Enhanced Iron Uptake Research Articles

Mitochondrial acyl carrier protein, Acp1, required for iron-sulfur cluster assembly in mitochondria and cytoplasm in Saccharomyces cerevisiae

Mitochondria perform vital biosynthetic processes, including fatty acid synthesis and iron-sulfur (FeS) cluster biogenesis. In Saccharomyces cerevisiae mitochondria, the acyl carrier protein Acp1 participates in type II fatty acid synthesis, requiring a 4-phosphopantetheine (PP) prosthetic group. Acp1 also interacts with the mitochondrial FeS cluster assembly complex that contains the cysteine desulfurase Nfs1. Here we investigated the role of Acp1 in FeS cluster biogenesis in mitochondria and cytoplasm. In the Acp1-depleted (Acp1↓) cells, biogenesis of mitochondrial FeS proteins was impaired, likely due to greatly reduced Nfs1 protein and/or its persulfide-forming activity. Formation of cytoplasmic FeS proteins was also deficient, suggesting a disruption in generating the (Fe-S)int intermediate, that is exported from mitochondria and is utilized for cytoplasmic FeS cluster assembly. Iron homeostasis was perturbed, with enhanced iron uptake into the cells and accumulation of iron in mitochondria. The Δppt2 strain, lacking the mitochondrial ability to add PP to Acp1, phenocopied the Acp1↓ cells. These data suggest that the holo form of Acp1 with the PP-conjugated acyl chain is required for stability of the Nfs1 protein and/or stimulation of its persulfide-forming activity. Thus, mitochondria lacking Acp1 (or Ppt2) cannot support FeS cluster biogenesis in mitochondria or cytoplasm, leading to disrupted iron homeostasis.

Enhancing Iron and Zinc Uptake in Spring Wheat Through Commercial Arbuscular Mycorrhizal Fungi Inoculation under Different Soil Phosphorus Addition Levels

Improving the concentrations and bioavailability of micronutrients, especially iron (Fe) and zinc (Zn), in crop grains is important to alleviate their deficiencies in humans. Inoculating crops with arbuscular mycorrhizal fungi (AMF) can potentially enhance soil nutrient supply and crop yield, but the effectiveness is influenced by soil factors, particularly soil phosphorus (P) availability. A greenhouse pot experiment was conducted to evaluate the effect of a commercial AMF product on spring wheat (Triticum aestivum L.) yield and grain concentrations of Zn and Fe under different soil P addition levels (0, 5 and 20 mg P kg-1 dry soil). Results showed that AMF inoculation significantly increased root colonization rate of wheat across all P addition levels. Wheat growth, as evidenced by dry weights of shoot and grain, was significantly enhanced by AMF and high P addition treatments. AMF inoculation did not affect grain Zn concentration, but significantly increased grain Fe concentration compared to the un-inoculated control. As expected, P addition resulted in a significant reduction in grain concentrations of Fe and Zn, primarily due to a growth dilution effect. An integrated analysis using the radar plot concludes that AMF inoculation is most effective in increasing crop yield and grain micronutrient concentrations when soil P levels are low. Importantly, while adequate P supply is crucial for maintaining crop productivity, it may decrease grain micronutrient availability without complementary strategies.

Increased intracellular H2S levels enhance iron uptake in Escherichia coli.

H2S is recognized as a second messenger in bacteria, playing a vital role in diverse intracellular and extracellular activities, including oxidative stress responses and antibiotic resistance. Both H2S and iron serve as essential signaling molecules for gut bacteria. However, the intricate intracellular coordination between them, governing bacterial physiology, remains poorly understood. This study unveils a close relationship between intracellular H2S accumulation and iron uptake activity, a relationship critical for antibiotic resistance. We present additional evidence expanding the role of intracellular H2S synthesis in bacterial physiology.

Enhancing plant resistance to biotic stresses through rhizobacteria for sustainable agriculture

Plant Growth-Promoting Rhizobacteria (PGPR) play a crucial role in the enhancement of plant growth. These microorganisms inhabit plant roots and positively influence plant growth through various mechanisms. PGPR facilitate nutrient absorption, combat pathogens, and regulate plant hormone levels. Their impact is achieved through direct actions such as hormone production, enhanced iron uptake via siderophores, phosphate solubilization, and emission of volatile compounds that affect plant signaling and metabolism. In addition, PGPR interactions with rhizosphere microorganisms and the soil indirectly improve plant growth. Numerous biotic stressors affect plant PGPR. The interaction between plants and microorganisms boosts the host resistance to biotic stress. This interaction also regulates the rhizosphere soil by converting organic compounds into plant-absorbable forms, increasing molecule mobilization, and supplying amino acids, carbohydrates, lipids, metabolites, and phytohormones to the host plants. In instances where plants do not secrete lipids, amino acids, carbohydrates, or terpenoids during these interactions, microorganisms contribute these compounds to plants. Investigating these mechanisms, along with changes in gene expression and receptor-mediated signaling in plants, is vital. Utilization of microbial sources as alternatives to conventional agricultural methods is a promising approach. Incorporation of these sources can enhance plant production, quality, growth, and yield.

FETPY: a Diiron(I) Thio-Carbyne Complex with Prominent Anticancer Activity In Vitro and In Vivo.

FETPY, an organo-diiron(I) complex, showed strong cytotoxicity across a panel of human and mouse cancer cell lines, combined with an outstanding selectivity compared to nonmalignant cells. Enhanced iron uptake in aggressive, low-differentiated cell lines, caused membrane lipid peroxidation, which resulted in ferroptosis in human ovarian cancer cells. FETPY induced significant morphological changes in murine B16-F1 and B16-F10 melanoma cells, leading to senescence and/or trans-differentiation into Schwann-like cells, thus significantly reducing their tumorigenic potential. Additionally, FETPY substantially suppressed tumor growth in low- and high-grade syngeneic melanoma models when administered in a therapeutic regimen. FETPY is featured by satisfactory water solubility (millimolar range), an amphiphilic character (Log Pow = -0.17), and excellent stability in a biological medium (DMEM). These important requisites for drug development are rarely met in iron complexes investigated so far as possible anticancer agents. Overall, FETPY holds promise as a safe and potent targeted antitumor agent.

Mechanisms of cadmium mitigation in tomato plants under orthophosphate and polyphosphate fertilization regimes

Cadmium (Cd) is one of the most toxic elements in soil, affecting morphological, physiological, and biochemical processes in plants. Mineral plant nutrition was tested as an effective approach to mitigate Cd stress in several crop species. In this regard, the present study aimed to elucidate how different phosphorus (P) fertilization regimes can improve some bio-physiological processes in tomato plants exposed to Cd stress. In a hydroponic experiment, the impact of two phosphorus fertilizer forms (Polyphosphate (poly-P): condensed P-form with 100% polymerization rate and orthophosphate (ortho-P): from orthophosphoric acid) on the photosynthetic activity, plant growth, and nutrient uptake was assessed under three levels of Cd stress (0, 12, and 25 µM of CdCl2). The obtained results confirmed the negative effects of Cd stress on the chlorophyll content and the efficiency of the photosynthesis machinery. The application of poly-P fertilizer significantly improved the chlorophyll stability index (82%) under medium Cd stress (Cd12), as compared to the ortho-P form (55%). The analysis of the chlorophyll α fluorescence transient curve revealed that the amplitude of Cd effect on the different steps of electron transfer between PSII and PSI was significantly reduced under the poly-P fertilization regime compared to ortho-P, especially under Cd12. The evaluation of the RE0/RC parameter showed that the electron flux reducing end electron acceptors at the PSI acceptor side per reaction center was significantly improved in the poly-P treatment by 42% under Cd12 compared to the ortho-P treatment. Moreover, the use of poly-P fertilizer enhanced iron uptake and its stoichiometric homeostasis in the shoot tissue which maintained an adequate absorption of iron under Cd stress conditions. Findings from this study revealed for the first time that inorganic polyphosphate fertilizers can reduce Cd toxicity in tomato plants by enhancing photosynthesis activity, nutrient uptake, plant growth, and biomass accumulation despite the high level of cadmium accumulation in shoot tissues.

Siderophore of plant growth promoting rhizobacterium origin reduces reactive oxygen species mediated injury in Solanum spp. caused by fungal pathogens.

The study aims to explore antifungal properties of bacillibactin siderophore produced by the plant growth-promoting rhizobacterium (PGPR) Bacillus subtilis against fungal phytopathogens Alternaria porri and Fusarium equiseti isolated from Solanum lycopersicum and Solanum melongena plants. Alternaria porri and F. equiseti were isolated from infected plants of eggplant and tomato, respectively. A plate assay was employed to assess the effect of bacillibactin against the phytopathogens. The antifungal potential of the PGPR was evaluated by estimation of dry fungal biomass, visualization of cellular deformity using compound and scanning electron microscopy, antioxidative enzyme assay and analysis of membrane damage via using lipid peroxidation. Inductively coupled plasma atomic emission spectroscopy (ICP-AES) analysis was employed to investigate changes in intracellular iron content. The impact of bacillibactin on pathogenesis was evaluated by infecting detached leaves of S. lycopersicum and S. melongena plants with both the pathogens and treating the infected leaves with bacillibactin. Leaves were further investigated for ROS accumulation, extent of necrosis and cell death. Our findings revealed significant damage to the hyphal structure of A. porri and F. equiseti following treatment with bacillibactin. Biomass reduction, elevated antioxidative enzyme levels, and membrane damage further substantiated the inhibitory effects of the siderophore on fungal growth. ICP-AES analysis indicates an increase in intracellular iron content suggesting enhanced iron uptake facilitated by bacillibactin. Moreover, application of 1500µg ml-1 bacillibactin on infected leaves demonstrated a substantial inhibition of ROS accumulation, necrosis, and cell death upon bacillibactin treatment. This study confirms the potent antagonistic activity of bacillibactin against both the phytopathogens A. porri and F. equiseti growth, supporting its potential as a promising biological control agent for fungal plant diseases. Bacillibactin-induced morphological, physiological, and biochemical alterations in the isolated fungi and pathogen-infected leaves highlight the prospects of bacillibactin as an effective and sustainable solution to mitigate economic losses associated with fungal infections in vegetable crops.

Identification and Validation of Ferroptosis-Related Genes As Novel Prognosis Prediction Panel for Acute Myeloid Leukemia

Acute myeloid leukemia (AML) is a main type of adult acute leukemia, especially in elderly population. The development of AML ascribed to various factors including chromosomal abnormalities, isolated gene mutations, etc. and the 5-year survival rate is around 30%. Currently, the most popular and precise assessment of AML is based on cytogenetic differences, and the patients with higher risk molecular mutations had inferior prognosis. However, with the development and application of new drugs, including bcl-2 inhibitors, many AML with high risks (such as FLT3, P53 mutated) also achieve better remission and longer survival. Up to date, many novel prognosis models are in process, with the better understanding of the initiation and development of leukemia. Ferroptosis, a widespread and ancient form of cell death driven by iron-dependent phospholipid peroxidation. Its involvement in AML has been reported, as leukemic cells frequently exhibit enhanced iron uptake and reduced iron efflux, resulting in elevated intracellular iron levels. Targeting iron homeostasis and inducing ferroptosis may provide novel insights into AML therapy. Herein, we integrated multi-gene information to identify a novel prediction model for ferroptosis-related genes (FRGs), and validated the accuracy of the model using clinical samples from our center (Figure A). In this study, we downloaded RNA-seq data and clinicopathological features of 151 AML patients from The Cancer Genome Atlas (TCGA) database (https://www.cancer.gov/ccg/research/genome-sequencing/tcga) and 70 corresponding health samples from the Genotype-Tissue Expression (GTEx) database (https://gtexportal.org/). Retrieve the ferroptosis-related genes (FRGs) set from the FerrDb database (http://www.zhounan.org/ferrdb/current/). The difference analysis, LASSO regression and Cox regression were used to determine the FRGs signature to construct prognostic models (Figure B). We finally identified 10 FRGs signature (ACSF2, SOCS1, CDO1, MYB, LPIN1, DNAJB6, PSAT1, GPX4, MT1G, FH) to establish a risk scoring model, and AML patients were divided into high-risk and low-risk group according to the median risk score. The risk score for each sample was determined using the following formula: . Kaplan-meier analysis showed that the overall survival of patients in the high-risk group was significantly worse( P<0.001) (Figure C). Cox regression analysis, ROC and DCA results found that these features have good predictive ability for prognosis of AML (Figure D-F). We also grouped the TCGA AML patients into poor/adverse and favorable/intermediate group based on NCCN guideline (risk stratification based on genomic mutation background), and found that the survival differences based on classical risk model were not that obvious ( P=0.062) (Figure G) when compared to our model ( P<0.001 in Figure C). Which suggested that our model may have its superior in distinguishing real high risk AML patients. In order to validate the accuracy of our model, we also conducted a retrospective study on 30 AML patients and 13 healthy controls (bone marrow stem cell donor) from September 2019 to September 2022. Bone marrow mononuclear cells (BMNC) from our biobank were obtained, and the ten FRGs panel was applied. Results indicated that there was a significantly difference between normal control and AMLs in FRGs expression (Figure H), and the survival data of high-risk AML patients with higher FRGs level was significantly inferior than that in low-risk group as expected ( P<0.05) (Figure I). To search for possible therapeutic drugs for high-risk patients, we downloaded AMLs data from the GDSC database (https://www.cancerrxgene.org/) and calculated the IC50 of commonly used chemotherapeutic drugs. We found that bcl-2 inhibitor (Obatoclax Mesylate) and TKI (Gefitinib) may have less sensitivity in our high-risk group ( P<0.05), while some unconventional drugs (paclitaxe, dactinomycin, camptothecin, irinotecan and vinorelbine) may benefit in patients with higher FRGs expression (Figure J). In summary, we identified and validated 10 FRGs signature to well predict the prognosis and drug sensitivity of AML. Based on our findings, appropriate combination of new drugs at the time of treatment may achieve unexpected therapeutic outcomes, but still need to go through further verification.

Exploring the Roles of Arbuscular Mycorrhizal Fungi in Plant–Iron Homeostasis

Arbuscular mycorrhizal fungi (AMF) form a vital symbiotic relationship with plants. Through their extensive hyphal networks, AMF extend the absorptive capacity of plant roots, thereby allowing plants to reach otherwise inaccessible micronutrient sources. Iron, a critical micronutrient involved in photosynthesis and other metabolic processes, often becomes inaccessible owing to its tendency to form insoluble complexes in soil. AMF symbiosis significantly ameliorates this challenge by enhancing iron uptake and homeostasis in plants, altering root architecture, and producing root exudates that improve iron solubility. Moreover, the interaction with diverse soil bacteria, particularly plant growth-promoting rhizobacteria, can potentiate the benefits of AMF symbiosis. Siderophores are low-molecular-weight chelators with iron-binding capacities produced by various microorganisms and plant roots. They play pivotal roles in regulating intracellular iron and have been identified in different mycorrhizal associations, including AMF. While molecular mechanisms behind AMF-mediated iron uptake have been partially explored, the intricate networks involving AMF, plants, siderophores, and other soil microbiota are largely unknown. This review focuses on the multifaceted roles of AMF in plant–iron homeostasis, interactions with soil bacteria, and the potential of siderophores in these processes, emphasizing the possibilities for harnessing these relationships for sustainable agriculture and enhancing plant productivity.

Mitochondrial ATP and labile fe (II) pool simultaneous imaging in ferroptosis regulated by energy-stress mediated AMPK activation

Ferroptosis was a kind of widely-concerned cell death pathway to overcome drug-resistance in tumor therapies. Mitochondria, as the center of iron utilization and cell homeostasis, was studied for many years in the field of ferroptosis. Mitochondrial iron homeostasis was closely twisted with ATP production and energy stress. So, we developed a case of fluorescent probe with dual-emission to reveal the connection between ATP and LIP (liable iron (II) pool). We showed the enhanced iron uptake by extracellular ATP and activation of mitochondrial ATP in iron abundant environment through confocal fluorescence imaging in vitro and in vivo. For further research, we found and visualized the facilitation of ferroptosis by ATP and Fe2+ in ferroptosis-inert cell lines by ATP-Fe. Through confocal imaging of ATP-Fe, we also observed the morphology of cells and the mitochondrial ATP and LIP in ferroptosis regulated by energy-stress mediated AMPK activation or inhibition. Our research hinted that ATP-Fe could be a powerful tool to indicated iron homeostasis, mitochondrial morphology and metabolism in resolving ferroptosis-resistance and drug-resistance.

New Insights into Ferroptosis Initiating Therapies (FIT) by Targeting the Rewired Lipid Metabolism in Ovarian Cancer Peritoneal Metastases

Ovarian cancer is one of the most lethal gynecological cancers worldwide. The poor prognosis of this malignancy is substantially attributed to the inadequate symptomatic biomarkers for early diagnosis and effective remedies to cure the disease against chemoresistance and metastasis. Ovarian cancer metastasis is often relatively passive, and the single clusters of ovarian cancer cells detached from the primary ovarian tumor are transcoelomic spread by the peritoneal fluid throughout the peritoneum cavity and omentum. Our earlier studies revealed that lipid-enriched ascitic/omental microenvironment enforced metastatic ovarian cancer cells to undertake metabolic reprogramming and utilize free fatty acids as the main energy source for tumor progression and aggression. Intriguingly, cell susceptibility to ferroptosis has been tightly correlated with the dysregulated fatty acid metabolism (FAM), and enhanced iron uptake as the prominent features of ferroptosis are attributed to the strengthened lipid peroxidation and aberrant iron accumulation, suggesting that ferroptosis induction is a targetable vulnerability to prevent cancer metastasis. Therefore, the standpoints about tackling altered FAM in combination with ferroptosis initiation as a dual-targeted therapy against advanced ovarian cancer were highlighted herein. Furthermore, a discussion on the prospect and challenge of inducing ferroptosis as an innovative therapeutic approach for reversing remedial resistance in cancer interventions was included. It is hoped this proof-of-concept review will indicate appropriate directions for speeding up the translational application of ferroptosis-inducing compounds (FINs) to improve the efficacy of ovarian cancer treatment.

Artesunate inhibits osteoclast differentiation by inducing ferroptosis and prevents iron overload-induced bone loss.

Artemisinin compounds have been demonstrated to have anti-osteoporosis effects by inhibiting bone resorption. During osteoclast differentiation, osteoclasts take up a large amount of iron through transferrin receptor 1 (TfR1) mediated endocytosis of transferrin (Tf). Since iron-dependent cleavage of endoperoxide bridge is of great importance for the antimalarial effects of artemisinin compounds, we raised a hypothesis that the cytotoxic effects of artemisinin compounds on osteoclasts were associated with enhanced iron uptake. In the present study, we found that Tf aggravated the inhibitory effects of artesunate (ART) on osteoclast viability and differentiation. ART induced the production of malondialdehyde (MDA) and 4-hydroxynonenal (4-HNE) in a dose-dependent manner and led to the appearance of mitochondrial features of ferroptotic cells. TfR1 knockdown alleviated these cytotoxic effects of ART on osteoclasts. In addition, ART effectively prevented bone loss induced by iron overload. Our results indicate that ART inhibits iron-uptake stimulated osteoclast differentiation by inducing ferroptosis. Artemisinin compounds are potential drugs for treating iron overload-induced osteoporosis.

Iron overload in alcoholic liver disease: underlying mechanisms, detrimental effects, and potential therapeutic targets.

Alcoholic liver disease (ALD) is a global public health challenge due to the high incidence and lack of effective therapeutics. Evidence from animal studies and ALD patients has demonstrated that iron overload is a hallmark of ALD. Ethanol exposure can promote iron absorption by downregulating the hepcidin expression, which is probably mediated by inducing oxidative stress and promoting erythropoietin (EPO) production. In addition, ethanol may enhance iron uptake in hepatocytes by upregulating the expression of transferrin receptor (TfR). Iron overload in the liver can aggravate ethanol-elicited liver damage by potentiating oxidative stress via Fenton reaction, promoting activation of Kupffer cells (KCs) and hepatic stellate cells (HSCs), and inducing a recently discovered programmed iron-dependent cell death, ferroptosis. This article reviews the current knowledge of iron metabolism, regulators of iron homeostasis, the mechanism of ethanol-induced iron overload, detrimental effects of iron overload in the liver, and potential therapeutic targets.

Chlorophyll fluorescence as a light signal enhances iron uptake by the marine diatom Phaeodactylum tricornutum under high-cell density conditions

BackgroundDiatoms usually dominate phytoplankton blooms in open oceans, exhibiting extremely high population densities. Although the iron uptake rate of diatoms largely determines the magnitude and longevity of diatom blooms, the underlying mechanisms regulating iron uptake remain unclear.ResultsThe transcription of two iron uptake proteins, ISIP2a and ISIP1, in the marine diatom Phaeodactylum tricornutum was enhanced with increasing cell density, whereas the cellular iron content showed the opposite trend. When compared with the wild-type strain, knockdown of ISIP2a resulted in 43% decrease in cellular iron content, implying the involvement of ISIP2a in iron uptake under high-cell density conditions. Incubation of the diatom cells with sonicated cell lysate conditioned by different cell densities did not affect ISIP2a and ISIP1 expression, ruling out regulation via chemical cues. In contrast, ISIP2a and ISIP1 transcription were strongly induced by red light. Besides, chlorophyll fluorescence excited from the blue light was also positively correlated with population density. Subsequently, a “sandwich” illumination incubator was designed to filter out stray light and ensure that the inner layer cells only receive the emitted chlorophyll fluorescence from outer layers, and the results showed that the increase in outer cell density significantly elevated ISIP2a and ISIP1 transcription in inner layer cells. In situ evidence from Tara oceans also showed positively correlated between diatom ISIP transcripts and chlorophyll content.ConclusionsThis study shows that chlorophyll fluorescence derived from neighboring cells is able to upregulate ISIP2a and ISIP1 expression to facilitate iron assimilation under high-cell density. These results provide novel insights into biotic signal sensing in phytoplankton, which can help to elucidate the underlying mechanisms of marine diatom blooms.

CBIO-06. CELL INTRINSIC HFE DRIVES SEX-SPECIFIC GLIOBLASTOMA GROWTH

Abstract Iron is an essential element required for a number of cellular processes and can contribute to malignant transformation and tumor expansion. In glioblastoma (GBM), tumor cells have been shown to modulate expression of iron-associated proteins to enhance iron uptake from the surrounding microenvironment, driving proliferation and tumor growth. The homeostatic iron regulatory (HFE) gene encodes a transmembrane glycoprotein that aids in iron homeostasis by modulating iron uptake and release. HFE is upregulated in GBM tumors compared to non-tumor brain and expression of HFE increases with tumor grade. Furthermore, HFE mRNA expression is associated with significantly reduced survival specifically in female patients with GBM. However, it is unclear how HFE impacts sex-specific GBM growth. To interrogate the underlying mechanism of HFE-mediated sex differences, we employed genetic loss and gain of function approaches using syngeneic mouse glioma models. We observed significant alterations in the expression of several iron-associated genes with Hfe knockdown or overexpression, suggesting global disruption of iron homeostasis. We found that knockdown of Hfe decreased cell number and increased apoptosis in vitro and led to a significant impairment of tumor growth in vivo, with a more pronounced effect seen in female mice. Conversely, overexpression of Hfe increased cell number and significantly decreased survival only in female animals. These findings support the hypothesis that Hfe is a critical regulator of cellular iron status and contributes to tumor aggression in a sex-dependent manner. These data also suggest an unexplored link between cell intrinsic iron signaling and sex-specific microenvironmental and immune responses, which is the focus of ongoing studies.

Radiochemical Evidence for the Contribution of Chemotyped Siderophore Producing Bacteria Towards Plant Iron Nutrition.

Fe deficiency is a major challenge that limits agricultural productivity and is a serious human health concern worldwide. Under iron-limiting conditions soil microorganisms produce siderophores, that chelates Fe3+ (ferric) and make it available to the plants. Selection of efficient siderophore producing bacteria and establishing their role in enhancing iron uptake is a strategic approach for improving plant nutrition. Hence 3 efficient isolates Pantoea agglomerans, Pseudomonas plecoglossida and Lactococcus lactis, selected from a repository of 154 bacteria, producing catecholate, hydroxamate and carboxylate siderophores, respectively, were assessed for Fe chelation efficiency using 59Fe and their role in plant biometric parameters, Fe uptake and antioxidant enzymes with tomato (Strategy I) and wheat (Strategy II) test plants under hydroponic system. Cell-free siderophore preparation (Sid) improved plant parameters and iron nutrition more efficiently than bacterial inoculants. Pantoea agglomerans was proven best as its 59Fe-bound siderophore complex showed the highest uptake of 4.25 and 1.59Bq plant-1 in wheat and tomato, respectively. Further, the Fe-starved plants (1µm Fe-EDTA) showed around two-fold higher 59Fe uptake than those raised under Fe-sufficient condition (100µm Fe-EDTA). Results indicated that probably the bacterial mediated iron translocation in plants is Strategy III, complementing both Strategy I and II by facilitating higher availability of chelated Fe to plant reductases directly and/or through ligand exchange with phytosiderophores, respectively. This study highlights the need for integration of siderophore based formulations in INM strategies for enhancing plant iron content to address the Fe deficiency challenge of the soil and human nutrition.

Erratum: Liu et al., "S-Nitrosylation of Divalent Metal Transporter 1 Enhances Iron Uptake to Mediate Loss of Dopaminergic Neurons and Motoric Deficit".

In the article “S-Nitrosylation of Divalent Metal Transporter 1 Enhances Iron Uptake to Mediate Loss of Dopaminergic Neurons and Motoric Deficit,” by Chao Liu, Cheng-Wu Zhang, Shun Qiang Lo, Seok Ting Ang, Katherine Chee Meng Chew, Dejie Yu, Bing Han Chai, Bobby Tan, Fai Tsang, Yee Kit Tai,

Pulsed Electric Field (PEF) Enhances Iron Uptake by the Yeast Saccharomyces cerevisiae.

The aim of the study was to investigate the influence of a pulsed electric field (PEF) on the level of iron ion accumulation in Saccharomyces cerevisiae cells and to select PEF conditions optimal for the highest uptake of this element. Iron ions were accumulated most efficiently when their source was iron (III) nitrate. When the following conditions of PEF treatment were used: voltage 1500 V, pulse width 10 μs, treatment time 20 min, and a number of pulses 1200, accumulation of iron ions in the cells from a 20 h-culture reached a maximum value of 48.01 mg/g dry mass. Application of the optimal PEF conditions thus increased iron accumulation in cells by 157% as compared to the sample enriched with iron without PEF. The second derivative of the FTIR spectra of iron-loaded and -unloaded yeast cells allowed us to determine the functional groups which may be involved in metal ion binding. The exposure of cells to PEF treatment only slightly influenced the biomass and cell viability. However, iron-enriched yeast (both with or without PEF) showed lower fermentative activity than a control sample. Thus obtained yeast biomass containing a high amount of incorporated iron may serve as an alternative to pharmacological supplementation in the state of iron deficiency.

CBIO-10. REDUCED IRON EXPORT FUNCTIONS IN A CELL INTRINSIC MANNER TO DRIVE GLIOBLASTOMA GROWTH

Abstract Glioblastoma (GBM), the most common primary malignant brain tumor in adults, is characterized by invasive growth and poor prognosis. Iron is a critical regulator of many cellular processes, and GBM tumor cells have been shown to modulate expression of iron-associated proteins to enhance iron uptake from the surrounding microenvironment, driving tumor initiation and growth. While iron uptake has been the central focus of previous investigations, additional mechanisms of iron regulation, such as compensatory iron efflux, have not been explored in the context of GBM. The hemochromatosis (HFE) gene encodes a transmembrane glycoprotein that aids in iron homeostasis by limiting cellular iron release, resulting in a sequestration phenotype. We find that HFE is upregulated in GBM tumors compared to non-tumor brain and that expression of HFE increases with tumor grade. Furthermore, HFE mRNA expression is associated with significantly reduced survival specifically in female patients with GBM. Based on these findings, we hypothesize that GBM tumor cells upregulate HFE expression to augment cellular iron loading and drive proliferation, ultimately leading to reduced survival of female patients. To test this hypothesis, we generated Hfe knockdown and overexpressing mouse glioma cell lines. We observed significant alterations in the expression of several iron handling genes with Hfe knockdown or overexpression, suggesting global disruption of iron homeostasis. Additionally, we show that knockdown of Hfe in these cells increases apoptosis and leads to a significant impairment of tumor growth in vivo. These findings support the hypothesis that Hfe is a critical regulator of cellular iron status and contributes to tumor aggression. Future work will include further exploration of the mechanisms that contribute to these phenotypes as well as interactions with the tumor microenvironment. Elucidating the mechanisms by which iron effulx contributes to GBM may inform the development of next-generation targeted therapies.

Impact of Ascorbic Acid on the In Vitro Iron Bioavailability of a Casein-Based Iron Fortificant.

A new iron–casein complex (ICC) has been developed for iron (Fe) fortification of dairy matrices. The objective was to assess the impact of ascorbic acid (AA) on its in vitro bioavailability in comparison with ferrous sulfate (FeSO4) and ferric pyrophosphate (FePP). A simulated digestion coupled with the Caco-2 cell culture model was used in parallel with solubility and dissociation tests. Under diluted acidic conditions, the ICC was as soluble as FeSO4, but only part of the iron was found to dissociate from the caseins, indicating that the ICC was an iron chelate. The Caco-2 cell results in milk showed that the addition of AA (2:1 molar ratio) enhanced iron uptake from the ICCs and FeSO4 to a similar level (p = 0.582; p = 0.852) and to a significantly higher level than that from FePP (p < 0.01). This translated into a relative in vitro bioavailability to FeSO4 of 36% for FePP and 114 and 104% for the two ICCs. Similar results were obtained from water. Increasing the AA to iron molar ratio (4:1 molar ratio) had no additional effect on the ICCs and FePP. However, ICC absorption remained similar to that from FeSO4 (p = 0.666; p = 0.113), and was still significantly higher than that from FePP (p < 0.003). Therefore, even though iron from ICC does not fully dissociate under gastric digestion, iron uptake suggested that ICCs are absorbed to a similar amount as FeSO4 in the presence of AA and thus provide an excellent source of iron.