-
1.
Glutaredoxins and iron-sulfur protein biogenesis at the interface of redox biology and iron metabolism.
Mühlenhoff, U, Braymer, JJ, Christ, S, Rietzschel, N, Uzarska, MA, Weiler, BD, Lill, R
Biological chemistry. 2020;(12):1407-1428
Abstract
The physiological roles of the intracellular iron and redox regulatory systems are intimately linked. Iron is an essential trace element for most organisms, yet elevated cellular iron levels are a potent generator and amplifier of reactive oxygen species and redox stress. Proteins binding iron or iron-sulfur (Fe/S) clusters, are particularly sensitive to oxidative damage and require protection from the cellular oxidative stress protection systems. In addition, key components of these systems, most prominently glutathione and monothiol glutaredoxins are involved in the biogenesis of cellular Fe/S proteins. In this review, we address the biochemical role of glutathione and glutaredoxins in cellular Fe/S protein assembly in eukaryotic cells. We also summarize the recent developments in the role of cytosolic glutaredoxins in iron metabolism, in particular the regulation of fungal iron homeostasis. Finally, we discuss recent insights into the interplay of the cellular thiol redox balance and oxygen with that of Fe/S protein biogenesis in eukaryotes.
-
2.
Using Volatile Organic Compounds to Investigate the Effect of Oral Iron Supplementation on the Human Intestinal Metabolome.
Ahmed, A, Slater, R, Lewis, S, Probert, C
Molecules (Basel, Switzerland). 2020;(21)
Abstract
Patients with iron deficiency anaemia are treated with oral iron supplementation, which is known to cause gastrointestinal side effects by likely interacting with the gut microbiome. To better study this impact on the microbiome, we investigated oral iron-driven changes in volatile organic compounds (VOCs) in the faecal metabolome. Stool samples from patients with iron deficiency anaemia were collected pre- and post-treatment (n = 45 and 32, respectively). Faecal headspace gas analysis was performed by gas chromatography-mass spectrometry and the changes in VOCs determined. We found that the abundance of short-chain fatty acids and esters fell, while aldehydes increased, after treatment. These changes in pre- vs. post-iron VOCs resemble those reported when the gut is inflamed. Our study shows that iron changes the intestinal metabolome, we suggest by altering the structure of the gut microbial community.
-
3.
Quantitative transcranial sonography of the substantia nigra as a predictor of therapeutic response to intravenous iron therapy in restless legs syndrome.
Garcia-Malo, C, Wanner, V, Miranda, C, Romero Peralta, S, Agudelo, L, Cano-Pumarega, I, Granizo, JJ, Garcia-Borreguero, D
Sleep medicine. 2020;:123-129
Abstract
OBJECTIVE To analyze changes in substantia nigra (SN) iron deposits, assessed by quantitative transcranial sonography (TCS), to obtain and compare substantia nigra echogenicity indices (SNEI) at baseline and after intravenous (IV) iron therapy in patients with restless legs syndrome (RLS)/Willis-Ekbom disease (WED). METHODS A total of 30 consecutive subjects diagnosed with RLS/WED were recruited and underwent IV iron treatment. The SNEI, total daily dose of dopamine equivalents, and International Restless Legs Syndrome Rating Scale (IRLS) scores were obtained at baseline and following IV iron administration. Comparative statistics were performed by means of nonparametric testing. RESULTS The sample was stratified into two groups according to the median baseline SNEI and the grade of SN hypoechogenicity: severely hypoechogenic (HE) (n = 13) and moderately HE (n = 17). Following IV iron, the increase in SNEI among severely HE subjects was 19% (0.038 ± 0.046 cm2; P < 0.01), whereas in moderately HE subjects it was 10% (0.021 ± 0.069 cm2; P = 0.28). Among severely HE subjects, the average reduction in IRLS following IV iron was 10 ± 7.12 points (P < 0.01), in contrast to 1.85 ± 9.85 (not significant) among moderately HE subjects. Finally, we quantified the percentage of patients in each group who were able to reduce by ≥30% their total daily dopaminergic requirements (TDR) after IV iron, with a 57.14% reduction in the severely HE group vs 25% in the moderately HE group (P = 0.1). Three of 30 subjects (17%) were able to completely cease all dopaminergic treatment. CONCLUSION Intravenous iron caused changes in SNEI in both groups of patients, reflecting an increase in brain iron stores. However, the increase in SNEI was greater in patients previously defined as severely HE. Furthermore, RLS/WED symptoms also improved more in severely HE subjects, and there was a greater reduction in TDR. This study highlights the role of TCS in quantifying brain iron deposits and in predicting which patients will likely benefit from IV iron.
-
4.
Ferroptosis Is Regulated by Mitochondria in Neurodegenerative Diseases.
Zhou, J, Jin, Y, Lei, Y, Liu, T, Wan, Z, Meng, H, Wang, H
Neuro-degenerative diseases. 2020;(1):20-34
Abstract
BACKGROUND Neurodegenerative diseases are characterized by a gradual decline in motor and/or cognitive function caused by the selective degeneration and loss of neurons in the central nervous system, but their pathological mechanism is still unclear. Previous research has revealed that many forms of cell death, such as apoptosis and necrosis, occur in neurodegenerative diseases. Research in recent years has noticed that there is a new type of cell death in neurodegenerative diseases: ferroptosis. An increasing body of literature provides evidence for an involvement of ferroptosis in neurodegenerative diseases. SUMMARY In this article, we review a new form of cell death in neurodegenerative diseases: ferroptosis. Ferroptosis is defined as an iron-dependent form of regulated cell death, which occurs through the lethal accumulation of lipid-based reactive oxygen species when glutathione-dependent lipid peroxide repair systems are compromised. Several salient and established features of neurodegenerative diseases (including lipid peroxidation and iron dyshomeostasis) are consistent with ferroptosis, which means that ferroptosis may be involved in the progression of neurodegenerative diseases. In addition, as the center of energy metabolism in cells, mitochondria are also closely related to the regulation of iron homeostasis in the nervous system. At the same time, neurodegenerative diseases are often accompanied by degeneration of mitochondrial activity. Mitochondrial damage has been found to be involved in lipid peroxidation and iron dyshomeostasis in neurodegenerative diseases. Key Messages: Based on the summary of the related mechanisms of ferroptosis, we conclude that mitochondrial damage may affect neurodegenerative diseases by regulating many aspects of ferroptosis, including cell metabolism, iron dyshomeostasis, and lipid peroxidation.
-
5.
Influence of Periodizing Dietary Carbohydrate on Iron Regulation and Immune Function in Elite Triathletes.
McKay, AKA, Heikura, IA, Burke, LM, Peeling, P, Pyne, DB, van Swelm, RPL, Laarakkers, CM, Cox, GR
International journal of sport nutrition and exercise metabolism. 2020;(1):34-41
Abstract
Sleeping with low carbohydrate (CHO) availability is a dietary strategy that may enhance training adaptation. However, the impact on an athlete's health is unclear. This study quantified the effect of a short-term "sleep-low" dietary intervention on markers of iron regulation and immune function in athletes. In a randomized, repeated-measures design, 11 elite triathletes completed two 4-day mixed cycle run training blocks. Key training sessions were structured such that a high-intensity training session was performed in the field on the afternoon of Days 1 and 3, and a low-intensity training (LIT) session was performed on the following morning in the laboratory (Days 2 and 4). The ingestion of CHO was either divided evenly across the day (HIGH) or restricted between the high-intensity training and LIT sessions, so that the LIT session was performed with low CHO availability (LOW). Venous blood and saliva samples were collected prior to and following each LIT session and analyzed for interleukin-6, hepcidin 25, and salivary immunoglobulin-A. Concentrations of interleukin-6 increased acutely after exercise (p < .001), but did not differ between dietary conditions or days. Hepcidin 25 increased 3-hr postexercise (p < .001), with the greatest increase evident after the LOW trial on Day 2 (2.5 ± 0.9 fold increase ±90% confidence limit). The salivary immunoglobulin-A secretion rate did not change in response to exercise; however, it was highest during the LOW condition on Day 4 (p = .046). There appears to be minimal impact to markers of immune function and iron regulation when acute exposure to low CHO availability is undertaken with expert nutrition and coaching input.
-
6.
Systematic Review of the Clinical Outcomes of Iron Reduction in Hereditary Hemochromatosis.
Prabhu, A, Cargill, T, Roberts, N, Ryan, JD
Hepatology (Baltimore, Md.). 2020;(4):1469-1482
-
7.
Iron-Only and Vanadium Nitrogenases: Fail-Safe Enzymes or Something More?
Harwood, CS
Annual review of microbiology. 2020;:247-266
Abstract
The enzyme molybdenum nitrogenase converts atmospheric nitrogen gas to ammonia and is of critical importance for the cycling of nitrogen in the biosphere and for the sustainability of life. Alternative vanadium and iron-only nitrogenases that are homologous to molybdenum nitrogenases are also found in archaea and bacteria, but they have a different transition metal, either vanadium or iron, at their active sites. So far alternative nitrogenases have only been found in microbes that also have molybdenum nitrogenase. They are less widespread than molybdenum nitrogenase in bacteria and archaea, and they are less efficient. The presumption has been that alternative nitrogenases are fail-safe enzymes that are used in situations where molybdenum is limiting. Recent work indicates that vanadium nitrogenase may play a role in the global biological nitrogen cycle and iron-only nitrogenase may contribute products that shape microbial community interactions in nature.
-
8.
Bacterial siderophores in community and host interactions.
Kramer, J, Özkaya, Ö, Kümmerli, R
Nature reviews. Microbiology. 2020;(3):152-163
-
-
Free full text
-
Abstract
Iron is an essential trace element for most organisms. A common way for bacteria to acquire this nutrient is through the secretion of siderophores, which are secondary metabolites that scavenge iron from environmental stocks and deliver it to cells via specific receptors. While there has been tremendous interest in understanding the molecular basis of siderophore synthesis, uptake and regulation, questions about the ecological and evolutionary consequences of siderophore secretion have only recently received increasing attention. In this Review, we outline how eco-evolutionary questions can complement the mechanistic perspective and help to obtain a more integrated view of siderophores. In particular, we explain how secreted diffusible siderophores can affect other community members, leading to cooperative, exploitative and competitive interactions between individuals. These social interactions in turn can spur co-evolutionary arms races between strains and species, lead to ecological dependencies between them and potentially contribute to the formation of stable communities. In brief, this Review shows that siderophores are much more than just iron carriers: they are important mediators of interactions between members of microbial assemblies and the eukaryotic hosts they inhabit.
-
9.
Persisting alterations of iron homeostasis in COVID-19 are associated with non-resolving lung pathologies and poor patients' performance: a prospective observational cohort study.
Sonnweber, T, Boehm, A, Sahanic, S, Pizzini, A, Aichner, M, Sonnweber, B, Kurz, K, Koppelstätter, S, Haschka, D, Petzer, V, et al
Respiratory research. 2020;(1):276
Abstract
BACKGROUND Severe coronavirus disease 2019 (COVID-19) is frequently associated with hyperinflammation and hyperferritinemia. The latter is related to increased mortality in COVID-19. Still, it is not clear if iron dysmetabolism is mechanistically linked to COVID-19 pathobiology. METHODS We herein present data from the ongoing prospective, multicentre, observational CovILD cohort study (ClinicalTrials.gov number, NCT04416100), which systematically follows up patients after COVID-19. 109 participants were evaluated 60 days after onset of first COVID-19 symptoms including clinical examination, chest computed tomography and laboratory testing. RESULTS We investigated subjects with mild to critical COVID-19, of which the majority received hospital treatment. 60 days after disease onset, 30% of subjects still presented with iron deficiency and 9% had anemia, mostly categorized as anemia of inflammation. Anemic patients had increased levels of inflammation markers such as interleukin-6 and C-reactive protein and survived a more severe course of COVID-19. Hyperferritinemia was still present in 38% of all individuals and was more frequent in subjects with preceding severe or critical COVID-19. Analysis of the mRNA expression of peripheral blood mononuclear cells demonstrated a correlation of increased ferritin and cytokine mRNA expression in these patients. Finally, persisting hyperferritinemia was significantly associated with severe lung pathologies in computed tomography scans and a decreased performance status as compared to patients without hyperferritinemia. DISCUSSION Alterations of iron homeostasis can persist for at least two months after the onset of COVID-19 and are closely associated with non-resolving lung pathologies and impaired physical performance. Determination of serum iron parameters may thus be a easy to access measure to monitor the resolution of COVID-19. TRIAL REGISTRATION ClinicalTrials.gov number: NCT04416100.
-
10.
Can diet-induced weight loss improve iron homoeostasis in patients with obesity: A systematic review and meta-analysis.
Teng, IC, Tseng, SH, Aulia, B, Shih, CK, Bai, CH, Chang, JS
Obesity reviews : an official journal of the International Association for the Study of Obesity. 2020;(12):e13080
Abstract
Despite the increasing worldwide prevalence of obesity and iron deficiency (ID), there are still no guidelines on how to treat and manage obesity-related ID. The aim of this systematic review and meta-analysis was to investigate whether weight loss can re-establish iron homoeostasis among subjects with unhealthy weight (overweight [OW] or obesity). PubMed, Medline, Embase, Web of Science, and the Cochrane Library were systemically searched for studies that compared the iron status before and after a weight-loss intervention. A random-effects model was used to calculate the pooled and subgroup weighted mean differences (WMDs) of iron biomarkers. In total, 879 subjects were pooled across 14 studies. Improved haemoglobin was found in longitudinal studies (WMD = 2.50 g/dl, 95% confidence interval [CI]: 0.88, 4.12 g/dl, I2 = 14%) but not in randomized controlled trials or after being stratified by dietary programmes. Significantly increased transferrin saturation was observed in pooled (WMD = 1.68%, 95% CI: 0.97%, 2.39%, I2 = 44%) and subgroup analyses. A meta-regression showed that changes in the iron status were positively correlated with changes in the body mass index (BMI) and the intervention duration but negatively correlated with the baseline body weight/BMI, age, gender and a standard hypocaloric diet. Our data suggested that in spite of energy restrictions, weight loss may help re-establish iron homoeostasis in people who are OW or obese.