Iron homeostasis: An anthropocentric perspective

Coffey, Richard; Ganz, Tomas

doi:10.1074/jbc.r117.781823

Cited by 159 publications

(170 citation statements)

References 101 publications

(92 reference statements)

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“…By design, there was a large (~4-fold) difference in plasma [ferritin] between groups. Hepcidin, a liver-secreted hormone described as the master regulator of iron homeostasis, increases in response to high iron stores (Coffee & Ganz 2017); consistent with this, we found that plasma [hepcidin] was more than 5-fold greater in High-ferritin vs. Low-ferritin. Systemic inflammation can influence [ferritin] and [hepcidin] but plasma [CRP] did not differ between groups, suggesting that the difference in plasma [ferritin] between groups reflects a large difference in body iron stores without a difference in a key marker of systemic inflammation.…”

Section: Resultssupporting

confidence: 84%

Plasma ferritin concentration is positively associated with in vivo fatty acid mobilization and insulin resistance in obese women

Ryan

Pelt

Guth

et al. 2018

Experimental Physiology

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High rates of fatty acid (FA) mobilization from adipose tissue are associated with insulin resistance (IR) in obesity. In vitro evidence suggests that iron stimulates lipolysis in adipocytes, but whether iron is related to in vivo FA mobilization is unknown. We hypothesized that plasma ferritin concentration ([ferritin]), a marker of body iron stores, would be positively associated with FA mobilization. We measured [ferritin], the rate of appearance of FA in the systemic circulation (FA Ra; stable isotope dilution), key adipose tissue lipolytic proteins and IR (hyperinsulinaemic-euglycaemic clamp) in 20 obese, premenopausal women. [Ferritin] was correlated with FA Ra (r = 0.65; P = 0.002) and IR (r = 0.57; P = 0.008); these relationships remained significant after controlling for body mass index and plasma [C-reactive protein] (a marker of systemic inflammation) in multiple regression analyses. We then stratified subjects into tertiles based on [ferritin] to compare subjects with 'High-ferritin' versus 'Low-ferritin'. Plasma [hepcidin] was more than fivefold greater (P < 0.05) in the High-ferritin versus Low-ferritin group, but there was no difference in plasma [C-reactive protein] between groups, indicating that the large difference in plasma [ferritin] reflects a difference in iron stores, not systemic inflammation. We found that FA Ra, adipose protein abundance of hormone-sensitive lipase and adipose triglyceride lipase, and IR were significantly greater in subjects with High-ferritin versus Low-ferritin (all P < 0.05). These data provide the first evidence linking iron and in vivo FA mobilization and suggest that elevated iron stores might contribute to IR in obesity by increasing systemic FA availability.

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Section: Resultssupporting

confidence: 84%

Plasma ferritin concentration is positively associated with in vivo fatty acid mobilization and insulin resistance in obese women

Ryan

Pelt

Guth

et al. 2018

Experimental Physiology

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“…Regulation of systemic iron homeostasis via hepcidin was recently reviewed in detail elsewhere. 16–18 Ferroportin is a conserved vertebrate iron exporter located on the cell surface of macrophages, duodenal enterocytes, placental cells, and hepatocytes. 19 These cells release iron into the plasma after oxidation to Fe 3+ , which becomes rapidly bound by transferrin (Tf), a glycoprotein that has two high affinity sites for ferric iron.…”

Section: Cellular Iron Uptake From the Circulationmentioning

confidence: 99%

Intracellular iron and heme trafficking and metabolism in developing erythroblasts

Kafina

Paw

2017

Metallomics

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Vertebrate red blood cells (RBCs) arise from erythroblasts in the human bone marrow through a process known as erythropoiesis. Iron uptake is a crucial hallmark, essential for heme biosynthesis in the differentiating erythroblasts, which are dedicated to producing hemoglobin. Erythropoiesis is facilitated by a network of intracellular transport proteins, chaperones, and circulating hormones. Intracellular iron is targeted to the mitochondria for incorporation into a porphyrin ring to form heme and cytosolic iron-sulfur proteins, including Iron Regulatory Protein 1 (IRP1). These processes are tightly regulated to prevent both excess and insufficient levels of iron and heme precursors. Crosstalk between the heme and iron-sulfur synthesizing pathways has been demonstrated to serve as a regulatory feedback mechanism. The activity of δ-aminolevulinic acid synthase (ALAS), the first and rate-limiting enzyme of heme biosynthesis, is a fundamental node of this regulation. Recently, the mitochondrial unfoldase, ClpX, has received attention as a novel key player that modulates this step in heme biogenesis, implicating a role in the pathophysiology of anemic diseases. This chapter reviews the canonical pathways in intracellular iron and heme trafficking and recent findings of iron and heme metabolism in vertebrate red cells. A discussion of the molecular approaches to studying iron and heme transport is provided to highlight opportunities for revealing therapeutic targets.

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“…10 Therefore, biological systems must control iron metabolism by providing the adequate amount of iron for proper cellular function while limiting iron toxicity. 11,12 Iron has also a role in pathogen virulence. The growth of microbial pathogens within the host usually requires iron as an essential nutrient.…”

Section: Introductionmentioning

confidence: 99%

The human iron-proteome†

et al. 2018

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Organisms from all kingdoms of life use iron-proteins in a multitude of functional processes. We applied a bioinformatics approach to investigate the human portfolio of iron-proteins. We separated ironproteins based on the chemical nature of their metal-containing cofactors: individual iron ions, heme cofactors and iron-sulfur clusters. We found that about 2% of human genes encode an iron-protein.Of these, 35% are proteins binding individual iron ions, 48% are heme-binding proteins and 17% are iron-sulfur proteins. More than half of the human iron-proteins have a catalytic function. Indeed, we predict that 6.5% of all human enzymes are iron-dependent. This percentage is quite different for the various enzyme classes. Human oxidoreductases feature the largest fraction of iron-dependent family members (about 37%). The distribution of iron proteins in the various cellular compartments is uneven.In particular, the mitochondrion and the endoplasmic reticulum are enriched in iron-proteins with respect to the average content of the cell. Finally, we observed that genes encoding iron-proteins are more frequently associated to pathologies than the all other human genes on average. The present research provides an extensive overview of iron usage by the human proteome, and highlights several specific features of the physiological role of iron ions in human cells. Significance to metallomicsIron is one of the most ancient and abundant metal ions in living organisms: it participates in fundamental biological processes, such as photosynthesis, and respiration. It is an essential metal ion for humans. Here, we applied a bioinformatics approach to predict the entire set of human proteins that use iron as cofactor. We found that about 2% of human genes encode an iron-protein. In particular, 35% are proteins binding individual iron ions, 48% are heme-binding proteins and 17% are iron-sulfur proteins. Most of these proteins are enzymes: 37% of the human oxidoreductases need an iron ion to perform their catalytic mechanisms. The analysis of the subcellular location highlighted that some organelles are enriched in iron-proteins, in particular about 7% of the proteins localized in the endoplasmic reticulum and in the mitochondrion bind iron. Finally, our data show that mutations in genes encoding iron-binding proteins are more likely to be associated with pathology than all human genes on average.

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Iron homeostasis: An anthropocentric perspective

Cited by 159 publications

References 101 publications

Plasma ferritin concentration is positively associated with in vivo fatty acid mobilization and insulin resistance in obese women

Plasma ferritin concentration is positively associated with in vivo fatty acid mobilization and insulin resistance in obese women

Intracellular iron and heme trafficking and metabolism in developing erythroblasts

The human iron-proteome†

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