scholarly journals Iron, Heme Synthesis and Erythropoietic Porphyrias: A Complex Interplay

Metabolites ◽  
2021 ◽  
Vol 11 (12) ◽  
pp. 798
Author(s):  
Antoine Poli ◽  
Caroline Schmitt ◽  
Boualem Moulouel ◽  
Arienne Mirmiran ◽  
Hervé Puy ◽  
...  
Keyword(s):  
Iron Status ◽  
Protoporphyrin Ix ◽  
Iron Level ◽  
Iron Availability ◽  
Intracellular Iron ◽  
Iron Sulfur Cluster ◽  
Heme Synthesis ◽  
Iron Heme ◽  
Post Transcriptional Regulation ◽  
Rate Limiting

Erythropoietic porphyrias are caused by enzymatic dysfunctions in the heme biosynthetic pathway, resulting in porphyrins accumulation in red blood cells. The porphyrins deposition in tissues, including the skin, leads to photosensitivity that is present in all erythropoietic porphyrias. In the bone marrow, heme synthesis is mainly controlled by intracellular labile iron by post-transcriptional regulation: translation of ALAS2 mRNA, the first and rate-limiting enzyme of the pathway, is inhibited when iron availability is low. Moreover, it has been shown that the expression of ferrochelatase (FECH, an iron-sulfur cluster enzyme that inserts iron into protoporphyrin IX to form heme), is regulated by intracellular iron level. Accordingly, there is accumulating evidence that iron status can mitigate disease expression in patients with erythropoietic porphyrias. This article will review the available clinical data on how iron status can modify the symptoms of erythropoietic porphyrias. We will then review the modulation of heme biosynthesis pathway by iron availability in the erythron and its role in erythropoietic porphyrias physiopathology. Finally, we will summarize what is known of FECH interactions with other proteins involved in iron metabolism in the mitochondria.

scholarly journals Erythropoiesis and Iron Sulfur Cluster Biogenesis

2010 ◽  
Vol 2010 ◽  
pp. 1-8 ◽  
Author(s):  
Hong Ye ◽  
Tracey A. Rouault
Keyword(s):  
Iron Status ◽  
Pyruvate Dehydrogenase Complex ◽  
Erythroid Cell ◽  
Cluster Assembly ◽  
Zebrafish Model ◽  
Iron Sulfur Cluster ◽  
Iron Regulatory Proteins ◽  
Heme Synthesis ◽  
Iron Sulfur ◽  
Iron Heme

Erythropoiesis in animals is a synchronized process of erythroid cell differentiation that depends on successful acquisition of iron. Heme synthesis depends on iron through its dependence on iron sulfur (Fe-S) cluster biogenesis. Here, we review the relationship between Fe-S biogenesis and heme synthesis in erythropoiesis, with emphasis on the proteins, GLRX5, ABCB7, ISCA, and C1orf69. These Fe-S biosynthesis proteins are highly expressed in erythroid tissues, and deficiency of each of these proteins has been shown to cause anemia in zebrafish model. GLRX5 is involved in the production and ABCB7 in the export of an unknown factor that may function as a gauge of mitochondrial iron status, which may indirectly modulate activity of iron regulatory proteins (IRPs). ALAS2, the enzyme catalyzing the first step in heme synthesis, is translationally controlled by IRPs. GLRX5 may also provide Fe-S cofactor for ferrochelatase, the last enzyme in heme synthesis. ISCA and C1orf69 are thought to assemble Fe-S clusters for mitochondrial aconitase and for lipoate synthase, the enzyme producing lipoate for pyruvate dehydrogenase complex (PDC). PDC and aconitase are involved in the production of succinyl-CoA, a substrate for heme biosynthesis. Thus, many steps of heme synthesis depend on Fe-S cluster assembly.

scholarly journals Simultaneous Analysis of Bacterioferritin Gene Expression and Intracellular Iron Status in Pseudomonas putida KT2440 by Using a Rapid Dual Luciferase Reporter Assay

2008 ◽  
Vol 75 (3) ◽  
pp. 866-868 ◽  
Author(s):  
Shicheng Chen ◽  
William F. Bleam ◽  
William J. Hickey
Keyword(s):  
Pseudomonas Putida ◽  
Iron Status ◽  
Iron Concentration ◽  
Luciferase Reporter ◽  
Iron Level ◽  
Reporter Assay ◽  
Intracellular Iron ◽  
Pseudomonas Putida Kt2440 ◽  
Cellular Iron ◽  
Dual Luciferase Reporter Assay

ABSTRACT A dual luciferase reporter (DLR) system utilizing firefly and Renilla luciferases was developed and tested in a model rhizobacterium, Pseudomonas putida KT2440. The DLR was applied to simultaneously analyze expression of three putative bacterioferritin genes (bfrα, bfrβ, and bfr) and assess the cellular iron status of strain KT2440 by monitoring expression of the Fur-regulated fepA-fes promoter. The DLR proved to be reproducible and sensitive. Expression of bfrα (PP0482) and bfrβ (PP1082) was consistent with expectations for bacterioferritin and varied directly with the iron level. However, expression of bfr (PP4856) was inversely related to the iron concentration and it was thus more likely to encode a Dps-like protein rather than a bacterioferritin.

Abstract 29: Heme Levels Are Increased in the Hearts of Patients with End-Stage Heart Failure

2012 ◽  
Vol 111 (suppl_1) ◽  
Author(s):  
Arineh Khechaduri ◽  
Marina Bayeva ◽  
Hossein Ardehali
Keyword(s):  
Heart Failure ◽  
Iron Homeostasis ◽  
Aminolevulinic Acid ◽  
Iron Status ◽  
Hereditary Hemochromatosis ◽  
Protoporphyrin Ix ◽  
Fold Increase ◽  
Heme Iron ◽  
Heme Synthesis ◽  
End Stage

Introduction: Diseases of iron imbalance can cause cardiomyopathy, as observed in hereditary hemochromatosis or Friedreich’s ataxia. However, the iron status of a failing heart has not been systematically examined. Results: The iron levels were quantified in ten hearts from human patients with end-stage cardiomyopathy and ten unmatched healthy control hearts. Total cellular and cytosolic non-heme iron levels were significantly reduced in failing hearts; however, there was a 2-fold increase in cytosolic heme levels in heart failure, as measured by the total protoporphyrin IX (PPIX) content. The amount of iron-free PPIX was low and did not differ between the two groups, suggesting that the majority of PPIX is complexed with iron to form heme, and thus our assay accurately estimates heme levels in the heart. To study the mechanism for the increased heme content in failing hearts, we examined the expression of genes involved in heme and iron homeostasis. Consistent with elevated heme, there was a decrease in the levels of the cellular iron importer (transferrin receptor 1 orTfR1) and the first enzyme in heme synthesis (δ-aminolevulinic acid synthase 1 or ALAS1), both of which are negatively regulated by heme. Other genes involved in heme synthesis, iron incorporation into PPIX, and heme degradation were not affected. However, we noted a significant increase in the mRNA and protein levels of ALAS2 in the failing hearts. ALAS2 is normally expressed in hemoatopoietic cells and displays very low expression in the heart. Its induction in the setting of heart failure provides a possible explanation for increased heme levels. We then assessed whether increase in ALA and heme in failing hearts is associated with generation of reactive oxygen species (ROS). Addition of exogenous ALA led to a four-fold increase in ROS, while incubation with hemin have doubled ROS levels in these cells, suggesting that augmentation of heme synthesis may exacerbate heart failure by increasing the oxidative stress. Conclusions: Our results suggest that heme levels are increased in human hearts with end-stage cardiomyopathy, possibly through the induction of ALAS2 expression. The elevated heme levels may exacerbate heart failure by increased production of ROS.

scholarly journals Recognized and Emerging Features of Erythropoietic and X-Linked Protoporphyria

Diagnostics ◽  
2022 ◽  
Vol 12 (1) ◽  
pp. 151
Author(s):  
Elena Di Pierro ◽  
Francesca Granata ◽  
Michele De Canio ◽  
Mariateresa Rossi ◽  
Andrea Ricci ◽  
...  
Keyword(s):  
Biosynthetic Pathway ◽  
Aminolevulinic Acid ◽  
Protoporphyrin Ix ◽  
Limiting Factor ◽  
Zinc Protoporphyrin ◽  
Complete Understanding ◽  
Inherited Disorders ◽  
Rate Limiting ◽  
Systemic Accumulation ◽  
Made In

Erythropoietic protoporphyria (EPP) and X-linked protoporphyria (XLP) are inherited disorders resulting from defects in two different enzymes of the heme biosynthetic pathway, i.e., ferrochelatase (FECH) and delta-aminolevulinic acid synthase-2 (ALAS2), respectively. The ubiquitous FECH catalyzes the insertion of iron into the protoporphyrin ring to generate the final product, heme. After hemoglobinization, FECH can utilize other metals like zinc to bind the remainder of the protoporphyrin molecules, leading to the formation of zinc protoporphyrin. Therefore, FECH deficiency in EPP limits the formation of both heme and zinc protoporphyrin molecules. The erythroid-specific ALAS2 catalyses the synthesis of delta-aminolevulinic acid (ALA), from the union of glycine and succinyl-coenzyme A, in the first step of the pathway in the erythron. In XLP, ALAS2 activity increases, resulting in the amplified formation of ALA, and iron becomes the rate-limiting factor for heme synthesis in the erythroid tissue. Both EPP and XLP lead to the systemic accumulation of protoporphyrin IX (PPIX) in blood, erythrocytes, and tissues causing the major symptom of cutaneous photosensitivity and several other less recognized signs that need to be considered. Although significant advances have been made in our understanding of EPP and XLP in recent years, a complete understanding of the factors governing the variability in clinical expression and the severity (progression) of the disease remains elusive. The present review provides an overview of both well-established facts and the latest findings regarding these rare diseases.

scholarly journals STUDY OF SERUM FERRITIN IN SMOKERS

2018 ◽  
Vol 11 (1) ◽  
pp. 374
Author(s):  
Meera Shivasekar ◽  
Vinodhini Vm ◽  
Rupesh Kumar Y
Keyword(s):  
Cigarette Smoking ◽  
Serum Ferritin ◽  
Binding Capacity ◽  
Iron Status ◽  
Public Health Problem ◽  
Premature Death ◽  
Iron Level ◽  
Global Public Health ◽  
Serum Iron Level ◽  
Clinical Biomarkers

 Objective: Cigarette smoking is a major global public health problem and increases in the prevalence of tobacco smoking is the cause premature death worldwide. Serum ferritin an intracellular protein that can store and release iron is considered to be one of the important clinical biomarkers to evaluate iron status. This study explores the effect of cigarette smoking on serum ferritin level.Methods: The study was carried out in 100 cigarette smokers and 100 nonsmokers.Results: Subjects with smoking habits showed a significant increase in the serum ferritin levels compared to nonsmokers. Serum iron level, as well as total iron-binding capacity, showed significant increase compared with nonsmokers. Serum ferritin is found to correlate with serum iron.Conclusion: This study supports the fact that cigarette smoking has adverse effect on serum ferritin and other hematologic parameters, and serum ferritin is one of the most reliable indicators of iron status.

scholarly journals Serum Iron Level as a Potential Predictor of Coronavirus Disease 2019 Severity and Mortality: A Retrospective Study

2020 ◽  
Vol 7 (7) ◽  
Author(s):  
Kang Zhao ◽  
Jucun Huang ◽  
Dan Dai ◽  
Yuwei Feng ◽  
Liming Liu ◽  
...  
Keyword(s):  
Iron Deficiency ◽  
Serum Iron ◽  
Iron Status ◽  
Iron Concentration ◽  
Iron Level ◽  
Serum Iron Level ◽  
Amyloid A ◽  
Significant Difference ◽  
Before And After ◽  
Low Serum

Abstract Background Various types of pulmonary diseases are associated with iron deficiency. However, information on iron status in coronavirus disease 2019 (COVID-19) is scarce. Methods This study included 50 hospitalized patients with confirmed COVID-19. The role of serum iron in predicting severity and mortality of COVID-19 was evaluated. Results The most common symptoms of COVID-19 patients in this study were cough (82%), fever (64%), and chest distress (42%). Of the 50 patients, 45 (90%) patients had abnormally low serum iron levels (<7.8 μmol/L). The severity of COVID-19 was negatively correlated with serum iron levels before and after treatment and was positively correlated with C-reactive protein, serum amyloid A, D-dimer, lactate dehydrogenase, urea nitrogen, and myoglobin levels. Decreased serum iron level could predict the transition of COVID-19 from mild to severe and critical illness. Seven (53.8%) patients with a lower serum iron level after treatment in the critical group had died. There was a significant difference in posttreatment serum iron levels between COVID-19 survivors and nonsurvivors. Conclusions Serum iron deficiency was detected in the patients with COVID-19. The severity and mortality of the disease was closely correlated with serum iron levels. Low serum iron concentration was an independent risk factor for death in COVID-19 patients.

scholarly journals Iron Status in Malnourished Children : A Cross Sectional Study

2014 ◽  
Vol 13 (3) ◽  
pp. 50-53
Author(s):  
Shormin Ara Ferdousi ◽  
Rajat Sanker Roy Biswas ◽  
Nayan Kanti Paul ◽  
Mohammed Rezaul Karim
Keyword(s):  
Serum Iron ◽  
Iron Status ◽  
Transferrin Saturation ◽  
Age Groups ◽  
Cross Sectional Study ◽  
Iron Level ◽  
Serum Iron Level ◽  
Cross Sectional ◽  
Malnourished Children ◽  
Different Types

Objectives: Malnutrition is a common condition among children and iron status varies in different types of malnutrition. So the present study is aimed to find the different iron status among severe malnourished children in our context. Methods: A hospital based cross sectional study was done in the Paediatrics ward Chittagong Medical College Hospital in a period of 6 months from January to July 2013 among the 50 cases of malnourished children of age range between 1 to 5 years and Weight for Height Z score(WHZ) was <-2  SD. Sampling technique was continuous purposive sampling. Venous blood was collected to assay the different iron profile mainly serum iron level, total iron binding capacity(TIBC) and transferrin saturation(TSAT). Data was analyzed after correction by SPSS-19. Results: Among the 50 study children of different age groups 15 patients were 1 to 2 years, 18 patients were 2 to 3 years, 10 patients were 3 to 4 years and 7 patients were at 4-5 years of age groups. Among the patients, 29 (58%) of patients were female and 21(42%) of the patients were male. Most of the children were from the families of low socioeconomic status 38(76%). 2(4%) children were from upper middle class who had step mother. Among the selected patients the dominating clinical features were anemia was found among 45(90%) of patients which was mild(66.6%), moderate(26.6%) and severe(6.6%). Skin changes(32%), eye  changes (10%) and hair changes(48%) were also found. Among the 50 study subjects prelacteal feeding was given among 43(86%) children, breast feeding was given 45(90%), exclusive breast feeding was given to 24(48%) of children and complementary feeding after 6 months was given to 29(58%) patients. Among the 50 patients -2 to -3 SD weight for height was found in 20(40%) patients and <-3 SD was found in 30(60%) patients. Most of the children was found to have Mid Upper Arm Circumference (MUAC) 115-125 mm(50%). Iron status was measured among all patients where serum iron level was found 77.72 ± 11.22 mcgm/dl, TIBC was found 340.07 ± 22.67 mcgm/dl and transferrin saturation was found 22.38 ± 2.9 %. Iron status were measured among the different types of malnutrition where serum iron level and transferrin saturation was high among all patients with malnutrition while TIBC was lower than standard level in all patients. Different biochemical status were measured among the different types of malnutrition where serum total protein, serum albumin, Hb% were lower than standard level in all patients.Conclusion: Change in different iron status is a common findings in malnourished children. Screening of all children for anemia and providing iron and folic acid (IFA) or multiple micronutrients (MMN) supplements to children and Infant and Young Child Feeding (IYCF) should be addressed at all level to overcome the situation.DOI: http://dx.doi.org/10.3329/cmoshmcj.v13i3.21024

scholarly journals CSIG-20. EFFECT OF TUMOR-TREATING FIELDS (TTFIELDS) ON EGFR PHOSPHORYLATION IN GBM CELL LINES

2019 ◽  
Vol 21 (Supplement_6) ◽  
pp. vi48-vi48
Author(s):  
Maria Luisa D’Angelo ◽  
Deborah Piffaretti ◽  
Floriana Burgio ◽  
Alessio Chiappini ◽  
Francesco Marchi ◽  
...  
Keyword(s):  
Cell Lines ◽  
Protoporphyrin Ix ◽  
Growth Factor Receptor ◽  
Iron Chelator ◽  
Heme Oxygenase 1 ◽  
Tumor Treating Fields ◽  
Epidermal Growth ◽  
Tin Protoporphyrin ◽  
Novel Strategy ◽  
Rate Limiting

Abstract Glioblastoma (GBM) is the most common high grade and most devastating brain tumor among adults. About 50% of GBM express EGFR (epidermal growth factor receptor) and from these another 50% the mutated form EGFRvIII which is associated with a more aggressive disease and poorer prognosis. We have previously shown that expression of different status of EGFR in GBM cell lines drives the 5-ALA induced fluorescence downstream by influencing the rate-limiting enzyme heme oxygenase-1 (HO-1) probably via PI3K/Akt signalling. We demonstrated that 5-ALA-induced protoporphyrin IX (PpIX) fluorescence is pharmacologically influenced by adding different drugs such as deferoxamine (DFO) and tin-protoporphyrin (SnPP), which are an iron chelator of Fe2+ and an inhibitor of HO-1 respectively, or genistein that promotes PpIX accumulation via functional repression of ABCG2 (ABC transporter G2). Our aim is to increase these pharmacological effects on PpIX fluorescence using tumor-treating fields (TTFields). TTFields, a new therapeutic technology for treating newly diagnosed or recurrent GBM, is able to suppress the growth of cancer cells destabilising microtubule elongation and increasing membrane permeability. Interestingly, TTFields, like as other destabilising drugs and compounds, is able to inhibit the phosphorylation of EGFR and subsequent downregulation of EGFR-induced signalling acting for example on the mechanism that regulate the HO-1 activity. Here, we investigate the effects of TTFields on glioma cells, with different EGFR status and consequently different PpIX fluorescence. Exposure to TTFields during or after pharmacological treatments may represent a novel strategy to block or diminish the phosphorylation of EGFR to ameliorate the visualization of PpIX fluorescence in patients where it is not enough to ensure a safe and precise removal of the tumor bulk. In fact, if a combination of TTFields and drug treatment should give the desired results, this strategy could be applied on patients before being subjected to surgical resection.

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