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Frontiers in Bioscience (Landmark... Aug 2023As a spherical protein that acts as a repository for intracellular iron, Ferritin is the most important iron storage form and is known to influence tumor immunity.... (Review)
Review
As a spherical protein that acts as a repository for intracellular iron, Ferritin is the most important iron storage form and is known to influence tumor immunity. Unbound ferritin is composed of 24 subunits, made up of ferritin light chain (FTL) and ferritin heavy chain (FTH). Ferritin can be automatically put together to form hollow nanocages that measure 12 nm around the outside and 8 nm around the inside. Cancer causes the second-most deaths worldwide, effective elimination of tumor cells while protecting normal cells is the foundation of modern tumor therapy. To this end, the innate tumor-targeting activity of human FTH1, first identified ten years ago, is highly appealing. Unmodified human FTH1 binds to its receptor, transferrin receptor 1 (TfR1), which is frequently overexpressed in cancer cells. FTH1-TfR1 binding permits improved drug efficacy by promoting ferritin-mediated targeted delivery. In addition, FTH is also associated with the prognosis of multiple typies of cancer. The level of FTH1 is significantly and positively correlated with the infiltration of tumor-associated macrophages. FTH1 also plays an important role in regulating the tumor immunity of solid cancer. As such, FTH1 has been extensively applied in the targeted delivery of anticancer drugs, diagnostic molecules (e.g., radioisotopes and fluorophones), and inorganic nanoparticles (NPs) to tumors.This article reviews the role of FTH in cancer and its potential as a therapeutic target.
Topics: Humans; Ferritins; Neoplasms; Iron; Nanoparticles
PubMed: 37664922
DOI: 10.31083/j.fbl2808182 -
Archives of Biochemistry and Biophysics Sep 2023Ferritin is a spherical nanocage protein for iron storage, composed of 24 light- or heavy-polypeptide chain subunits. A single ferritin molecule can carry up to 4500... (Review)
Review
Ferritin is a spherical nanocage protein for iron storage, composed of 24 light- or heavy-polypeptide chain subunits. A single ferritin molecule can carry up to 4500 iron atoms in its core, which plays an important role in suppressing intracellular iron toxicity. Serum ferritin levels are used as a marker for the total amount of iron stored in the body. Most serum ferritin is iron-free (apo-ferritin) and it is unclear how ferritin is released from cells. Ferritin is secreted into serum via extracellular vesicles (EVs) or the secretory autophagy pathway but not via the classical endoplasmic reticulum (ER)-to-Golgi secretion pathway. We recently discovered that the level of tetraspanin CD63, a common EV marker, is post-transcriptionally regulated by the intracellular iron level and both CD63 and ferritin expression is induced by iron loading. Ferritin is incorporated into CD63(+)-EVs through the ferritin-specific autophagy adapter molecule, NCOA4, and then secreted from cells. EV production differs drastically depending on cell type and physiological conditions. Extracellular matrix detached cells express pentaspanin prominin 2 and prominin 2(+)-EVs secrete ferritin independently of NCOA4 trafficking. Ferritin is tightly bound to iron in EVs and functions as an iron-carrier protein in the extracellular environment. Cells can suppress ferroptosis by secreting holo-ferritin, which reduces intracellular iron concentration. However, this exposes the neighboring cells receiving the secreted holo-ferritin to a large excess of iron. This results in cellular toxicity through increased generation of reactive oxygen species (ROS). Here we review the machinery by which ferritin is incorporated into EVs and its role as an intercellular communication molecule.
Topics: AC133 Antigen; Biological Transport; Extracellular Vesicles; Autophagy; Ferritins
PubMed: 37683905
DOI: 10.1016/j.abb.2023.109737 -
The American Journal of Clinical... Jul 2023Genetic correlations (Rg) and bidirectional causal effects between systemic iron status and epigenetic clocks have not been fully investigated, although observational...
BACKGROUND
Genetic correlations (Rg) and bidirectional causal effects between systemic iron status and epigenetic clocks have not been fully investigated, although observational studies have suggested systemic iron status is associated with human aging.
OBJECTIVES
We explored the genetic correlations and bidirectional causal effects between systemic iron status and epigenetic clocks.
METHODS
Leveraging large-scale genome-wide association study summary-level statistics for 4 systemic iron status biomarkers (ferritin, serum iron, transferrin, and transferrin saturation) (N = 48,972) and 4 measures for epigenetic age (GrimAge, PhenoAge, intrinsic epigenetic age acceleration (IEAA), and HannumAge) (N = 34,710), genetic correlations, and bidirectional causal effects were estimated between them mainly by applying linkage disequilibrium score (LDSC) regression, Mendelian randomization (MR), and MR based on Bayesian model averaging. The main analyses were conducted employing multiplicative random-effects inverse-variance weighted MR. MR-Egger, weighted median, weighted mode, and MR-PRESSO were performed as sensitivity analyses to support the robustness of causal effects.
RESULTS
The LDSC results illustrated Rg between serum iron and PhenoAge (Rg = 0.1971, P = 0.048) and between transferrin saturation and PhenoAge (Rg = 0.196, P = 0.0469). We found that increased ferritin and transferrin saturation significantly increased all 4 measures of epigenetic age acceleration (all P < 0.0125, β > 0). Each standard deviation genetically increases in serum iron only significantly associated with increased IEAA (β: 0.36; 95% CI: 0.16, 0.57; P = 6.01 × 10) and increased HannumAge acceleration (β: 0.32; 95% CI: 0.11, 0.52; P = 2.69 × 10). Evidence showed a suggestively significant causal effect of transferrin on epigenetic age acceleration (all 0.0125
CONCLUSIONS
All 4 iron status biomarkers had a significant or suggestively significant causal effect on epigenetic clocks, whereas reverse MR studies did not.
Topics: Humans; Iron; Bayes Theorem; Genome-Wide Association Study; Mendelian Randomization Analysis; Transferrin; Ferritins; Epigenesis, Genetic
PubMed: 37146762
DOI: 10.1016/j.ajcnut.2023.05.004 -
Biochimica Et Biophysica Acta.... Jun 2024Iron-sulfur clusters serve as indispensable cofactors within proteins across all three domains of life. Fe/S clusters emerged early during the evolution of life on our... (Review)
Review
Iron-sulfur clusters serve as indispensable cofactors within proteins across all three domains of life. Fe/S clusters emerged early during the evolution of life on our planet and the biogeochemical cycle of sulfur is one of the most ancient and important element cycles. It is therefore no surprise that Fe/S proteins have crucial roles in the multiple steps of microbial sulfur metabolism. During dissimilatory sulfur oxidation in prokaryotes, Fe/S proteins not only serve as electron carriers in several steps, but also perform catalytic roles, including unprecedented reactions. Two cytoplasmic enzyme systems that oxidize sulfane sulfur to sulfite are of particular interest in this context: The rDsr pathway employs the reverse acting dissimilatory sulfite reductase rDsrAB as its key enzyme, while the sHdr pathway utilizes polypeptides resembling the HdrA, HdrB and HdrC subunits of heterodisulfide reductase from methanogenic archaea. Both pathways involve components predicted to bind unusual noncubane Fe/S clusters acting as catalysts for the formation of disulfide or sulfite. Mapping of Fe/S cluster machineries on the sulfur-oxidizing prokaryote tree reveals that ISC, SUF, MIS and SMS are all sufficient to meet the Fe/S cluster maturation requirements for operation of the sHdr or rDsr pathways. The sHdr pathway is dependent on lipoate-binding proteins that are assembled by a novel pathway, involving two Radical SAM proteins, namely LipS1 and LipS2. These proteins coordinate sulfur-donating auxiliary Fe/S clusters in atypical patterns by three cysteines and one histidine and act as lipoyl synthases by jointly inserting two sulfur atoms to an octanoyl residue. This article is part of a Special Issue entitled: Biogenesis and Function of Fe/S proteins.
Topics: Oxidation-Reduction; Sulfur; Iron-Sulfur Proteins; Bacterial Proteins; Archaea; Oxidoreductases
PubMed: 38631440
DOI: 10.1016/j.bbamcr.2024.119732 -
Biochimica Et Biophysica Acta.... Jun 2024Reactions catalysed by iron-sulfur (Fe-S) enzymes appear in a variety of biosynthetic pathways that produce valuable natural products. Harnessing these biosynthetic... (Review)
Review
Reactions catalysed by iron-sulfur (Fe-S) enzymes appear in a variety of biosynthetic pathways that produce valuable natural products. Harnessing these biosynthetic pathways by expression in microbial cell factories grown on an industrial scale would yield enormous economic and environmental benefits. However, Fe-S enzymes often become bottlenecks that limits the productivity of engineered pathways. As a consequence, achieving the production metrics required for industrial application remains a distant goal for Fe-S enzyme-dependent pathways. Here, we identify and review three core challenges in harnessing Fe-S enzyme activity, which all stem from the properties of Fe-S clusters: 1) limited Fe-S cluster supply within the host cell, 2) Fe-S cluster instability, and 3) lack of specialized reducing cofactor proteins often required for Fe-S enzyme activity, such as enzyme-specific flavodoxins and ferredoxins. We highlight successful methods developed for a variety of Fe-S enzymes and electron carriers for overcoming these difficulties. We use heterologous nitrogenase expression as a grand case study demonstrating how each of these challenges can be addressed. We predict that recent breakthroughs in protein structure prediction and design will prove well-suited to addressing each of these challenges. A reliable toolkit for harnessing Fe-S enzymes in engineered metabolic pathways will accelerate the development of industry-ready Fe-S enzyme-dependent biosynthesis pathways.
Topics: Iron-Sulfur Proteins; Synthetic Biology; Biosynthetic Pathways; Nitrogenase; Sulfur; Ferredoxins
PubMed: 38574823
DOI: 10.1016/j.bbamcr.2024.119718 -
Methods in Molecular Biology (Clifton,... 2024Structural studies of bio-complexes using single particle cryo-Electron Microscopy (cryo-EM) is nowadays a well-established technique in structural biology and has... (Review)
Review
Structural studies of bio-complexes using single particle cryo-Electron Microscopy (cryo-EM) is nowadays a well-established technique in structural biology and has become competitive with X-ray crystallography. Development of digital registration systems for electron microscopy images and algorithms for the fast and efficient processing of the recorded images and their following analysis has facilitated the determination of structures at near-atomic resolution. The latest advances in EM have enabled the determination of protein complex structures at 1.4-3 Å resolution for an extremely broad range of sizes (from ~100 kDa up to hundreds of MDa (Bartesaghi et al., Science 348(6239):1147-1151, 2015; Herzik et al., Nat Commun 10:1032, 2019; Wu et al., J Struct Biol X 4:100020, 2020; Zhang et al., Nat Commun 10:5511, 2019; Zhang et al., Cell Res 30(12):1136-1139, 2020; Yip et al., Nature 587(7832):157-161, 2020; https://www.ebi.ac.uk/emdb/statistics/emdb_resolution_year )). In 2022, nearly 1200 structures deposited to the EMDB database were at a resolution of better than 3 Å ( https://www.ebi.ac.uk/emdb/statistics/emdb_resolution_year ).To date, the highest resolutions have been achieved for apoferritin, which comprises a homo-oligomer of high point group symmetry (O432) and has rigid organization together with high stability (Zhang et al., Cell Res 30(12):1136-1139, 2020; Yip et al., Nature 587(7832):157-161, 2020). It has been used as a test object for the assessments of modern cryo-microscopes and processing methods during the last 5 years. In contrast to apoferritin bacterial secretion systems are typical examples of multi protein complexes exhibiting high flexibility owing to their functions relating to the transportation of small molecules, proteins, and DNA into the extracellular space or target cells. This makes their structural characterization extremely challenging (Barlow, Methods Mol Biol 532:397-411, 2009; Costa et al., Nat Rev Microbiol 13:343-359, 2015). The most feasible approach to reveal their spatial organization and functional modification is cryo-electron microscopy (EM). During the last decade, structural cryo-EM has become broadly used for the analysis of the bio-complexes that comprise multiple components and are not amenable to crystallization (Lyumkis, J Biol Chem 294:5181-5197, 2019; Orlova and Saibil, Methods Enzymol 482:321-341, 2010; Orlova and Saibil, Chem Rev 111(12):7710-7748, 2011).In this review, we will describe the basics of sample preparation for cryo-EM, the principles of digital data collection, and the logistics of image analysis focusing on the common steps required for reconstructions of both small and large biological complexes together with refinement of their structures to nearly atomic resolution. The workflow of processing will be illustrated by examples of EM analysis of Type IV Secretion System.
Topics: Cryoelectron Microscopy; Apoferritins; Algorithms; Bacterial Secretion Systems; Crystallization
PubMed: 37930544
DOI: 10.1007/978-1-0716-3445-5_27 -
Nutrition (Burbank, Los Angeles County,... Feb 2024The aim of this study was to assess the association of genetically determined iron status with the risk for non-alcoholic fatty liver disease (NAFLD) using two-sample...
OBJECTIVES
The aim of this study was to assess the association of genetically determined iron status with the risk for non-alcoholic fatty liver disease (NAFLD) using two-sample Mendelian randomization (MR) analysis.
METHODS
We applied single nucleotide polymorphisms (SNPs) associated at genome-wide significance with iron status proxied by serum iron, ferritin, transferrin, and transferrin saturation from the Genetics of Iron status Consortium (N = 48 793), in a genome-wide association study of 1664 NAFLD cases and 400 055 controls from the United Kingdom Biobank. A SNP associated with multiple markers of iron status was only applied to one marker with the strongest association in the main analysis. Their effects on NAFLD were calculated using inverse variance weighting after excluding SNPs associated with alkaline phosphatase and lipid metabolism.
RESULTS
The risk for NAFLD is negatively associated with genetically predicted serum transferrin level with a 20% reduction in NAFLD risk per SD (0.65g/L) increase in transferrin (95% confidence interval [CI], 0.66-0.97), and trending positive association with transferrin saturation (odds ratio [OR], 1.50; 95% CI, 0.96-2.35) but it was not associated with serum iron (OR, 0.90; 95% CI, 0.63-1.29) and ferritin (OR, 1.33; 95% CI, 0.54-3.30).
CONCLUSIONS
MR analysis provided evidence that genetically predicted higher serum transferrin, indicating lower iron status, may be protective against NAFLD, whereas higher transferrin saturation, indicating higher iron status, might increase the risk for NAFLD and its pathogenesis.
Topics: Humans; Iron; Non-alcoholic Fatty Liver Disease; Genome-Wide Association Study; Mendelian Randomization Analysis; Ferritins; Transferrin; Polymorphism, Single Nucleotide
PubMed: 38103266
DOI: 10.1016/j.nut.2023.112295 -
Current Opinion in Chemical Biology Oct 2023Inorganic complexes of iron and sulfur, that is, iron-sulfur [FeS] clusters, have played a fundamental role in life on Earth since the prebiotic period. These clusters... (Review)
Review
Inorganic complexes of iron and sulfur, that is, iron-sulfur [FeS] clusters, have played a fundamental role in life on Earth since the prebiotic period. These clusters were involved in elementary reactions leading to the emergence of life and, since then, gained function in processes, such as respiration, replication, transcription, and the immune response. We discuss how three [FeS] proteins involved in the innate immune response play a role in oncogene expression/function and oncometabolism. Our analysis highlights the importance of future research into understanding the [FeS] clusters' roles in cancer progression and proliferation. The outcomes of these studies will help identify new targets and develop new anticancer therapeutics.
Topics: Iron; Oncogenes; Sulfur; Iron-Sulfur Proteins
PubMed: 37295349
DOI: 10.1016/j.cbpa.2023.102338 -
Journal of Cachexia, Sarcopenia and... Aug 2023Loss of muscle mass is linked with impaired quality of life and an increased risk of morbidity and premature mortality. Iron is essential for cellular processes such as...
BACKGROUND
Loss of muscle mass is linked with impaired quality of life and an increased risk of morbidity and premature mortality. Iron is essential for cellular processes such as energy metabolism, nucleotide synthesis and numerous enzymatic reactions. As the effects of iron deficiency (ID) on muscle mass and function are largely unknown, we aimed to assess the relation between ID and muscle mass in a large population-based cohort, and subsequently studied effects of ID on cultured skeletal myoblasts and differentiated myocytes.
METHODS
In a population-based cohort of 8592 adults, iron status was assessed by plasma ferritin and transferrin saturation, and muscle mass was estimated using 24-h urinary creatinine excretion rate (CER). The relationships of ferritin and transferrin saturation with CER were assessed by multivariable logistic regression. Furthermore, mouse C2C12 skeletal myoblasts and differentiated myocytes were subjected to deferoxamine with or without ferric citrate. Myoblast proliferation was measured with a colorimetric 5-bromo-2'-deoxy-uridine ELISA assay. Myocyte differentiation was assessed using Myh7-stainings. Myocyte energy metabolism, oxygen consumption rate and extracellular acidification rate were assessed using Seahorse mitochondrial flux analysis, and apoptosis rate with fluorescence-activated cell sorting. RNA sequencing (RNAseq) was used to identify ID-related gene and pathway enrichment in myoblasts and myocytes.
RESULTS
Participants in the lowest age- and sex-specific quintile of plasma ferritin (OR vs middle quintile 1.62, 95% CI 1.25-2.10, P < 0.001) or transferrin saturation (OR 1.34, 95% CI 1.03-1.75, P = 0.03) had a significantly higher risk of being in the lowest age- and sex-specific quintile of CER, independent of body mass index, estimated GFR, haemoglobin, hs-CRP, urinary urea excretion, alcohol consumption and smoking status. In C2C12 myoblasts, deferoxamine-induced ID reduced myoblast proliferation rate (P-trend <0.001) but did not affect differentiation. In myocytes, deferoxamine reduced myoglobin protein expression (-52%, P < 0.001) and tended to reduce mitochondrial oxygen consumption capacity (-28%, P = 0.10). Deferoxamine induced gene expression of cellular atrophy markers Trim63 (+20%, P = 0.002) and Fbxo32 (+27%, P = 0.048), which was reversed by ferric citrate (-31%, P = 0.04 and -26%, P = 0.004, respectively). RNAseq indicated that both in myoblasts and myocytes, ID predominantly affected genes involved in glycolytic energy metabolism, cell cycle regulation and apoptosis; co-treatment with ferric citrate reversed these effects.
CONCLUSIONS
In population-dwelling individuals, ID is related to lower muscle mass, independent of haemoglobin levels and potential confounders. ID impaired myoblast proliferation and aerobic glycolytic capacity, and induced markers of myocyte atrophy and apoptosis. These findings suggest that ID contributes to loss of muscle mass.
Topics: Animals; Female; Male; Mice; Atrophy; Cell Proliferation; Deferoxamine; Ferritins; Independent Living; Iron; Iron Deficiencies; Muscles; Myoblasts, Skeletal; Quality of Life; Transferrins; Humans; Adult
PubMed: 37386912
DOI: 10.1002/jcsm.13277 -
Cutis Aug 2023Ferritin is a key regulator of iron homeostasis that serves as an important clinical indicator of body iron status. Low serum ferritin is a highly specific and sensitive... (Review)
Review
Ferritin is a key regulator of iron homeostasis that serves as an important clinical indicator of body iron status. Low serum ferritin is a highly specific and sensitive marker for diagnosing iron deficiency. In patients presenting with diffuse hair loss, serum ferritin may be a clinically useful tool for ruling out underlying iron deficiency as a cause of alopecia. As an acute-phase reactant, ferritin may be nonspecifically elevated in a wide range of inflammatory conditions; however, the role of ferritin in disorders of the skin and hair is not well understood. In this article, we review the structure and function of ferritin, and we provide a guide for clinical use.
Topics: Humans; Iron; Ferritins; Alopecia Areata; Iron Deficiencies; Hair
PubMed: 37820340
DOI: 10.12788/cutis.0837