Esther G. Meyron‐Holtz

Technion – Israel Institute of Technology

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Tracey A. Rouault

Eunice Kennedy Shriver National Institute of Child Health and Human Development

Kuanyu Li

Nanjing University

Abraham M. Konijn

Hadassah Medical Center

Lulu Fahoum

Technion – Israel Institute of Technology

Hongting Zhao

Hangzhou Dianzi University

Fanis Missirlis

Center for Research and Advanced Studies of the National Polytechnic Institute

Tianze Xu

Nanjing Drum Tower Hospital

Lei Wang

Nanjing Drum Tower Hospital

Jing Cai

Union Hospital

Lyora A. Cohen

Technion – Israel Institute of Technology

Cooperative Institutions

Technion – Israel Institute of Technology

National Institutes of Health

Hebrew University of Jerusalem

Nanjing University

Eunice Kennedy Shriver National Institute of Child Health and Human Development

Rappaport Family Institute for Research in the Medical Sciences

University of Giessen

Tel Aviv University

Ben-Gurion University of the Negev

Nanjing Medical University

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Iron regulatory protein deficiency compromises mitochondrial function in murine embryonic fibroblasts

Scientific Reports (2018)

Huihui Li Hongting Zhao Shuangying Hao Longcheng Shang Jing Wu

Abstract Iron is essential for growth and proliferation of mammalian cells. The maintenance of cellular iron homeostasis is regulated by iron regulatory proteins (IRPs) through binding to the cognate iron-responsive elements in target mRNAs and thereby regulating the expression of target genes. Irp1 or Irp2 -null mutation is known to reduce the cellular iron level by decreasing transferrin receptor 1 and increasing ferritin. Here, we report that Irp1 or Irp2 -null mutation also causes downregulation of frataxin and IscU, two of the core components in the iron-sulfur cluster biogenesis machinery. Interestingly, while the activities of some of iron-sulfur cluster-containing enzymes including mitochondrial aconitase and cytosolic xanthine oxidase were not affected by the mutations, the activities of respiratory chain complexes were drastically diminished resulting in mitochondrial dysfunction. Overexpression of human ISCU and frataxin in Irp1 or Irp2 -null cells was able to rescue the defects in iron-sulfur cluster biogenesis and mitochondrial quality. Our results strongly suggest that iron regulatory proteins regulate the part of iron sulfur cluster biogenesis tailored specifically for mitochondrial electron transport chain complexes.

Iron–sulfur cluster

Frataxin

Transferrin receptor

Ferroportin

10.1038/s41598-018-23175-y

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Citations (38)

Mitochondrial ferritin deficiency reduces male fertility in mice

Reproduction Fertility and Development (2017)

Federica Maccarinelli Maria Regoni Fernando Carmona Maura Poli Esther G. Meyron‐Holtz

Mitochondrial ferritin (FtMt) is a functional ferritin targeted to mitochondria that is highly expressed in the testis. To investigate the role of FtMt in the testis we set up a series of controlled matings between FtMt gene-deletion mice (FtMt–/–) with FtMt+/+ mice. We found that the number of newborns per litter and the fertility rate were strongly reduced for the FtMt–/– males, but not for the females, indicating that FtMt has an important role for male fertility. The morphology of the testis and of the spermatozoa of FtMt–/– mice was normal and we did not detect alterations in sperm parameters or in oxidative stress indices. In contrast, we observed that the cauda epididymides of FtMt–/– mice were significantly lighter and contained a lower number of spermatozoa compared with the controls. Also, the ATP content of FtMt–/– spermatozoa was found to be lower than that of FtMt+/+ spermatozoa. These data show that FtMt contributes to sperm epididymis maturation and to male fertility.

10.1071/rd16348

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Citations (15)

Expression of the iron transporter ferroportin in synaptic vesicles and the blood–brain barrier

Brain Research (2004)

Laura Wu A. G. Miriam Leenders Sharon Cooperman Esther G. Meyron‐Holtz Sophia R. Smith

Ferroportin

Ependymal Cell

DMT1

Transferrin receptor

Immunoelectron microscopy

Homeostasis

10.1016/j.brainres.2003.10.066

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Citations (205)

Availability of Ferritin-Bound Iron to Enterobacteriaceae

International Journal of Molecular Sciences (2022)

Clemens M. Gehrer Alexander Hoffmann Richard Hilbe Philipp Grubwieser Anna‐Maria Mitterstiller

The sequestration of iron in case of infection, termed nutritional immunity, is an established strategy of host defense. However, the interaction between pathogens and the mammalian iron storage protein ferritin is hitherto not completely understood. To better characterize the function of ferritin in Gram-negative infections, we incubated iron-starved cultures of Salmonella Typhimurium and knockout mutant strains defective for major iron uptake pathways or Escherichia coli with horse spleen ferritin or ionic iron as the sole iron source. Additionally, we added bovine superoxide dismutase and protease inhibitors to the growth medium to assess the effect of superoxide and bacterial proteases, respectively, on Salmonella proliferation and reductive iron release. Compared to free ionic iron, ferritin-bound iron was less available to Salmonella, but was still sufficient to significantly enhance the growth of the bacteria. In the absence of various iron acquisition genes, the availability of ferritin iron further decreased. Supplementation with superoxide dismutase significantly reduced the growth of the ΔentC knockout strain with holoferritin as the sole iron source in comparison with ionic ferrous iron. In contrast, this difference was not observed in the wildtype strain, suggesting that superoxide dismutase undermines bacterial iron uptake from ferritin by siderophore-independent mechanisms. Ferritin seems to diminish iron availability for bacteria in comparison to ionic iron, and its iron sequestering effect could possibly be enhanced by host superoxide dismutase activity.

10.3390/ijms232113087

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The Hyperferritinemic Syndrome: macrophage activation syndrome, Still’s disease, septic shock and catastrophic antiphospholipid syndrome

BMC Medicine (2013)

Cristina Rosário Gisele Zandman‐Goddard Esther G. Meyron‐Holtz David D’Cruz Yehuda Shoenfeld

Over the last few years, accumulating data have implicated a role for ferritin as a signaling molecule and direct mediator of the immune system. Hyperferritinemia is associated with a multitude of clinical conditions and with worse prognosis in critically ill patients.There are four uncommon medical conditions characterized by high levels of ferritin, namely the macrophage activation syndrome (MAS), adult onset Still's disease (AOSD), catastrophic antiphospholipid syndrome (cAPS) and septic shock, that share a similar clinical and laboratory features, and also respond to similar treatments, suggesting a common pathogenic mechanism. Ferritin is known to be a pro-inflammatory mediator inducing expression of pro-inflammatory molecules, yet it has opposing actions as a pro-inflammatory and as an immunosuppressant. We propose that the exceptionally high ferritin levels observed in these uncommon clinical conditions are not just the product of the inflammation but rather may contribute to the development of a cytokine storm.Here we review and compare four clinical conditions and the role of ferritin as an immunomodulator. We would like to propose including these four conditions under a common syndrome entity termed "Hyperferritinemic Syndrome".

Macrophage Activation Syndrome

Cytokine Storm

Toxic shock syndrome

Pathophysiology

Catastrophic antiphospholipid syndrome

10.1186/1741-7015-11-185

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Citations (431)

Harnessing proteins to control crystal size and morphology, for improved delivery performance of hydrophobic bioactives, using genistein as a model

Food Hydrocolloids (2016)

Gal Israeli-Lev Marina Pitchkhadze Sahar Nevo Lulu Fahoum Esther G. Meyron‐Holtz

Hydrophobin

Hydrophobic effect

10.1016/j.foodhyd.2016.08.026

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Citations (17)

A newly identified ferritin L‐subunit variant results in increased proteasomal subunit degradation, impaired complex assembly, and severe hypoferritinemia

American Journal of Hematology (2023)

Dayana Shagidov Noga Guttmann‐Raviv Séverine Cunat Liora Frech Muriel Giansily‐Blaizot

Abstract Ferritin is a hetero‐oligomeric nanocage, composed of 24 subunits of two types, FTH1 and FTL. It protects the cell from excess reactive iron, by storing iron in its cavity. FTH1 is essential for the recruitment of iron into the ferritin nanocage and for cellular ferritin trafficking, whereas FTL contributes to nanocage stability and iron nucleation inside the cavity. Here we describe a female patient with a medical history of severe hypoferritinemia without anemia. Following inadequate heavy IV iron supplementation, the patient developed severe iron overload and musculoskeletal manifestations. However, her serum ferritin levels rose only to normal range. Genetic analyses revealed an undescribed homozygous variant of FTL (c.92A > G), which resulted in a Tyr31Cys substitution (FTL Y31C ). Analysis of the FTL structure predicted that the Y31C mutation will reduce the variant's stability. Expression of the FTL Y31C variant resulted in significantly lower cellular ferritin levels compared with the expression of wild‐type FTL (FTL WT ). Proteasomal inhibition significantly increased the initial levels of FTL Y31C , but could not protect FTL Y31C subunits from successive degradation. Further, variant subunits successfully incorporated into hetero‐polymeric nanocages in the presence of sufficient levels of FTH1. However, FTL Y31C subunits poorly assembled into nanocages when FTH1 subunit levels were low. These results indicate an increased susceptibility of unassembled monomeric FTL Y31C subunits to proteasomal degradation. The decreased cellular assembly of FTL Y31C ‐rich nanocages may explain the low serum ferritin levels in this patient and emphasize the importance of a broader diagnostic approach of hypoferritinemia without anemia, before IV iron supplementation.

Nanocages

10.1002/ajh.27124

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Citations (1)

Serum ferritin is derived primarily from macrophages through a nonclassical secretory pathway

Blood (2010)

Lyora A. Cohen Lucía Gutiérrez Avital Weiss Yael Leichtmann‐Bardoogo De‐Liang Zhang

10.1182/blood-2009-11-253815

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Citations (419)

Digestive fate of dietary carrageenan: Evidence of interference with digestive proteolysis and disruption of gut epithelial function

Molecular Nutrition & Food Research (2016)

Lulu Fahoum Alice Moscovici Shlomit David Ron Shaoul Geila S. Rozen

Scope The objective of this study was to interrogate two mechanisms by which commercial Carrageenans (E407) (CGN) may adversely affect human health: (i) Through modification of gastric proteolysis and (ii) Through affecting gut epithelial structure and function. Methods and results Three commercial CGN samples with distinct zeta‐potentials (stable at the pH range of 3–7 and varied with physiological levels of CaCl 2 ) were mixed with milk, soy or egg protein isolates, then subjected to a semi‐dynamic in vitro digestion model and analyzed by SDS‐PAGE. This revealed varying levels of interference with gastric digestive proteolysis and a significant decrease in pepsin activity. Further, a Caco‐2 cell model was used to explore various effects of physiologically digested CGN (pdCGN) on various epithelial cell functions and characteristics. Samples of pdCGN (0.005–0.5 mg/mL) affected the epithelial barrier function, including redistribution of the tight‐junction protein Zonula Occludens (Zo)‐1, changes in cellular F‐actin architecture and increased monolayer permeability to the transfer of macromolecules. Moreover, pdCGN induced elevation in the levels of the pro‐inflammatory IL‐8 receptor CXCR1. Conclusion This work raises the possibility that CGN may reduce protein and peptide bioaccessibility, disrupt normal epithelial function, promote intestinal inflammation, and consequently compromise consumer health.

Proteolysis

Barrier function

Caco-2

Pepsin

Digestion

10.1002/mnfr.201600545

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Citations (65)

Reviewer #2 (Public Review): Aging-related iron deposit prevents the benefits of HRT from late postmenopausal atherosclerosis

Tianze Xu Jing Cai Lei Wang Li Xu Hongting Zhao

Postmenopausal atherosclerosis has been attributed to estrogen deficiency. The beneficial effect of hormone replacement therapy (HRT), however, is lost in late postmenopausal women with atherogenesis. We asked whether aging-related iron accumulation affects estrogen receptor α (ERα) expression explaining HRT inefficacy. A negative correlation between aging-related systemic iron deposition and ERα expression in postmenopausal AS patients was established. In an ovariectomized ApoE-/- mouse model, estradiol treatment had contrasting effects on ERα expression in early versus late postmenopausal mice. ERα expression was inhibited by iron treatment in cell culture and iron-overloaded mice. Combined treatment with estradiol and iron further decreased ERα expression, mediated by iron-regulated E3 ligase Mdm2. In line with these observations, cellular cholesterol efflux was reduced and endothelial homeostasis was disrupted and, consequently, atherosclerosis was aggravated. Accordingly, systemic iron chelation attenuated estradiol-triggered progressive atherosclerosis in late postmenopausal mice. Thus, iron and estradiol together downregulate ERα through Mdm2-mediated proteolysis, explaining failures of HRT in late postmenopausal subjects with aging-related iron accumulation. HRT is recommended immediately after menopause along with appropriate iron chelation to protect from atherosclerosis.

10.7554/elife.80494.1.sa1

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Citations (0)