nephrotoxicity, neurotoxcity, and hemolytic uremic syndrome are often observed at its clinical doses (~60 mg/m2), which limit its broader application. In earlier studies, little attention was paid to the subtle changes in the architecture of lymphatic organs after low doses of cisplatin treatment. This paper reviews current understanding of cisplatin-induced erythrocyte injury, and presents our latest finding that a low dose of cisplatin (3.6 mg/m2/day, 14 days) could induce specific hemosiderin deposition in spleen of both normal and hepatoma-22 (H22) inoculated Balb/C mice. This dose of cisplatin significantly inhibited H22-induced acute ascites development. No significant toxicity was induced by this dose of cisplatin to tissues except for hemosiderin accumulation in the spleen of both normal and H22 tumor-bearing mice. Increased splenic iron content and erythrocyte injury were observed after treatment with the low dose of cisplatin. The mRNA levels of ferroportin (FPN1) and ferritin were upregulated by 25 and 5-fold in spleen, respectively. Overexpression of FPN1 and ferritin protein were also been observed at protein levels by Western blotting analysis. In addition, the mRNA expression of hepcidin was also increased, suggesting blockage of iron recycling through FPN1 in spleen with cisplatin treatment. In conclusion, cisplatin treatment damages the erythrocytes which accumulate in the red pulp of spleen with defective recycling of FPN1 and ferritin protein. Hepcidin inhibits the function of FPN1 as iron-exporter leading to iron overloaded inside ferritins of splenic cells, which are stained with abnormal hemosiderin accumulation. These results demonstrate that cisplatin-caused hemosiderin deposition in spleen provides a valuable clue for understanding the molecular basis of toxicity of cisplatin and

  5. Iron metabolism and related genetic diseases: A cleared land, keeping mysteries.

    PubMed

    Brissot, Pierre; Loréal, Olivier

    2016-02-01

    Body iron has a very close relationship with the liver. Physiologically, the liver synthesizes transferrin, in charge of blood iron transport; ceruloplasmin, acting through its ferroxidase activity; and hepcidin, the master regulator of systemic iron. It also stores iron inside ferritin and serves as an iron reservoir, both protecting the cell from free iron toxicity and ensuring iron delivery to the body whenever needed. The liver is first in line for receiving iron from the gut and the spleen, and is, therefore, highly exposed to iron overload when plasma iron is in excess, especially through its high affinity for plasma non-transferrin bound iron. The liver is strongly involved when iron excess is related either to hepcidin deficiency, as in HFE, hemojuvelin, hepcidin, and transferrin receptor 2 related haemochromatosis, or to hepcidin resistance, as in type B ferroportin disease. It is less involved in the usual (type A) form of ferroportin disease which targets primarily the macrophagic system. Hereditary aceruloplasminemia raises important pathophysiological issues in light of its peculiar organ iron distribution.

  6. Bacillus subtilis Metabolism and Energetics in Carbon-Limited and Excess-Carbon Chemostat Culture

    PubMed Central

    Dauner, Michael; Storni, Tazio; Sauer, Uwe

    2001-01-01

    The energetic efficiency of microbial growth is significantly reduced in cultures growing under glucose excess compared to cultures growing under glucose limitation, but the magnitude to which different energy-dissipating processes contribute to the reduced efficiency is currently not well understood. We introduce here a new concept for balancing the total cellular energy flux that is based on the conversion of energy and carbon fluxes into energy equivalents, and we apply this concept to glucose-, ammonia-, and phosphate-limited chemostat cultures of riboflavin-producing Bacillus subtilis. Based on [U-13C6]glucose-labeling experiments and metabolic flux analysis, the total energy flux in slow-growing, glucose-limited B. subtilis is almost exclusively partitioned in maintenance metabolism and biomass formation. In excess-glucose cultures, in contrast, uncoupling of anabolism and catabolism is primarily achieved by overflow metabolism, while two quantified futile enzyme cycles and metabolic shifts to energetically less efficient pathways are negligible. In most cultures, about 20% of the total energy flux could not be assigned to a particular energy-consuming process and thus are probably dissipated by processes such as ion leakage that are not being considered at present. In contrast to glucose- or ammonia-limited cultures, metabolic flux analysis revealed low tricarboxylic acid (TCA) cycle fluxes in phosphate-limited B. subtilis, which is consistent with CcpA-dependent catabolite repression of the cycle and/or transcriptional activation of genes involved in overflow metabolism in the presence of excess glucose. ATP-dependent control of in vivo enzyme activity appears to be irrelevant for the observed differences in TCA cycle fluxes. PMID:11717290

  7. [Quality of life and iron metabolism in patients with anemic syndrome developed on the background of chronic heart failure].

    PubMed

    Ryndina, N; Kravchun, P; Tytova, G

    2013-03-01

    The presence of concomitant anemia in many aspects defines an unfavorable course of chronic heart failure, affects patient's quality of life. Among anemic patients with chronic heart failure prevailed persons with a relative deficiency of iron. Aim of the study - to evaluate the quality of life for patients with anemia on the background of chronic heart failure, using a questionnaire FACT-An, and to analyze the existence and nature of the relations between quality of life and indicators of the iron metabolism, based on the study of transferrin saturation and ferritin. Ferritin concentration was determined by ELISA. Transferrin saturation were determined by the formula. Questionnaire FACT-An was used for assess the quality of life in anemic patients with chronic heart failure. The presence of functional iron deficiency in patients with chronic heart failure and anemic syndrome is accompanied by deterioration of parameters of quality of life mainly due to the scale of physical activity and social functioning.

  8. Divergent responses of Atlantic coastal and oceanic Synechococcus to iron limitation.

    PubMed

    Mackey, Katherine R M; Post, Anton F; McIlvin, Matthew R; Cutter, Gregory A; John, Seth G; Saito, Mak A

    2015-08-11

    Marine Synechococcus are some of the most diverse and ubiquitous phytoplankton, and iron (Fe) is an essential micronutrient that limits productivity in many parts of the ocean. To investigate how coastal and oceanic Atlantic Synechococcus strains acclimate to Fe availability, we compared the growth, photophysiology, and quantitative proteomics of two Synechococcus strains from different Fe regimes. Synechococcus strain WH8102, from a region in the southern Sargasso Sea that receives substantial dust deposition, showed impaired growth and photophysiology as Fe declined, yet used few acclimation responses. Coastal WH8020, from the dynamic, seasonally variable New England shelf, displayed a multitiered, hierarchical cascade of acclimation responses with different Fe thresholds. The multitiered response included changes in Fe acquisition, storage, and photosynthetic proteins, substitution of flavodoxin for ferredoxin, and modified photophysiology, all while maintaining remarkably stable growth rates over a range of Fe concentrations. Modulation of two distinct ferric uptake regulator (Fur) proteins that coincided with the multitiered proteome response was found, implying the coastal strain has different regulatory threshold responses to low Fe availability. Low nitrogen (N) and phosphorus (P) availability in the open ocean may favor the loss of Fe response genes when Fe availability is consistent over time, whereas these genes are retained in dynamic environments where Fe availability fluctuates and N and P are more abundant.

  9. Divergent responses of Atlantic coastal and oceanic Synechococcus to iron limitation

    PubMed Central

    Mackey, Katherine R. M.; Post, Anton F.; McIlvin, Matthew R.; Cutter, Gregory A.; John, Seth G.; Saito, Mak A.

    2015-01-01

    Marine Synechococcus are some of the most diverse and ubiquitous phytoplankton, and iron (Fe) is an essential micronutrient that limits productivity in many parts of the ocean. To investigate how coastal and oceanic Atlantic Synechococcus strains acclimate to Fe availability, we compared the growth, photophysiology, and quantitative proteomics of two Synechococcus strains from different Fe regimes. Synechococcus strain WH8102, from a region in the southern Sargasso Sea that receives substantial dust deposition, showed impaired growth and photophysiology as Fe declined, yet used few acclimation responses. Coastal WH8020, from the dynamic, seasonally variable New England shelf, displayed a multitiered, hierarchical cascade of acclimation responses with different Fe thresholds. The multitiered response included changes in Fe acquisition, storage, and photosynthetic proteins, substitution of flavodoxin for ferredoxin, and modified photophysiology, all while maintaining remarkably stable growth rates over a range of Fe concentrations. Modulation of two distinct ferric uptake regulator (Fur) proteins that coincided with the multitiered proteome response was found, implying the coastal strain has different regulatory threshold responses to low Fe availability. Low nitrogen (N) and phosphorus (P) availability in the open ocean may favor the loss of Fe response genes when Fe availability is consistent over time, whereas these genes are retained in dynamic environments where Fe availability fluctuates and N and P are more abundant. PMID:26216989

  10. Metabolic Implications in the Biochemical Responses to Iron Deficiency in Cucumber (Cucumis sativus L.) Roots.

    PubMed Central

    Rabotti, G.; De Nisi, P.; Zocchi, G.

    1995-01-01

    Strategy I plants respond to Fe deficiency by inducing morphological and biochemical modifications at the root level that are apt to make iron available for uptake. Cucumber (Cucumis sativus L.) grown in the absence of Fe has been shown to increase the capacity to acidify the rhizosphere and Fe3+ reduction activity. We have determined in these roots some metabolic activities that might be correlated with the increased proton extrusion. Proton efflux from roots may be followed by a mechanism regulating the cytosolic pH according to the pH-stat theory. Roots grown in the absence of Fe showed an increase in dark 14CO2 fixation and organic acid synthesis and a 6-fold increase in the extractable phosphoenolpyruvate carboxylase activity with respect to the control roots. Dehydrogenase activities producing cytosolic NAD(P)H were also increased under Fe deficiency. The presence of Fe2+, but not Fe3+, inhibited dark 14CO2 fixation in a range between 24 and 52% but did not show any effect on the in vitro phosphoenolpyruvate carboxylase activity. PMID:12228426

  11. [Biomarkers of iron metabolism and inflammation in patients with chronic heart failure and various types of left ventricular dysfunction].

    PubMed

    Kazymyrko, V K; Kutovyĭ, V V; Ivanyts'ka, L M; Dubkova, A G; Silant'ieva, T S

    2013-09-01

    Study the level of some of the indicators of iron metabolism and inflammatory markers in patients with chronic heart failure due to hypertension and coronary heart disease. The results of the study in systolic and diastolic dysfunction of the left ventricle, the varying degrees of severity of heart failure. The level of the studied parameters determined by the severity of heart failure and does not depend on the nature of left ventricular dysfunction.

  12. Relationships among smoking habits, airflow limitations, and metabolic abnormalities in school workers.

    PubMed

    Horie, Masafumi; Noguchi, Satoshi; Tanaka, Wakae; Goto, Yasushi; Yoshihara, Hisanao; Kawakami, Masaki; Suzuki, Masaru; Sakamoto, Yoshio

    2013-01-01

    Chronic obstructive pulmonary disease is caused mainly by habitual smoking and is common among elderly individuals. It involves not only airflow limitation but also metabolic disorders, leading to increased cardiovascular morbidity and mortality. We evaluated relationships among smoking habits, airflow limitation, and metabolic abnormalities. Between 2001 and 2008, 15,324 school workers (9700 males, 5624 females; age: ≥ 30 years) underwent medical checkups, including blood tests and spirometry. They also responded to a questionnaire on smoking habits and medical history. Airflow limitation was more prevalent in current smokers than in ex-smokers and never-smokers in men and women. The frequency of hypertriglyceridemia was higher in current smokers in all age groups, and those of low high-density-lipoprotein cholesterolemia and diabetes mellitus were higher in current smokers in age groups ≥ 40 s in men, but not in women. There were significant differences in the frequencies of metabolic abnormalities between subjects with airflow limitations and those without in women, but not in men. Smoking index was an independent factor associated with increased frequencies of hypertriglyceridemia (OR 1.015; 95% CI: 1.012-1.018; p<0.0001) and low high-density-lipoprotein cholesterolemia (1.013; 1.010-1.016; p<0.0001) in men. Length of smoking cessation was an independent factor associated with a decreased frequency of hypertriglyceridemia (0.984; 0.975-0.994; p = 0.007). Habitual smoking causes high incidences of airflow limitation and metabolic abnormalities. Women, but not men, with airflow limitation had higher frequencies of metabolic abnormalities.

  13. Comparison of primary and secondary rat astrocyte cultures regarding glucose and glutathione metabolism and the accumulation of iron oxide nanoparticles.

    PubMed

    Petters, Charlotte; Dringen, Ralf

    2014-01-01

    Astrocyte-rich primary cultures (APCs) are frequently used as a model system for the investigation of properties of brain astrocytes. However, as APCs contain a substantial number of microglial and oligodendroglial cells, biochemical parameters determined for such cultures may at least in part reflect also the presence of the contaminating cell types. To lower the potential contributions of microglial and oligodendroglial cells on properties of the astrocytes in APCs we prepared rat astrocyte-rich secondary cultures (ASCs) by subculturing of APCs and compared these ASCs with APCs regarding basal metabolic parameters, specific enzyme activities and the accumulation of iron oxide nanoparticles. Immunocytochemical characterization revealed that ASCs contained only minute amounts of microglial and oligodendroglial cells. ASCs and APCs did not significantly differ in their specific glucose consumption and lactate production rates, in their specific iron and glutathione contents, in their specific activities of various enzymes involved in glucose and glutathione metabolism nor in their accumulation of iron oxide nanoparticles. Thus, the absence or presence of some contaminating microglial and oligodendroglial cells appears not to substantially modulate the investigated metabolic parameters of astrocyte cultures.

  14. First-pass metabolism limits the intestinal absorption of enteral alpha-ketoglutarate in young pigs

    USDA-ARS?s Scientific Manuscript database

    Our results in a previous study indicated that the portal absorption of intragastrically fed alpha-ketoglutarate (AKG) was limited in young pigs. Our aim was to quantify the net portal absorption, first-pass metabolism, and whole-body flux of enterally infused AKG. In study 1, we quantified the net ...

  15. Differential Role of Ferritins in Iron Metabolism and Virulence of the Plant-Pathogenic Bacterium Erwinia chrysanthemi 3937▿

    PubMed Central

    Boughammoura, Aïda; Matzanke, Berthold F.; Böttger, Lars; Reverchon, Sylvie; Lesuisse, Emmanuel; Expert, Dominique; Franza, Thierry

    2008-01-01

    During infection, the phytopathogenic enterobacterium Erwinia chrysanthemi has to cope with iron-limiting conditions and the production of reactive oxygen species by plant cells. Previous studies have shown that a tight control of the bacterial intracellular iron content is necessary for full virulence. The E. chrysanthemi genome possesses two loci that could be devoted to iron storage: the bfr gene, encoding a heme-containing bacterioferritin, and the ftnA gene, coding for a paradigmatic ferritin. To assess the role of these proteins in the physiology of this pathogen, we constructed ferritin-deficient mutants by reverse genetics. Unlike the bfr mutant, the ftnA mutant had increased sensitivity to iron deficiency and to redox stress conditions. Interestingly, the bfr ftnA mutant displayed an intermediate phenotype for sensitivity to these stresses. Whole-cell analysis by Mössbauer spectroscopy showed that the main iron storage protein is FtnA and that there is an increase in the ferrous iron/ferric iron ratio in the ftnA and bfr ftnA mutants. We found that ftnA gene expression is positively controlled by iron and the transcriptional repressor Fur via the small antisense RNA RyhB. bfr gene expression is induced at the stationary phase of growth. The σS transcriptional factor is necessary for this control. Pathogenicity tests showed that FtnA and the Bfr contribute differentially to the virulence of E. chrysanthemi depending on the host, indicating the importance of a perfect control of iron homeostasis in this bacterial species during infection. PMID:18165304

  16. Differential role of ferritins in iron metabolism and virulence of the plant-pathogenic bacterium Erwinia chrysanthemi 3937.

    PubMed

    Boughammoura, Aïda; Matzanke, Berthold F; Böttger, Lars; Reverchon, Sylvie; Lesuisse, Emmanuel; Expert, Dominique; Franza, Thierry

    2008-03-01

    During infection, the phytopathogenic enterobacterium Erwinia chrysanthemi has to cope with iron-limiting conditions and the production of reactive oxygen species by plant cells. Previous studies have shown that a tight control of the bacterial intracellular iron content is necessary for full virulence. The E. chrysanthemi genome possesses two loci that could be devoted to iron storage: the bfr gene, encoding a heme-containing bacterioferritin, and the ftnA gene, coding for a paradigmatic ferritin. To assess the role of these proteins in the physiology of this pathogen, we constructed ferritin-deficient mutants by reverse genetics. Unlike the bfr mutant, the ftnA mutant had increased sensitivity to iron deficiency and to redox stress conditions. Interestingly, the bfr ftnA mutant displayed an intermediate phenotype for sensitivity to these stresses. Whole-cell analysis by Mössbauer spectroscopy showed that the main iron storage protein is FtnA and that there is an increase in the ferrous iron/ferric iron ratio in the ftnA and bfr ftnA mutants. We found that ftnA gene expression is positively controlled by iron and the transcriptional repressor Fur via the small antisense RNA RyhB. bfr gene expression is induced at the stationary phase of growth. The sigmaS transcriptional factor is necessary for this control. Pathogenicity tests showed that FtnA and the Bfr contribute differentially to the virulence of E. chrysanthemi depending on the host, indicating the importance of a perfect control of iron homeostasis in this bacterial species during infection.

  17. Sequestration efficiency in the iron-limited North Atlantic: Implications for iron supply mode to fertilized blooms

    NASA Astrophysics Data System (ADS)

    Le Moigne, Frédéric A. C.; Moore, C. Mark; Sanders, Richard J.; Villa-Alfageme, Maria; Steigenberger, Sebastian; Achterberg, Eric P.

    2014-07-01

    Estimates of the amount of carbon sequestered in the ocean interior per unit iron (Fe) supplied, as quantified by the sequestration efficiency (Ceffx), vary widely. Such variability in Ceffx has frequently been attributed to estimate uncertainty rather than intrinsic variability. Here we derive new estimates of Ceffx for the subpolar North Atlantic, where Fe stressed conditions have recently been demonstrated. Derived values of Ceffx from across the region, including areas subject to atypical external Fe fertilization events during the year of sample collection (2010), ranged from 17 to 19 kmol C (mol Fe-1). Comparing these estimates with values from other systems, considered in the context of variable bloom durations in the different oceanographic settings, we suggest that apparent variability in Ceffx may be related to the mode of Fe delivery.

  18. Alcanivorax borkumensis produces an extracellular siderophore in iron-limitation condition maintaining the hydrocarbon-degradation efficiency.

    PubMed

    Denaro, R; Crisafi, F; Russo, D; Genovese, M; Messina, E; Genovese, L; Carbone, M; Ciavatta, M L; Ferrer, M; Golyshin, P; Yakimov, M M

    2014-10-01

    Obligate marine hydrocarbonoclastic bacteria possess genetic and physiological features to use hydrocarbons as sole source of carbon and to compete for the uptake of nutrients in usually nutrient-depleted marine habitats. In the present work we have studied the siderophore-based iron uptake systems in Alcanivorax borkumensis SK2 and their functioning during biodegradation of an aliphatic hydrocarbon, tetradecane, under iron limitation conditions. The antiSMASH analysis of SK2 genome revealed the presence of two different putative operons of siderophore synthetases. Search for the predicted core structures indicated that one siderophore is clearly affiliated to the family of complex oligopeptidic siderophores possessing an Orn-Ser-Orn carboxyl motif whereas the second one is likely to belong to the family of SA (salicylic acid)-based siderophores. Analyzing the supernatant of SK2 culture, an extracellular siderophore was identified and its structure was resolved. Thus, along with the recently described membrane-associated amphiphilic tetrapeptidic siderophore amphibactin, strain SK2 additionally produces an extracellular type of iron-chelating molecule with structural similarity to pseudomonins. Comparative Q-PCR analysis of siderophore synthetases demonstrated their significant up-regulation in iron-depleted medium. Different expression patterns were recorded for two operons during the early and late exponential phases of growth, suggesting a different function of these two siderophores under iron-depleted conditions.

  19. Responses to iron limitation in Hordeum vulgare L. as affected by the atmospheric CO2 concentration.

    PubMed

    Haase, S; Rothe, A; Kania, A; Wasaki, J; Römheld, V; Engels, C; Kandeler, E; Neumann, G

    2008-01-01

    Elevated atmospheric CO2 treatments stimulated biomass production in Fe-sufficient and Fe-deficient barley plants, both in hydroponics and in soil culture. Root/shoot biomass ratio was increased in severely Fe-deficient plants grown in hydroponics but not under moderate Fe limitation in soil culture. Significantly increased biomass production in high CO2 treatments, even under severe Fe deficiency in hydroponic culture, indicates an improved internal Fe utilization. Iron deficiency-induced secretion of PS in 0.5 to 2.5 cm sub-apical root zones was increased by 74% in response to elevated CO2 treatments of barley plants in hydroponics but no PS were detectable in root exudates collected from soil-grown plants. This may be attributed to suppression of PS release by internal Fe concentrations above the critical level for Fe deficiency, determined at final harvest for soil-grown barley plants, even without additional Fe supply. However, extremely low concentrations of easily plant-available Fe in the investigated soil and low Fe seed reserves suggest a contribution of PS-mediated Fe mobilization from sparingly soluble Fe sources to Fe acquisition of the soil-grown barley plants during the preceding culture period. Higher Fe contents in shoots (+52%) of plants grown in soil culture without Fe supply under elevated atmospheric CO2 concentrations may indicate an increased efficiency for Fe acquisition. No significant influence on diversity and function of rhizosphere-bacterial communities was detectable in the outer rhizosphere soil (0-3 mm distance from the root surface) by DGGE of 16S rRNA gene fragments and analysis of marker enzyme activities for C-, N-, and P-cycles.

  20. Limiting iron concentrations early in the season off the West Antarctic Peninsula

    NASA Astrophysics Data System (ADS)

    Middag, R.; Alderkamp, A. C.; Arrigo, K. R.; Van Hale, R.

    2016-02-01

    Iron (Fe) has been shown to be a limiting nutrient for phytoplankton growth in Antarctic waters, even over the productive continental shelves surrounding the Antarctic continent. The abundance of dissolved Fe (dFe) in seawater is controlled by a balance between Fe input (via sediment resuspension, sea-ice and glacial melt, upwelling, atmospheric deposition, hydrothermal inputs and lateral and vertical diffusion from sources), stabilization processes via organic complexation that keep Fe in the dissolved phase, and by removal processes like (oxidative) precipitation, adsorptive scavenging, and phytoplankton uptake. Concentrations of dFe measured on a recent cruise in the Bellingshausen Sea ranged from 12 pM to 8.8 nM, with a median of 0.36 nM for the entire dataset. The dFe concentrations in the surface waters of the open ocean were extremely low with values well below 0.1 nM. Concentrations increased with depth to about 0.15 nM at 300 m and 0.2 -0.3 nM at 750 m. These very low concentrations were surprising, as it is currently assumed that dFe concentrations are replenished over the winter and available for uptake in the spring/summer. Samples were taken weeks after the ice had retreated and primary productivity was low. Bioassays conducted on board indicated primary productivity was limited by both light and dFe availability. No effects were seen for the addition of manganese or Vitamin B-12. Towards the continent over the continental shelf the highest concentrations (up to 8.8 nM) were observed. Over the shelf, high concentrations were observed near the surface as well as near the bottom, indicating both a surface source as well as a sedimentary source. Highest concentrations were generally observed closest to the continent along three transects from the open ocean to the coast, all showing a similar trend of low concentrations offshore with increasing concentrations towards the continent.

  1. Stable iron isotope studies in Rwandese women indicate that the common bean has limited potential as a vehicle for iron biofortification.

    PubMed

    Petry, Nicolai; Egli, Ines; Gahutu, Jean B; Tugirimana, Pierrot L; Boy, Erick; Hurrell, Richard

    2012-03-01

    Biofortification of plants is a new approach to combat iron deficiency. Common beans (Phaseolus vulgaris) can be bred with a higher iron concentration but are rich in iron absorption inhibitors, phytic acid (PA), and polyphenols (PP). To evaluate the potential of beans to combat iron deficiency, three iron absorption studies were carried out in 61 Rwandese women with low iron status. Studies 1 and 2 compared iron absorption from high and low PP beans, similar in PA and iron, fed as bean puree in a double meal design or with rice and potatoes as multiple meals. Study 3 compared iron absorption from high and normal iron beans with similar PP levels and a PA:iron molar ratio, fed with potatoes or rice in multiple meals. Iron absorption was measured as erythrocyte incorporation of stable iron isotopes. In study 1, iron absorption from the high PP bean (3.4%) was 27% lower (P < 0.01) than from low PP bean (4.7%), but when fed in multiple meals (study 2), there was no difference (7 and 7.4%, respectively; P > 0.05). In study 3, iron absorption from the high iron bean (3.8%) was 40% lower (P < 0.001) than from the normal iron bean (6.3%), resulting in equal amounts of iron absorbed. When beans were combined with other meal components in multiple meals, high PP concentration had no negative impact on iron absorption. However, the quantity of iron absorbed from composite meals with high iron beans was no higher than with normal iron beans, indicating that efficacious iron biofortification may be difficult to achieve in beans rich in PA and PP.

  2. Invited Commentary: Limitations and Usefulness of the Metabolically Healthy Obesity Phenotype

    PubMed Central

    Bradshaw, Patrick T.; Stevens, June

    2015-01-01

    The fraction of the obese population who appear to be free of the metabolic abnormalities that usually accompany excess adiposity has garnered a great deal of attention recently. The so-called “metabolically healthy obesity” concept is thought to offer a refinement of the traditional obesity definitions that are based solely on anthropometry. The commentary by Rey-López et al. (Am J Epidemiol. 2015;182(9):737–741) in this issue of the Journal highlights several limitations of the “metabolically healthy obesity” concept and calls into question its usefulness as a public health metric. We discuss several of the issues raised by these authors and offer some perspective on why the utility of this concept remains unresolved. PMID:26363515

  3. [Iron and invasive fungal infection].

    PubMed

    Álvarez, Florencio; Fernández-Ruiz, Mario; Aguado, José María

    2013-01-01

    Iron is an essential factor for both the growth and virulence of most of microorganisms. As a part of the innate (or nutritional) immune system, mammals have developed different mechanisms to store and transport this element in order to limit free iron bioavailability. To survive in this hostile environment, pathogenic fungi have specific uptake systems for host iron sources, one of the most important of which is based on the synthesis of siderophores-soluble, low-molecular-mass, high-affinity iron chelators. The increase in free iron that results from iron-overload conditions is a well-established risk factor for invasive fungal infection (IFI) such as mucormycosis or aspergillosis. Therefore, iron chelation may be an appealing therapeutic option for these infections. Nevertheless, deferoxamine -the first approved iron chelator- paradoxically increases the incidence of IFI, as it serves as a xeno-siderophore to Mucorales. On the contrary, the new oral iron chelators (deferiprone and deferasirox) have shown to exert a deleterious effect on fungal growth both in vitro and in animal models. The present review focuses on the role of iron metabolism in the pathogenesis of IFI and summarises the preclinical data, as well as the limited clinical experience so far, in the use of new iron chelators as treatment for mucormycosis and invasive aspergillosis.

  4. Relation between iron metabolism and antioxidants enzymes and δ-ALA-D activity in rats experimentally infected by Fasciola hepatica.

    PubMed

    Bottari, Nathieli B; Mendes, Ricardo E; Baldissera, Matheus D; Bochi, Guilherme V; Moresco, Rafael N; Leal, Marta L R; Morsch, Vera M; Schetinger, Maria R C; Christ, Ricardo; Gheller, Larissa; Marques, Éder J; Da Silva, Aleksandro S

    2016-06-01

    The aim of this study was to evaluate the iron metabolism in serum, as well as antioxidant enzymes, in addition to the Delta-Aminolevulinic Acid Dehydratase (δ-ALA-D) activity in the liver of rats experimentally infected by Fasciola hepatica. Thirty male adult rats (Wistar) specific pathogen free were divided into four groups: two uninfected group (CTRL 1 and CTRL 2) with five animals each and two infected groups (INF 1 and INF 2) with 10 animals each. Infection was performed orally with 20 metacercariae at day 1. On day 15 (CTRL 1 and INF 1 groups) and 87 PI (CTRL 2 and INF 2 groups) blood and bone marrow were collected and the animals were subsequently euthanized for liver sampling. Blood was allocated in tubes without anticoagulant for serum acquisition to measure iron, transferrin and unsaturated iron binding capacity (UIBC). δ-ALA-D, superoxide dismutase (SOD), and catalase (CAT) activities were measured in the liver. A decrease in iron, transferrin and UIBC levels was observed in all infected animals compared to control groups (P < 0.05). Furthermore, iron accumulation was observed in bone marrow of infected mice. Infected animals showed an increase in δ-ALA-D activity at 87 post-infection (PI) (INF 2) as well as in SOD activity at days 15 (INF 1) and 87 PI (INF 2). On the other hand, CAT activity was reduced in rats infected by F. hepatica during acute and chronic phase of fasciolosis (INF 1 and INF 2 groups), when moderate (acute) and severe necrosis in the liver histopathology were observed. These results may suggest that oxidative damage to tissues along with antioxidant mechanisms might have taken part in fasciolosis pathogenesis and are also involved in iron deficiency associated to changes in δ-ALA-D activity during chronic phase of disease.

  5. Wearing red for signaling: the heme-bach axis in heme metabolism, oxidative stress response and iron immunology.

    PubMed

    Igarashi, Kazuhiko; Watanabe-Matsui, Miki

    2014-04-01

    The connection between gene regulation and metabolism is an old issue that warrants revisiting in order to understand both normal as well as pathogenic processes in higher eukaryotes. Metabolites affect the gene expression by either binding to transcription factors or serving as donors for post-translational modification, such as that involving acetylation and methylation. The focus of this review is heme, a prosthetic group of proteins that includes hemoglobin and cytochromes. Heme has been shown to bind to several transcription factors, including Bach1 and Bach2, in higher eukaryotes. Heme inhibits the transcriptional repressor activity of Bach1, resulting in the derepression of its target genes, such as globin in erythroid cells and heme oxygenase-1 in diverse cell types. Since Bach2 is important for class switch recombination and somatic hypermutation of immunoglobulin genes as well as regulatory and effector T cell differentiation and the macrophage function, the heme-Bach2 axis may regulate the immune response as a signaling cascade. We discuss future issues regarding the topic of the iron/heme-gene regulation network based on current understanding of the heme-Bach axis, including the concept of "iron immunology" as the synthesis of the iron metabolism and the immune response.

  6. Effect of Iron Chelation Therapy on Glucose Metabolism in Non-Transfusion-Dependent Thalassaemia.

    PubMed

    Chuansumrit, Ampaiwan; Pengpis, Pimprae; Mahachoklertwattana, Pat; Sirachainan, Nongnuch; Poomthavorn, Preamrudee; Sungkarat, Witaya; Kadegasem, Praguywan; Khlairit, Patcharin; Wongwerawattanakoon, Pakawan

    2017-01-01

    To compare insulin sensitivity, β-cell function and iron status biomarkers in non-transfusion-dependent thalassaemia (NTDT) with iron excess during pre- and post-iron chelation. Subjects with NTDT, aged older than 10 years, with serum ferritin >300 ng/ml, were included. Iron chelation with deferasirox (10 mg/kg/day) was prescribed daily for 6 months. Ten patients with a median age of 17.4 years were enrolled. The comparison between pre- and post-chelation demonstrated significantly lower iron load: median serum ferritin (551.4 vs. 486.2 ng/ml, p = 0.047), median TIBC (211.5 vs. 233.5 µg/dl, p = 0.009) and median non-transferrin binding iron (5.5 vs. 1.4 µM, p = 0.005). All patients had a normal oral glucose tolerance test (OGTT) both pre- and post-chelation. However, fasting plasma glucose was significantly reduced after iron chelation (85.0 vs.79.5 mg/dl, p = 0.047). MRI revealed no significant changes of iron accumulation in the heart and liver after chelation, but there was a significantly lower iron load in the pancreas, assessed by higher T2* at post-chelation compared with pre-chelation (41.9 vs. 36.7 ms, p = 0.047). No adverse events were detected. A trend towards improving insulin sensitivity and β-cell function as well as a reduced pancreatic iron load was observed following 6 months of iron chelation (TCTR20160523003). © 2016 S. Karger AG, Basel.

  7. The effect of 8-week different-intensity walking exercises on serum hepcidin, IL-6, and iron metabolism in pre-menopausal women.

    PubMed

    Buyukyazi, G; Ulman, C; Çelik, A; Çetinkaya, C; Şişman, A R; Çimrin, D; Doğru, Y; Kaya, D

    2017-03-01

    Objective Hepcidin may be an important mediator in exercise-induced iron deficiency. Despite the studies investigating acute exercise effects on hepcidin and markers of iron metabolism, we found no studies examining the chronic effects of walking exercises (WE) on hepcidin and markers of iron metabolism in premenopausal women. The chronic effects of two 8-week different-intensity WE on hepcidin, interleukin 6 (IL-6), and markers of iron metabolism in pre-menopausal women were examined. Methods Exercise groups (EG) [moderate tempo walking group (MTWG), n = 11; brisk walking group (BWG), n = 11] walked 3 days/week, starting from 30 to 51 min. Control group (CG; n = 8) did not perform any exercises. BWG walked at ∼70%-75%; MTWG at ∼50%-55% of HRRmax. VO2max, hepcidin, IL-6, and iron metabolism markers were determined before and after the intervention. Results VO2max increased in both EGs, favoring the BWG. Hepcidin increased in the BWG (p < 0.01) and CG (p < 0.05). IL-6 decreased in the BWG and the MTWG (p < 0.05; p < 0.01). While iron, ferritin, transferrin, and transferrin saturation levels did not change in any group, total iron binding capacity (p < 0.05), red blood cells (p < 0.05), and hematocrit (p < 0.01) increased only in the BWG. Conclusion Both WE types may be useful to prevent inflammation. However, brisk walking is advisable due to the positive changes in VO2max and some iron metabolism parameters, which may contribute to prevent iron deficiency. The increase in hepcidin levels remains unclear and necessitates further studies.

  8. Iron and carbon metabolism by a mineral-oxidizing Alicyclobacillus-like bacterium.

    PubMed

    Yahya, Adibah; Hallberg, Kevin B; Johnson, D Barrie

    2008-04-01

    A novel iron-oxidizing, moderately thermophilic, acidophilic bacterium (strain "GSM") was isolated from mineral spoil taken from a gold mine in Montana. Biomolecular analysis showed that it was most closely related to Alicyclobacillus tolerans, although the two bacteria differed in some key respects, including the absence (in strain GSM) of varpi-alicyclic fatty acids and in their chromosomal base compositions. Isolate GSM was able to grow in oxygen-free media using ferric iron as terminal electron acceptor confirming that it was a facultative anaerobe, a trait not previously described in Alicyclobacillus spp.. The acidophile used both organic and inorganic sources of energy and carbon, although growth and iron oxidation by isolate GSM was uncoupled in media that contained both fructose and ferrous iron. Fructose utilization suppressed iron oxidation, and oxidation of ferrous iron occurred only when fructose was depleted. In contrast, fructose catabolism was suppressed when bacteria were harvested while actively oxidizing iron, suggesting that both ferrous iron- and fructose-oxidation are inducible in this acidophile. Isolate GSM accelerated the oxidative dissolution of pyrite in liquid media either free of, or amended with, organic carbon, although redox potentials were significantly different in these media. The potential of this isolate for commercial mineral processing is discussed.

  9. Iron limitation enhances acyl homoserine lactone (AHL) production and biofilm formation in clinical isolates of Acinetobacter baumannii

    PubMed Central

    Modarresi, Farzan; Azizi, Omid; Shakibaie, Mohammad Reza; Motamedifar, Mohammad; Mosadegh, Ellahe; Mansouri, Shahla

    2015-01-01

    Abstract Acinetobacter baumannii is an important source of infections in intensive care units (ICUs) of our hospitals in Kerman, Iran and the most frequently isolated strains produce biofilm. There is a little information about role of iron (Fe) levels on acyl homoserine lactone (AHL) production and biofilm formation in this microorganism. In the present study, we investigated the influence of iron-III limitation on AHL, siderophore, catechol and virulence factors in the biofilm forming clinical strains of A. baumannii. A total of 65 non-duplicated multidrug resistance (MDR) strains of A. baumannii were isolated from patients in ICUs of 2 hospitals in Kerman, Iran. Antibiotic susceptibility, siderophore and other iron chelators, hemolysis, cell twitching motility, capsule, gelatinase and DNase were studied. Presence of quorum sensing, LuxI and LuxR genes was detected by multiplex-PCR. AHL activity quantified by colorimetric method and the functional groups were determined by Fourier Transform Infra-Red Spectroscopy (FT-IR). Biofilm formation was detected by microtiter plate technique. All of the isolates were resistant to third generation of cephalosporins, ciprofloxacin, levofloxacin, tetracycline, whereas, 78% and 81% were resistant to amikacin and carbapenems, respectively. The siderophore activity was highest at 20 μM Fe3+ (70%); however, it decreased to 45% as concentration of Fe3+ increased to 80 μM. Furthermore, screening of the isolates for LuxI and LuxR genes showed that presence of both genes required in the isolates with high AHL activity. FT-IR analysis indicated C=O bond of the lactone ring and primary amides. Significantly, a higher amount of AHL (70%) was detected in the presence of low concentration of iron-III (20 μM); as iron concentration increased to 80 μM, the AHL activity was reduced to 40% (P ≤ 0.05). All the isolates exhibited twitching motility and had a capsule. No any gelatinase or DNase activity was detected. Quantification of

  10. Iron limitation enhances acyl homoserine lactone (AHL) production and biofilm formation in clinical isolates of Acinetobacter baumannii.

    PubMed

    Modarresi, Farzan; Azizi, Omid; Shakibaie, Mohammad Reza; Motamedifar, Mohammad; Mosadegh, Ellahe; Mansouri, Shahla

    2015-01-01

    Acinetobacter baumannii is an important source of infections in intensive care units (ICUs) of our hospitals in Kerman, Iran and the most frequently isolated strains produce biofilm. There is a little information about role of iron (Fe) levels on acyl homoserine lactone (AHL) production and biofilm formation in this microorganism. In the present study, we investigated the influence of iron-III limitation on AHL, siderophore, catechol and virulence factors in the biofilm forming clinical strains of A. baumannii. A total of 65 non-duplicated multidrug resistance (MDR) strains of A. baumannii were isolated from patients in ICUs of 2 hospitals in Kerman, Iran. Antibiotic susceptibility, siderophore and other iron chelators, hemolysis, cell twitching motility, capsule, gelatinase and DNase were studied. Presence of quorum sensing, LuxI and LuxR genes was detected by multiplex-PCR. AHL activity quantified by colorimetric method and the functional groups were determined by Fourier Transform Infra-Red Spectroscopy (FT-IR). Biofilm formation was detected by microtiter plate technique. All of the isolates were resistant to third generation of cephalosporins, ciprofloxacin, levofloxacin, tetracycline, whereas, 78% and 81% were resistant to amikacin and carbapenems, respectively. The siderophore activity was highest at 20 μM Fe(3+) (70%); however, it decreased to 45% as concentration of Fe(3+) increased to 80 μM. Furthermore, screening of the isolates for LuxI and LuxR genes showed that presence of both genes required in the isolates with high AHL activity. FT-IR analysis indicated C=O bond of the lactone ring and primary amides. Significantly, a higher amount of AHL (70%) was detected in the presence of low concentration of iron-III (20 μM); as iron concentration increased to 80 μM, the AHL activity was reduced to 40% (P ≤ 0.05). All the isolates exhibited twitching motility and had a capsule. No any gelatinase or DNase activity was detected. Quantification of the

  11. Iron Metabolism Dysregulation and Cognitive Dysfunction in Pediatric Obesity: Is There a Connection?

    PubMed Central

    Grandone, Anna; Marzuillo, Pierluigi; Perrone, Laura; Miraglia del Giudice, Emanuele

    2015-01-01

    Obesity and iron deficiency (ID) are two of the most common nutritional disorders in the world. In children both conditions deserve particular attention. Several studies revealed an association between obesity and iron deficiency in children and, in some cases, a reduced response to oral supplementation. The connecting mechanism, however, is not completely known. This review is focused on: (1) iron deficiency in obese children and the role of hepcidin in the connection between body fat and poor iron status; (2) iron status and consequences on health, in particular on cognitive function; (3) cognitive function and obesity; (4) suggestion of a possible link between cognitive dysfunction and ID in pediatric obesity; and implications for therapy and future research. PMID:26561830

  12. Evaluation of iron metabolism indices and their relation with physical work capacity in athletes.

    PubMed Central

    Karamizrak, S O; Işlegen, C; Varol, S R; Taşkiran, Y; Yaman, C; Mutaf, I; Akgün, N

    1996-01-01

    OBJECTIVE--To evaluate the relation between iron status and physical working capacity, and to assess the effect of oral iron treatment on these variables, in athletes with borderline iron status. METHODS--Blood haemoglobin (Hb), packed cell volume (PCV), red blood cell count (RBC), serum iron, total iron binding capacity (TIBC), and ferritin determinations were compared in 71 male and 18 female athletes participating in various sports and in matched male (n = 11) and female (n = 8) controls. The first aim was to assess the relations between these variables and performance in a physical work capacity test (PWC170). Oral iron treatment (175-350 mg ferrous fumarate daily) was provided for three weeks to six male and five female athletes with borderline Hb concentrations, to determine the effects of such treatment on both iron status and performance. RESULTS--Among females, handball players had the lowest serum ferritin concentrations (P < 0.05), the highest TIBC values, and lowest PWC170 scores (P < 0.01); runners had the highest ferritin concentrations and PWC170 scores (P < 0.01). There were significant correlations (P < 0.01) between PWC170 and PCV, serum ferritin, and transferrin saturation of female athletes. Hb, serum iron, serum ferritin, and transferrin saturation increased with iron treatment in both males (P < 0.01) and females (P < 0.05). CONCLUSIONS--Serum ferritin determination may prove a valuable addition to the screening of athletes and may indicate the need for iron treatment, even though a causal effect on improvement of work capacity may not be present. PMID:8665109

  13. Sodium ascorbate kills Candida albicans in vitro via iron-catalyzed Fenton reaction: importance of oxygenation and metabolism.

    PubMed

    Avci, Pinar; Freire, Fernanda; Banvolgyi, Andras; Mylonakis, Eleftherios; Wikonkal, Norbert M; Hamblin, Michael R

    2016-12-01

    Ascorbate can inhibit growth and even decrease viability of various microbial species including Candida albicans. However the optimum conditions and the mechanism of action are unclear. Materials/methodology: Candida albicans shaken for 90 min in a buffered solution of ascorbate (90 mM) gave a 5-log reduction of cell viability, while there was no killing without shaking, in growth media with different carbon sources or at 4°C. Killing was inhibited by the iron chelator 2,2'-bipyridyl. Hydroxyphenyl fluorescein probe showed the intracellular generation of hydroxyl radicals. Ascorbate-mediated killing of C. albicans depends on oxygenation and metabolism, involves iron-catalyzed generation of hydroxyl radicals via Fenton reaction and depletion of intracellular NADH. Ascorbate could serve as a component of a topical antifungal therapy.

  14. An insight into the metabolic responses of ultra-small superparamagnetic particles of iron oxide using metabonomic analysis of biofluids

    NASA Astrophysics Data System (ADS)

    Feng, Jianghua; Liu, Huili; Zhang, Limin; Bhakoo, Kishore; Lu, Lehui

    2010-10-01

    Ultra-small superparamagnetic particles of iron oxides (USPIO) have been developed as intravenous organ/tissue-targeted contrast agents to improve magnetic resonance imaging (MRI) in vivo. However, their potential toxicity and effects on metabolism have attracted particular attention. In the present study, uncoated and dextran-coated USPIO were investigated by analyzing both rat urine and plasma metabonomes using high-resolution NMR-based metabonomic analysis in combination with multivariate statistical analysis. The wealth of information gathered on the metabolic profiles from rat urine and plasma has revealed subtle metabolic changes in response to USPIO administration. The metabolic changes include the elevation of urinary α-hydroxy-n-valerate, o- and p-HPA, PAG, nicotinate and hippurate accompanied by decreases in the levels of urinary α-ketoglutarate, succinate, citrate, N-methylnicotinamide, NAG, DMA, allantoin and acetate following USPIO administration. The changes associated with USPIO administration included a gradual increase in plasma glucose, N-acetyl glycoprotein, saturated fatty acid, citrate, succinate, acetate, GPC, ketone bodies (β-hydroxybutyrate, acetone and acetoacetate) and individual amino acids, such as phenylalanine, lysine, isoleucine, glycine, glutamine and glutamate and a gradual decrease of myo-inositol, unsaturated fatty acid and triacylglycerol. Hence USPIO administration effects are reflected in changes in a number of metabolic pathways including energy, lipid, glucose and amino acid metabolism. The size- and surface chemistry-dependent metabolic responses and possible toxicity were observed using NMR analysis of biofluids. These changes may be attributed to the disturbances of hepatic, renal and cardiac functions following USPIO administrations. The potential biotoxicity can be derived from metabonomic analysis and serum biochemistry analysis. Metabonomic strategy offers a promising approach for the detection of subtle

  15. The Association of Multiple Biomarkers of Iron Metabolism and Type 2 Diabetes - the EPIC-InterAct Study

    PubMed Central

    Podmore, Clara; Meidtner, Karina; Schulze, Matthias B; Scott, Robert A; Ramond, Anna; Butterworth, Adam S; Di Angelantonio, Emanuele; Danesh, John; Arriola, Larraitz; Barricarte, Aurelio; Boeing, Heiner; Clavel-Chapelon, Françoise; Cross, Amanda J; Dahm, Christina C; Fagherazzi, Guy; Franks, Paul W; Gavrila, Diana; Grioni, Sara; Gunter, Marc J; Gusto, Gaelle; Jakszyn, Paula; Katzke, Verena; Key, Timothy J; Kühn, Tilman; Mattiello, Amalia; Nilsson, Peter M; Olsen, Anja; Overvad, Kim; Palli, Domenico; Quirós, J. Ramón; Rolandsson, Olov; Sacerdote, Carlotta; Sánchez-Cantalejo, Emilio; Slimani, Nadia; Sluijs, Ivonne; Spijkerman, Annemieke MW; Tjonneland, Anne; Tumino, Rosario; van der A, Daphne L; van der Schouw, Yvonne T; Feskens, Edith JM; Forouhi, Nita G; Sharp, Stephen J; Riboli, Elio; Langenberg, Claudia; Wareham, Nicholas J

    2016-01-01

    Objective Observational studies show an association between ferritin and type 2 diabetes (T2D), suggesting a role of high iron stores for T2D development. However, ferritin is influenced by factors other than iron stores, which is less the case for other biomarkers of iron metabolism. We investigate associations of ferritin, transferrin saturation (TSAT), serum iron and transferrin with T2D incidence, to clarify the role of iron in the pathogenesis of T2D. Research and Design Methods The EPIC-InterAct study includes 12,403 incident T2D cases and a representative sub-cohort of 16,154 individuals from a European cohort with 3.99 million person-years of follow-up. We studied the prospective association of ferritin, TSAT, serum iron and transferrin with incident T2D in 11,052 cases and a random sub-cohort of 15,182 individuals and assessed whether these associations differed by subgroups of the population. Results Higher levels of ferritin and transferrin were associated with a higher risk of T2D [HR in men and women, respectively: 1.07 (95% CI: 1.01; 1.12) and 1.12 (1.05; 1.19) per 100 μg/L higher ferritin level; 1.11 (1.00; 1.24) and 1.22 (1.12; 1.33) per 0.5 g/L higher transferrin level] after adjustment for age, centre, BMI, physical activity, smoking status, education, hsCRP, ALT and GGT. Elevated TSAT (≥45% versus <45%) was associated with a lower risk of T2D in women [0.68 (0.54; 0.86)] but was not statistically significantly associated in men [0.90 (0.75; 1.08)]. Serum iron was not associated with T2D. The association of ferritin with T2D was stronger among leaner individuals (pinteraction<0.01). Conclusions The pattern of association of TSAT and transferrin with T2D suggests that the underlying relationship between iron stores and T2D is more complex than the simple link suggested by the association of ferritin with T2D. PMID:26861925

  16. Association of Multiple Biomarkers of Iron Metabolism and Type 2 Diabetes: The EPIC-InterAct Study.

    PubMed

    Podmore, Clara; Meidtner, Karina; Schulze, Matthias B; Scott, Robert A; Ramond, Anna; Butterworth, Adam S; Di Angelantonio, Emanuele; Danesh, John; Arriola, Larraitz; Barricarte, Aurelio; Boeing, Heiner; Clavel-Chapelon, Françoise; Cross, Amanda J; Dahm, Christina C; Fagherazzi, Guy; Franks, Paul W; Gavrila, Diana; Grioni, Sara; Gunter, Marc J; Gusto, Gaelle; Jakszyn, Paula; Katzke, Verena; Key, Timothy J; Kühn, Tilman; Mattiello, Amalia; Nilsson, Peter M; Olsen, Anja; Overvad, Kim; Palli, Domenico; Quirós, J Ramón; Rolandsson, Olov; Sacerdote, Carlotta; Sánchez-Cantalejo, Emilio; Slimani, Nadia; Sluijs, Ivonne; Spijkerman, Annemieke M W; Tjonneland, Anne; Tumino, Rosario; van der A, Daphne L; van der Schouw, Yvonne T; Feskens, Edith J M; Forouhi, Nita G; Sharp, Stephen J; Riboli, Elio; Langenberg, Claudia; Wareham, Nicholas J

    2016-04-01

    Observational studies show an association between ferritin and type 2 diabetes (T2D), suggesting a role of high iron stores in T2D development. However, ferritin is influenced by factors other than iron stores, which is less the case for other biomarkers of iron metabolism. We investigated associations of ferritin, transferrin saturation (TSAT), serum iron, and transferrin with T2D incidence to clarify the role of iron in the pathogenesis of T2D. The European Prospective Investigation into Cancer and Nutrition-InterAct study includes 12,403 incident T2D cases and a representative subcohort of 16,154 individuals from a European cohort with 3.99 million person-years of follow-up. We studied the prospective association of ferritin, TSAT, serum iron, and transferrin with incident T2D in 11,052 cases and a random subcohort of 15,182 individuals and assessed whether these associations differed by subgroups of the population. Higher levels of ferritin and transferrin were associated with a higher risk of T2D (hazard ratio [HR] [95% CI] in men and women, respectively: 1.07 [1.01-1.12] and 1.12 [1.05-1.19] per 100 μg/L higher ferritin level; 1.11 [1.00-1.24] and 1.22 [1.12-1.33] per 0.5 g/L higher transferrin level) after adjustment for age, center, BMI, physical activity, smoking status, education, hs-CRP, alanine aminotransferase, and γ-glutamyl transferase. Elevated TSAT (≥45% vs. <45%) was associated with a lower risk of T2D in women (0.68 [0.54-0.86]) but was not statistically significantly associated in men (0.90 [0.75-1.08]). Serum iron was not associated with T2D. The association of ferritin with T2D was stronger among leaner individuals (Pinteraction < 0.01). The pattern of association of TSAT and transferrin with T2D suggests that the underlying relationship between iron stores and T2D is more complex than the simple link suggested by the association of ferritin with T2D. © 2016 by the American Diabetes Association. Readers may use this article as long as the

  17. Spectroscopic studies of flavoproteins and non-haem iron proteins of submitochondrial particles of Torulopsis utilis modified by iron- and sulphate-limited growth in continuous culture

    PubMed Central

    Ragan, C. I.; Garland, P. B.

    1971-01-01

    1. A spectroscopic resolution has been made of the components contributing to the `iron-flavoprotein' trough extending from 450 to 520nm in the reduced-minus-oxidized difference spectrum of submitochondrial particles of Torulopsis utilis. 2. Seven components were identified other than cytochrome b, ubiquinone and succinate dehydrogenase. On the basis of the effects of iron- and sulphate-limited growth of cells on their subsequently derived electron-transport particles, and also by consideration of analytical measurements of the concentration of FMN, FAD, non-haem iron and acid-labile sulphide in the electron-transport particles in relation to the magnitude of the spectroscopic changes, it was possible to identify five of these components as follows: species 1a, the flavin of NADH dehydrogenase ferroflavoprotein; species 1b, the iron–sulphur component of NADH dehydrogenase ferroflavoprotein; species 1′, the flavin of an NADPH dehydrogenase; species 2, an iron–sulphur or ferroflavoprotein component; species 3, the flavin of l-3-glycerophosphate dehydrogenase. Two additional components were a fluorescent flavoprotein, probably lipoamide dehydrogenase, and a b-type cytochrome reducible by NADH or NADPH but not reoxidizable by the respiratory chain. 3. Species 1b and 2 were undetectable in electron-transport particles from iron- or sulphate-limited cells, but could be recovered in vivo under non-growing conditions. 4. The recovery in vivo of species 2 but not species 1b was inhibited by cycloheximide. 5. The recovery of species 1b correlates with the recovery of site 1 conservation. 6. The recovery of species 1b with species 2 correlates with the recovery of piericidin A sensitivity. 7. Evidence is presented for an NADPH dehydrogenase distinct from NADH dehydrogenase. The oxidation of NADH and NADPH by the respiratory chain is sensitive to piericidin A, and an iron–sulphur protein common to both pathways (species 2) is suggested as the piericidin A

  18. Shotgun proteomic analysis of Yersinia ruckeri isolates under normal and iron-limited conditions

    USDA-ARS?s Scientific Manuscript database

    Yersinia ruckeri is the causative agent of enteric redmouth disease of fish and causes significant economic losses, particularly in salmonids. Iron is an essential nutrient for many cellular processes and is involved in host sensing and virulence regulation in many bacteria. Bacterial pathogens diff...

  19. Iron metabolism and resistance to infection by invasive bacteria in the social amoeba Dictyostelium discoideum.

    PubMed

    Bozzaro, Salvatore; Buracco, Simona; Peracino, Barbara

    2013-01-01

    Dictyostelium cells are forest soil amoebae, which feed on bacteria and proliferate as solitary cells until bacteria are consumed. Starvation triggers a change in life style, forcing cells to gather into aggregates to form multicellular organisms capable of cell differentiation and morphogenesis. As a soil amoeba and a phagocyte that grazes on bacteria as the obligate source of food, Dictyostelium could be a natural host of pathogenic bacteria. Indeed, many pathogens that occasionally infect humans are hosted for most of their time in protozoa or free-living amoebae, where evolution of their virulence traits occurs. Due to these features and its amenability to genetic manipulation, Dictyostelium has become a valuable model organism for studying strategies of both the host to resist infection and the pathogen to escape the defense mechanisms. Similarly to higher eukaryotes, iron homeostasis is crucial for Dictyostelium resistance to invasive bacteria. Iron is essential for Dictyostelium, as both iron deficiency or overload inhibit cell growth. The Dictyostelium genome shares with mammals many genes regulating iron homeostasis. Iron transporters of the Nramp (Slc11A) family are represented with two genes, encoding Nramp1 and Nramp2. Like the mammalian ortholog, Nramp1 is recruited to phagosomes and macropinosomes, whereas Nramp2 is a membrane protein of the contractile vacuole network, which regulates osmolarity. Nramp1 and Nramp2 localization in distinct compartments suggests that both proteins synergistically regulate iron homeostasis. Rather than by absorption via membrane transporters, iron is likely gained by degradation of ingested bacteria and efflux via Nramp1 from phagosomes to the cytosol. Nramp gene disruption increases Dictyostelium sensitivity to infection, enhancing intracellular growth of Legionella or Mycobacteria. Generation of mutants in other "iron genes" will help identify genes essential for iron homeostasis and resistance to pathogens.

  20. Homeostatic Adjustment and Metabolic Remodeling in Glucose-limited Yeast CulturesD⃞

    PubMed Central

    Brauer, Matthew J.; Saldanha, Alok J.; Dolinski, Kara; Botstein, David

    2005-01-01

    We studied the physiological response to glucose limitation in batch and steady-state (chemostat) cultures of Saccharomyces cerevisiae by following global patterns of gene expression. Glucose-limited batch cultures of yeast go through two sequential exponential growth phases, beginning with a largely fermentative phase, followed by an essentially completely aerobic use of residual glucose and evolved ethanol. Judging from the patterns of gene expression, the state of the cells growing at steady state in glucose-limited chemostats corresponds most closely with the state of cells in batch cultures just before they undergo this “diauxic shift.” Essentially the same pattern was found between chemostats having a fivefold difference in steady-state growth rate (the lower rate approximating that of the second phase respiratory growth rate in batch cultures). Although in both cases the cells in the chemostat consumed most of the glucose, in neither case did they seem to be metabolizing it primarily through respiration. Although there was some indication of a modest oxidative stress response, the chemostat cultures did not exhibit the massive environmental stress response associated with starvation that also is observed, at least in part, during the diauxic shift in batch cultures. We conclude that despite the theoretical possibility of a switch to fully aerobic metabolism of glucose in the chemostat under conditions of glucose scarcity, homeostatic mechanisms are able to carry out metabolic adjustment as if fermentation of the glucose is the preferred option until the glucose is entirely depleted. These results suggest that some aspect of actual starvation, possibly a component of the stress response, may be required for triggering the metabolic remodeling associated with the diauxic shift. PMID:15758028

  1. The effect of iron deficiency on the temporal changes in the expression of genes associated with fat metabolism in the pregnant rat.

    PubMed

    Hay, Susan M; McArdle, Harry J; Hayes, Helen E; Stevens, Valerie J; Rees, William D

    2016-11-01

    Iron is essential for the oxidative metabolism of lipids. Lipid metabolism changes during gestation to meet the requirements of the growing fetus and to prepare for lactation. The temporal effects of iron deficiency during gestation were studied in female rats fed complete or iron-deficient diets. Plasma triglycerides were elevated in the iron-deficient group throughout gestation. There were time-dependent changes in the triglyceride content of the maternal liver, falling at the midpoint of gestation and then increasing on d21.5. Compared to the control, triglycerides in the maternal liver were not different in the iron-deficient group prior to pregnancy and on d12.5, but were markedly reduced by d21.5. The abundance of mRNAs in the maternal liver suggests that lipogenesis is unchanged and beta-oxidation is reduced on d21.5 by iron deficiency. On d21.5 of gestation, the expression of placental lipase was unchanged by iron deficiency, however, the abundance of mRNAs for SREBP-1c, FABP4 were reduced, suggesting that there were changes in fatty acid handling. In the fetal liver, iron deficiency produced a marked decrease in the abundance of the L-CPT-1 mRNA, suggesting that beta-oxidation is reduced. This study shows that the major effect of iron deficiency on maternal lipid metabolism occurs late in gestation and that perturbed lipid metabolism may be a common feature of models of fetal programming. © 2016 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of The Physiological Society and the American Physiological Society.

  2. Serum Hepcidin and Soluble Transferrin Receptor in the Assessment of Iron Metabolism in Children on a Vegetarian Diet.

    PubMed

    Ambroszkiewicz, Jadwiga; Klemarczyk, Witold; Mazur, Joanna; Gajewska, Joanna; Rowicka, Grażyna; Strucińska, Małgorzata; Chełchowska, Magdalena

    2017-03-24

    The aim of this study was to assess the effect of vegetarian diet on iron metabolism parameters paying special attention to serum hepcidin and soluble transferrin receptor (sTfR) concentrations in 43 prepubertal children (age range 4.5-9.0 years) on vegetarian and in 46 children on omnivorous diets. There were no significant differences according to age, weight, height, and body mass index (BMI) between vegetarian and omnivorous children. Vegetarians had similar intake of iron and vitamin B12 and a significantly higher intake of vitamin C (p < 0.05) compared with non-vegetarians. Hematologic parameters and serum iron concentrations were within the reference range in both groups of children. Serum transferrin levels were similar in all subjects; however, ferritin concentrations were significantly (p < 0.01) lower in vegetarians than in omnivores. In children on a vegetarian diet, median hepcidin levels were lower (p < 0.05) but sTfR concentrations significantly higher (p < 0.001) compared with omnivorous children. In the multivariate regression model, we observed associations between hepcidin level and ferritin concentration (β = 0.241, p = 0.05) in the whole group of children as well as between hepcidin concentration and CRP level (β = 0.419, p = 0.047) in vegetarians. We did not find significant associations with concentration of sTfR and selected biochemical, anthropometric, and dietary parameters in any of the studied groups of children. As hematologic parameters and iron concentrations in vegetarians and omnivores were comparable and ferritin level was lower in vegetarians, we suggest that inclusion of novel markers, in particular sTfR (not cofounded by inflammation) and hepcidin, can better detect subclinical iron deficiency in children following vegetarian diets.

  3. Limitations of a metabolic network-based reverse ecology method for inferring host-pathogen interactions.

    PubMed

    Takemoto, Kazuhiro; Aie, Kazuki

    2017-05-25

    Host-pathogen interactions are important in a wide range of research fields. Given the importance of metabolic crosstalk between hosts and pathogens, a metabolic network-based reverse ecology method was proposed to infer these interactions. However, the validity of this method remains unclear because of the various explanations presented and the influence of potentially confounding factors that have thus far been neglected. We re-evaluated the importance of the reverse ecology method for evaluating host-pathogen interactions while statistically controlling for confounding effects using oxygen requirement, genome, metabolic network, and phylogeny data. Our data analyses showed that host-pathogen interactions were more strongly influenced by genome size, primary network parameters (e.g., number of edges), oxygen requirement, and phylogeny than the reserve ecology-based measures. These results indicate the limitations of the reverse ecology method; however, they do not discount the importance of adopting reverse ecology approaches altogether. Rather, we highlight the need for developing more suitable methods for inferring host-pathogen interactions and conducting more careful examinations of the relationships between metabolic networks and host-pathogen interactions.

  4. Relativistic iron lines in accretion disks: the contribution of higher order images in the strong deflection limit

    NASA Astrophysics Data System (ADS)

    Aldi, Giulio Francesco; Bozza, Valerio

    2017-02-01

    The shapes of relativistic iron lines observed in spectra of candidate black holes carry the signatures of the strong gravitational fields in which the accretion disks lie. These lines result from the sum of the contributions of all images of the disk created by gravitational lensing, with the direct and first-order images largely dominating the overall shapes. Higher order images created by photons tightly winding around the black holes are often neglected in the modeling of these lines, since they require a substantially higher computational effort. With the help of the strong deflection limit, we present the most accurate semi-analytical calculation of these higher order contributions to the iron lines for Schwarzschild black holes. We show that two regimes exist depending on the inclination of the disk with respect to the line of sight. Many useful analytical formulae can be also derived in this framework.

  5. The Metabolic Status Drives Acclimation of Iron Deficiency Responses in Chlamydomonas reinhardtii as Revealed by Proteomics Based Hierarchical Clustering and Reverse Genetics*

    PubMed Central

    Höhner, Ricarda; Barth, Johannes; Magneschi, Leonardo; Jaeger, Daniel; Niehues, Anna; Bald, Till; Grossman, Arthur; Fufezan, Christian; Hippler, Michael

    2013-01-01

    Iron is a crucial cofactor in numerous redox-active proteins operating in bioenergetic pathways including respiration and photosynthesis. Cellular iron management is essential to sustain sufficient energy production and minimize oxidative stress. To produce energy for cell growth, the green alga Chlamydomonas reinhardtii possesses the metabolic flexibility to use light and/or carbon sources such as acetate. To investigate the interplay between the iron-deficiency response and growth requirements under distinct trophic conditions, we took a quantitative proteomics approach coupled to innovative hierarchical clustering using different “distance-linkage combinations” and random noise injection. Protein co-expression analyses of the combined data sets revealed insights into cellular responses governing acclimation to iron deprivation and regulation associated with photosynthesis dependent growth. Photoautotrophic growth requirements as well as the iron deficiency induced specific metabolic enzymes and stress related proteins, and yet differences in the set of induced enzymes, proteases, and redox-related polypeptides were evident, implying the establishment of distinct response networks under the different conditions. Moreover, our data clearly support the notion that the iron deficiency response includes a hierarchy for iron allocation within organelles in C. reinhardtii. Importantly, deletion of a bifunctional alcohol and acetaldehyde dehydrogenase (ADH1), which is induced under low iron based on the proteomic data, attenuates the remodeling of the photosynthetic machinery in response to iron deficiency, and at the same time stimulates expression of stress-related proteins such as NDA2, LHCSR3, and PGRL1. This finding provides evidence that the coordinated regulation of bioenergetics pathways and iron deficiency response is sensitive to the cellular and chloroplast metabolic and/or redox status, consistent with systems approach data. PMID:23820728

  6. Phosphate limited fed-batch processes: impact on carbon usage and energy metabolism in Escherichia coli.

    PubMed

    Schuhmacher, Tom; Löffler, Michael; Hurler, Thilo; Takors, Ralf

    2014-11-20

    Phosphate starvation is often applied as a tool to limit cell growth in microbial production processes without hampering carbon and/or nitrogen supply alternatively. This contribution focuses on the interplay of process induced phosphate starvation and microbial performance studying an l-tryptophan overproducing Escherichia coli strain as a model for highly ATP demanding processes in comparison with an E. coli wildtype strain. To enable a time-resolved analysis, constant phosphate feeding strategies were applied to elongate the transition from phosphate saturated to phosphate limited cell growth. With increasing phosphate limitation, a reduced cellular efficiency of ATP formation via respiratory chain activity and the ATP synthase complex was found for both strains. Process balancing, transcriptome analysis and flux balance analysis are pointing toward a multi-stage decoupling scenario, which in essence deteriorates the stoichiometric ratio of ATP formation to proton translocation, thereby affecting ATP availability from respiration and carbon usage. Starting off with a potential influence on ATP-synthase efficiency (stage 1), decoupling is further increased by modified respiratory activity (stage 2) and byproduct overflow (stage 3) finally resulting in a metabolic breakdown entering complete phosphate depletion (stage 4). The decoupling is initiated by phosphate limitation; further effects are mainly mediated on metabolic level through ATP availability and energy charge, additionally affected by ATP demanding product synthesis.

  7. Diffusive and metabolic limitations to photosynthesis under drought and salinity in C(3) plants.

    PubMed

    Flexas, J; Bota, J; Loreto, F; Cornic, G; Sharkey, T D

    2004-05-01

    Drought and salinity are two widespread environmental conditions leading to low water availability for plants. Low water availability is considered the main environmental factor limiting photosynthesis and, consequently, plant growth and yield worldwide. There has been a long-standing controversy as to whether drought and salt stresses mainly limit photosynthesis through diffusive resistances or by metabolic impairment. Reviewing in vitro and in vivo measurements, it is concluded that salt and drought stress predominantly affect diffusion of CO(2) in the leaves through a decrease of stomatal and mesophyll conductances, but not the biochemical capacity to assimilate CO(2), at mild to rather severe stress levels. The general failure of metabolism observed at more severe stress suggests the occurrence of secondary oxidative stresses, particularly under high-light conditions. Estimates of photosynthetic limitations based on the photosynthetic response to intercellular CO(2) may lead to artefactual conclusions, even if patchy stomatal closure and the relative increase of cuticular conductance are taken into account, as decreasing mesophyll conductance can cause the CO(2) concentration in chloroplasts of stressed leaves to be considerably lower than the intercellular CO(2) concentration. Measurements based on the photosynthetic response to chloroplast CO(2) often confirm that the photosynthetic capacity is preserved but photosynthesis is limited by diffusive resistances in drought and salt-stressed leaves.

  8. Glucose Limitation Alters Glutamine Metabolism in MUC1-Overexpressing Pancreatic Cancer Cells.

    PubMed

    Gebregiworgis, Teklab; Purohit, Vinee; Shukla, Surendra K; Tadros, Saber; Chaika, Nina V; Abrego, Jaime; Mulder, Scott E; Gunda, Venugopal; Singh, Pankaj K; Powers, Robert

    2017-10-06

    Pancreatic cancer cells overexpressing Mucin 1 (MUC1) rely on aerobic glycolysis and, correspondingly, are dependent on glucose for survival. Our NMR metabolomics comparative analysis of control (S2-013.Neo) and MUC1-overexpressing (S2-013.MUC1) cells demonstrates that MUC1 reprograms glutamine metabolism upon glucose limitation. The observed alteration in glutamine metabolism under glucose limitation was accompanied by a relative decrease in the proliferation of MUC1-overexpressing cells compared with steady-state conditions. Moreover, glucose limitation induces G1 phase arrest where S2-013.MUC1 cells fail to enter S phase and synthesize DNA because of a significant disruption in pyrimidine nucleotide biosynthesis. Our metabolomics analysis indicates that glutamine is the major source of oxaloacetate in S2-013.Neo and S2-013.MUC1 cells, where oxaloacetate is converted to aspartate, an important metabolite for pyrimidine nucleotide biosynthesis. However, glucose limitation impedes the flow of glutamine carbons into the pyrimidine nucleotide rings and instead leads to a significant accumulation of glutamine-derived aspartate in S2-013.MUC1 cells.

  9. Dynamic responses of reserve carbohydrate metabolism under carbon and nitrogen limitations in Saccharomyces cerevisiae.

    PubMed

    Parrou, J L; Enjalbert, B; Plourde, L; Bauche, A; Gonzalez, B; François, J

    1999-02-01

    The dynamic responses of reserve carbohydrates with respect to shortage of either carbon or nitrogen source was studied to obtain a sound basis for further investigations devoted to the characterization of mechanisms by which the yeast Saccharomyces cerevisiae can cope with nutrient limitation during growth. This study was carried out in well-controlled bioreactors which allow accurate monitoring of growth and frequent sampling without disturbing the culture. Under glucose limitation, genes involved in glycogen and trehalose biosynthesis (GLG1, GSY1, GSY2, GAC1, GLC3, TPS1), in their degradation (GPH1, NTHI), and the typical stress-responsive CTT1 gene were coordinately induced in parallel with glycogen, when the growth has left the pure exponential phase and while glucose was still plentiful in the medium. Trehalose accumulation was delayed until the diauxic shift, although TPS1 was induced much earlier, due to hydrolysis of trehalose by high trehalase activity. In contrast, under nitrogen limitation, both glycogen and trehalose began to accumulate at the precise time when the nitrogen source was exhausted from the medium, coincidentally with the transcriptional activation of genes involved in their metabolism. While this response to nitrogen starvation was likely mediated by the stress-responsive elements (STREs) in the promoter of these genes, we found that these elements were not responsible for the co-induction of genes involved in reserve carbohydrate metabolism during glucose limitation, since GLG1, which does not contain any STRE, was coordinately induced with GSY2 and TPS1.

  10. Global analysis of the Nitrosomonas europaea iron starvation stimulon.

    PubMed

    Vajrala, Neeraja; Sayavedra-Soto, Luis A; Bottomley, Peter J; Arp, Daniel J

    2012-04-01

    The importance of iron to the metabolism of the ammonia-oxidizing bacterium Nitrosomonas europaea is well known. However, the mechanisms by which N. europaea acquires iron under iron limitation are less well known. To obtain insight into these mechanisms, transcriptional profiling of N. europaea was performed during growth under different iron availabilities. Of 2,355 N. europaea genes on DNA microarrays, transcripts for 247 genes were identified as differentially expressed when cells were grown under iron limitation compared to cells grown under iron-replete conditions. Genes with higher transcript levels in response to iron limitation included those with confirmed or assigned roles in iron acquisition. Genes with lower transcript levels included those encoding iron-containing proteins. Our analysis identified several potentially novel iron acquisition systems in N. europaea and provided support for the primary involvement of a TonB-dependent heme receptor gene in N. europaea iron homeostasis. We demonstrated that hemoglobin can act as an iron source under iron-depleted conditions for N. europaea. In addition, we identified a hypothetical protein carrying a lipocalin-like domain that may have the ability to chelate iron for growth in iron-limited media.

  11. Gene expression profiling and phenotype analyses of S. cerevisiae in response to changing copper reveals six genes with new roles in copper and iron metabolism.

    PubMed

    van Bakel, Harm; Strengman, Eric; Wijmenga, Cisca; Holstege, Frank C P

    2005-08-11

    Exhaustive microarray time course analyses of Saccharomyces cerevisiae during copper starvation and copper excess reveal new aspects of metal-induced gene regulation. Aside from identifying targets of established copper- and iron-responsive transcription factors, we find that genes encoding mitochondrial proteins are downregulated and that copper-independent iron transport genes are preferentially upregulated, both during prolonged copper deprivation. The experiments also suggest the presence of a small regulatory iron pool that links copper and iron responses. One hundred twenty-eight genes with putative roles in metal metabolism were further investigated by several systematic phenotype screens. Of the novel phenotypes uncovered, hsp12-Delta and arn1-Delta display increased sensitivity to copper, cyc1-Delta and crr1-Delta show resistance to high copper, vma13-Delta exhibits increased sensitivity to iron deprivation, and pep12-Delta results in reduced growth in high copper and low iron. Besides revealing new components of eukaryotic metal trafficking pathways, the results underscore the previously determined intimate links between iron and copper metabolism and mitochondrial and vacuolar function in metal trafficking. The analyses further suggest that copper starvation can specifically lead to downregulation of respiratory function to preserve iron and copper for other cellular processes.

  12. Dysregulated iron metabolism in the choroid plexus in fragile X-associated tremor/ataxia syndrome

    PubMed Central

    Ariza, Jeanelle; Steward, Craig; Rueckert, Flora; Widdison, Matt; Coffman, Robert; Afjei, Atiyeh; Noctor, Stephen; Hagerman, Randi; Hagerman, Paul; Martínez-Cerdeño, Verónica

    2015-01-01

    Fragile X-associated tremor/ataxia syndrome (FXTAS) is a late-onset neurodegenerative disorder associated with premutation alleles of the FMR1 gene that is characterized by progressive action tremor, gait ataxia, and cognitive decline. Recent studies of mitochondrial dysfunction in FXTAS have suggested that iron dysregulation may be one component of disease pathogenesis. We tested the hypothesis that iron dysregulation is part of the pathogenic process in FXTAS. We analyzed postmortem choroid plexus from FXTAS and control subjects, and found that in FXTAS iron accumulated in the stroma, transferrin levels were decreased in the epithelial cells, and transferrin receptor 1 distribution was shifted from the basolateral membrane (control) to a predominantly intracellular location (FXTAS). In addition, ferroportin and ceruloplasmin were markedly decreased within the epithelial cells. These alterations have implications not only for understanding the pathophysiology of FXTAS, but also for the development of new clinical treatments that may incorporate selective iron chelation. PMID:25498860

  13. Dysregulated iron metabolism in the choroid plexus in fragile X-associated tremor/ataxia syndrome.

    PubMed

    Ariza, Jeanelle; Steward, Craig; Rueckert, Flora; Widdison, Matt; Coffman, Robert; Afjei, Atiyeh; Noctor, Stephen C; Hagerman, Randi; Hagerman, Paul; Martínez-Cerdeño, Verónica

    2015-02-19

    Fragile X-associated tremor/ataxia syndrome (FXTAS) is a late-onset neurodegenerative disorder associated with premutation alleles of the FMR1 gene that is characterized by progressive action tremor, gait ataxia, and cognitive decline. Recent studies of mitochondrial dysfunction in FXTAS have suggested that iron dysregulation may be one component of disease pathogenesis. We tested the hypothesis that iron dysregulation is part of the pathogenic process in FXTAS. We analyzed postmortem choroid plexus from FXTAS and control subjects, and found that in FXTAS iron accumulated in the stroma, transferrin levels were decreased in the epithelial cells, and transferrin receptor 1 distribution was shifted from the basolateral membrane (control) to a predominantly intracellular location (FXTAS). In addition, ferroportin and ceruloplasmin were markedly decreased within the epithelial cells. These alterations have implications not only for understanding the pathophysiology of FXTAS, but also for the development of new clinical treatments that may incorporate selective iron chelation.

  14. Early breast cancer screening using iron/iron oxide-based nanoplatforms with sub-femtomolar limits of detection

    PubMed Central

    Samarakoon, Thilani N; Yapa, Asanka S; Abayaweera, Gayani; Basel, Matthew T; Maynez, Pamela; Ortega, Raquel; Toledo, Yubisela; Bossmann, Leonie; Robinson, Colette; Janik, Katharine E; Koper, Olga B; Li, Ping; Motamedi, Massoud; Higgins, Daniel A; Gadbury, Gary

    2016-01-01

    Summary Proteases, including matrix metalloproteinases (MMPs), tissue serine proteases, and cathepsins (CTS) exhibit numerous functions in tumor biology. Solid tumors are characterized by changes in protease expression levels by tumor and surrounding tissue. Therefore, monitoring protease levels in tissue samples and liquid biopsies is a vital strategy for early cancer detection. Water-dispersable Fe/Fe3O4-core/shell based nanoplatforms for protease detection are capable of detecting protease activity down to sub-femtomolar limits of detection. They feature one dye (tetrakis(carboxyphenyl)porphyrin (TCPP)) that is tethered to the central nanoparticle by means of a protease-cleavable consensus sequence and a second dye (Cy 5.5) that is directly linked. Based on the protease activities of urokinase plasminogen activator (uPA), MMPs 1, 2, 3, 7, 9, and 13, as well as CTS B and L, human breast cancer can be detected at stage I by means of a simple serum test. By monitoring CTS B and L stage 0 detection may be achieved. This initial study, comprised of 46 breast cancer patients and 20 apparently healthy human subjects, demonstrates the feasibility of protease-activity-based liquid biopsies for early cancer diagnosis. PMID:27335730

  15. Early breast cancer screening using iron/iron oxide-based nanoplatforms with sub-femtomolar limits of detection.

    PubMed

    Udukala, Dinusha N; Wang, Hongwang; Wendel, Sebastian O; Malalasekera, Aruni P; Samarakoon, Thilani N; Yapa, Asanka S; Abayaweera, Gayani; Basel, Matthew T; Maynez, Pamela; Ortega, Raquel; Toledo, Yubisela; Bossmann, Leonie; Robinson, Colette; Janik, Katharine E; Koper, Olga B; Li, Ping; Motamedi, Massoud; Higgins, Daniel A; Gadbury, Gary; Zhu, Gaohong; Troyer, Deryl L; Bossmann, Stefan H

    2016-01-01

    Proteases, including matrix metalloproteinases (MMPs), tissue serine proteases, and cathepsins (CTS) exhibit numerous functions in tumor biology. Solid tumors are characterized by changes in protease expression levels by tumor and surrounding tissue. Therefore, monitoring protease levels in tissue samples and liquid biopsies is a vital strategy for early cancer detection. Water-dispersable Fe/Fe3O4-core/shell based nanoplatforms for protease detection are capable of detecting protease activity down to sub-femtomolar limits of detection. They feature one dye (tetrakis(