Iron and hepcidin: a story of recycling and balance

Hematology ◽  
2013 ◽  
Vol 2013 (1) ◽  
pp. 1-8 ◽  
Author(s):  
Clara Camaschella
Keyword(s):  
Iron Deficiency ◽  
Iron Overload ◽  
Iron Homeostasis ◽  
Inflammatory Diseases ◽  
Beta Thalassemia ◽  
Genetic Inactivation ◽  
Cellular Iron ◽  
Iron Sequestration ◽  
Total Body

Abstract To avoid iron deficiency and overload, iron availability is tightly regulated at both the cellular and systemic levels. The liver peptide hepcidin controls iron flux to plasma from enterocytes and macrophages through degradation of the cellular iron exporter ferroportin. The hepcidin-ferroportin axis is essential to maintaining iron homeostasis. Genetic inactivation of proteins of the hepcidin-activating pathway causes iron overload of varying severity in human and mice. Hepcidin insufficiency and increased iron absorption are also characteristic of anemia due to ineffective erythropoiesis in which, despite high total body iron, hepcidin is suppressed by the high erythropoietic activity, worsening both iron overload and anemia in a vicious cycle. Hepcidin excess resulting from genetic inactivation of a hepcidin inhibitor, the transmembrane protease serine 6 (TMPRSS6) leads to a form of iron deficiency refractory to oral iron. Increased hepcidin explains the iron sequestration and iron-restricted erythropoiesis of anemia associated with chronic inflammatory diseases. In mice, deletion of TMPRSS6 in vivo has profound effects on the iron phenotype of hemochromatosis and beta-thalassemia. Hepcidin manipulation to restrict iron is a successful strategy to improve erythropoiesis in thalassemia, as shown clearly in preclinical studies targeting TMPRSS6; attempts to control anemia of chronic diseases by antagonizing the hepcidin effect are ongoing. Finally, the metabolic pathways identified from iron disorders are now being explored in other human pathologic conditions, including cancer.

scholarly journals Ferroportin deficiency in erythroid cells causes serum iron deficiency and promotes hemolysis due to oxidative stress

Blood ◽  
2018 ◽  
Vol 132 (19) ◽  
pp. 2078-2087 ◽  
Author(s):  
De-Liang Zhang ◽  
Manik C. Ghosh ◽  
Hayden Ollivierre ◽  
Yan Li ◽  
Tracey A. Rouault
Keyword(s):  
Oxidative Stress ◽  
Iron Deficiency ◽  
Iron Overload ◽  
Serum Iron ◽  
Iron Homeostasis ◽  
Erythroid Cells ◽  
Loss Of Function ◽  
Hepatic Cells ◽  
Tissue Iron

Abstract Ferroportin (FPN), the only known vertebrate iron exporter, transports iron from intestinal, splenic, and hepatic cells into the blood to provide iron to other tissues and cells in vivo. Most of the circulating iron is consumed by erythroid cells to synthesize hemoglobin. Here we found that erythroid cells not only consumed large amounts of iron, but also returned significant amounts of iron to the blood. Erythroblast-specific Fpn knockout (Fpn KO) mice developed lower serum iron levels in conjunction with tissue iron overload and increased FPN expression in spleen and liver without changing hepcidin levels. Our results also showed that Fpn KO mice, which suffer from mild hemolytic anemia, were sensitive to phenylhydrazine-induced oxidative stress but were able to tolerate iron deficiency upon exposure to a low-iron diet and phlebotomy, supporting that the anemia of Fpn KO mice resulted from erythrocytic iron overload and resulting oxidative injury rather than a red blood cell (RBC) production defect. Moreover, we found that the mean corpuscular volume (MCV) values of gain-of-function FPN mutation patients were positively associated with serum transferrin saturations, whereas MCVs of loss-of-function FPN mutation patients were not, supporting that erythroblasts donate iron to blood through FPN in response to serum iron levels. Our results indicate that FPN of erythroid cells plays an unexpectedly essential role in maintaining systemic iron homeostasis and protecting RBCs from oxidative stress, providing insight into the pathophysiology of FPN diseases.

scholarly journals Is Tmprss6 Required for Hepcidin Inhibition By Erythroferrone?

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 1347-1347 ◽  
Author(s):  
Laura Silvestri ◽  
Grazia Rita Gelsomino ◽  
Antonella Nai ◽  
Marco Rausa ◽  
Alessia Pagani ◽  
...  
Keyword(s):  
Iron Deficiency ◽  
Iron Overload ◽  
Double Mutant ◽  
Iron Homeostasis ◽  
Conflicts Of Interest ◽  
Beta Thalassemia ◽  
The European Union ◽  
Ineffective Erythropoiesis ◽  
Deficient Diet ◽  
Iron Deficient

Abstract Introduction Hepcidin, the main regulator of iron homeostasis, is inhibited when erythropoiesis is expanded. Several candidates, as GDF15 and TWSG1, have been proposed to mediate this effect but their role remains unproven. Recently, erythroferrone (ERFE), a member of the C1q/tumors necrosis factor-related protein family, has been identified as a new hepcidin inhibitor (Kautz et al., 2014). ERFE is an erythropoietin (EPO) target gene produced by bone marrow and spleen erythroblasts in conditions of stress erythropoiesis, as after bleeding or EPO treatment, and in ineffective erythropoiesis, as in beta thalassemia. Inhibiting hepatocyte hepcidin, ERFE coordinates erythroid differentiation with iron availability. In beta-thalassemia Hbbth3/+ mice, inactivation of Erfe partially reduces liver iron content, suggesting that increased Erfe production contributes to thalassemia iron overload (Kautz et al., 2014). Here we analyzed spleen Erfe expression in models of low (iron loaded Hjv-/- and Tfr2-/- mice) and high (iron deficient, Tmprss6-/- mice) hepcidin, in secondary iron overload (Hbbth3/+ mice), in Hbbth3/+ Tmprss6-/- and Tfr2-/- Tmprss6-/- double mutants and in mice with a diet-induced iron deficiency. Methods Mice were maintained in accordance with the European Union guidelines. The study was approved by the IACUC of San Raffaele Scientific Institute, Milan, Italy. Hjv-/-, Tfr2-/-, Tmprss6-/- and double mutant (Tfr2-/- Tmprss6-/- or Hbbth3/+ Tmprss6-/-) adult male mice were studied. A group of adult wild type mice was maintained an iron-deficient diet (ID, <3 mg/kg iron) for 3 weeks. Appropriate controls were studied. Gene expression levels were measured by quantitative real-time-PCR. Hematological and iron parameters and serum erythropoietin were studied using standard procedures. Results We confirm that Erfe is increased in the spleen of Hbbth3/+ mice, characterized by anemia, ineffective erythropoiesis, high EPO, low hepcidin and iron overload. Erfe is upregulated also in Tmprss6-/- iron deficient animals, consistent with their increased serum Epo. However, their high hepcidin levels suggest that Tmprss6 is indispensable for Erfe-mediated hepcidin inhibition. Consistent with this interpretation, in Hbbth3/+Tmprss6-/- double mutant mice, in which ineffective erythropoiesis and anemia are partially rescued (Nai et al., 2012), hepcidin levels are higher than in Hbbth3/+ and comparable to those of Tmprss6-/- mice, although Erfe remains high and serum Epo levels are similarly increased in all the three genotypes (Tmprss6-/-, Hbbth3/+, Hbbth3/+Tmprss6-/-). To further confirm the need of Tmprss6 for Erfe function, in diet-induced iron deficient animals, in which Tmprss6 is supposed to be active, Erfe expression is increased and hepcidin strongly downregulated. In the spleen of Hjv-/- and Tfr2-/- mice, the expression of the erythroid markers Tfr1 and Glycophorin A (Gypa) is decreased, suggesting that splenic erythropoiesis is reduced in iron overload. In agreement Erfe is downregulated in Tfr2-/- and mildly decreased in Hjv-/- mice. Genetic inactivation of Tmprss6 in Tfr2-/- mice enhances Erfe, Tfr1 and Gypa expression and serum Epo to levels comparable to Tmprss6-/- mice and increases hepcidin although at levels lower than those found in Tmprss6-/-. Conclusions Erfe upregulation in iron deficiency indicates that it is a general mediator of hepcidin inhibition. In Tmprss6-/- mice, notwithstanding Erfe upregulation, hepcidin levels are not suppressed, suggesting that Erfe acts upstream Tmprss6, although results in the double mutant Tfr2-/-Tmprss6-/- require further studies. In disease models of iron overload Erfe expression is downregulated, consistent with decreased splenic erythropoiesis. The mechanisms of hepcidin inhibition by Erfe still remain to be investigated. Disclosures No relevant conflicts of interest to declare.

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

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii17-ii17
Author(s):  
Katie Troike ◽  
Erin Mulkearns-Hubert ◽  
Daniel Silver ◽  
James Connor ◽  
Justin Lathia
Keyword(s):  
Tumor Cells ◽  
Iron Uptake ◽  
Iron Homeostasis ◽  
Iron Status ◽  
Tumor Grade ◽  
Hfe Gene ◽  
Iron Release ◽  
Female Patients ◽  
Cellular Iron

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.

Iron Homeostasis and Disorders in Dogs and Cats: A Review

2011 ◽  
Vol 47 (3) ◽  
pp. 151-160 ◽  
Author(s):  
Jennifer L. McCown ◽  
Andrew J. Specht
Keyword(s):  
Iron Deficiency ◽  
Iron Overload ◽  
Iron Homeostasis ◽  
Diagnostic Testing ◽  
Clinical Manifestations ◽  
Essential Element ◽  
The Body ◽  
Deficiency Anemia ◽  
Enzyme Systems ◽  
Living Organisms

Iron is an essential element for nearly all living organisms and disruption of iron homeostasis can lead to a number of clinical manifestations. Iron is used in the formation of both hemoglobin and myoglobin, as well as numerous enzyme systems of the body. Disorders of iron in the body include iron deficiency anemia, anemia of inflammatory disease, and iron overload. This article reviews normal iron metabolism, disease syndromes of iron imbalance, diagnostic testing, and treatment of either iron deficiency or excess. Recent advances in diagnosing iron deficiency using reticulocyte indices are reviewed.

scholarly journals Liver iron sensing and body iron homeostasis

Blood ◽  
2019 ◽  
Vol 133 (1) ◽  
pp. 18-29 ◽  
Author(s):  
Chia-Yu Wang ◽  
Jodie L. Babitt
Keyword(s):  
Iron Deficiency ◽  
Iron Homeostasis ◽  
Inflammatory Diseases ◽  
Genetic Disorders ◽  
Hereditary Hemochromatosis ◽  
Deficiency Anemia ◽  
Iron Loading ◽  
Liver Iron ◽  
Body Iron ◽  
Iron Supply

Abstract The liver orchestrates systemic iron balance by producing and secreting hepcidin. Known as the iron hormone, hepcidin induces degradation of the iron exporter ferroportin to control iron entry into the bloodstream from dietary sources, iron recycling macrophages, and body stores. Under physiologic conditions, hepcidin production is reduced by iron deficiency and erythropoietic drive to increase the iron supply when needed to support red blood cell production and other essential functions. Conversely, hepcidin production is induced by iron loading and inflammation to prevent the toxicity of iron excess and limit its availability to pathogens. The inability to appropriately regulate hepcidin production in response to these physiologic cues underlies genetic disorders of iron overload and deficiency, including hereditary hemochromatosis and iron-refractory iron deficiency anemia. Moreover, excess hepcidin suppression in the setting of ineffective erythropoiesis contributes to iron-loading anemias such as β-thalassemia, whereas excess hepcidin induction contributes to iron-restricted erythropoiesis and anemia in chronic inflammatory diseases. These diseases have provided key insights into understanding the mechanisms by which the liver senses plasma and tissue iron levels, the iron demand of erythrocyte precursors, and the presence of potential pathogens and, importantly, how these various signals are integrated to appropriately regulate hepcidin production. This review will focus on recent insights into how the liver senses body iron levels and coordinates this with other signals to regulate hepcidin production and systemic iron homeostasis.

scholarly journals Iron Deficiency as a Therapeutic Target in Cardiovascular Disease

2019 ◽  
Vol 12 (3) ◽  
pp. 125 ◽  
Author(s):  
Samira Lakhal-Littleton
Keyword(s):  
Heart Failure ◽  
Cardiovascular Disease ◽  
Cardiovascular Diseases ◽  
Chronic Heart Failure ◽  
Iron Deficiency ◽  
Iron Supplementation ◽  
Iron Homeostasis ◽  
Iron Regulatory Proteins ◽  
Cellular Iron ◽  
Cellular Iron Homeostasis

Iron deficiency is the most common nutritional disorder in the world. It is prevalent amongst patients with cardiovascular disease, in whom it is associated with worse clinical outcomes. The benefits of iron supplementation have been established in chronic heart failure, but data on their effectiveness in other cardiovascular diseases are lacking or conflicting. Realising the potential of iron therapies in cardiovascular disease requires understanding of the mechanisms through which iron deficiency affects cardiovascular function, and the cell types in which such mechanisms operate. That understanding has been enhanced by recent insights into the roles of hepcidin and iron regulatory proteins (IRPs) in cellular iron homeostasis within cardiovascular cells. These studies identify intracellular iron deficiency within the cardiovascular tissue as an important contributor to the disease process, and present novel therapeutic strategies based on targeting the machinery of cellular iron homeostasis rather than direct iron supplementation. This review discusses these new insights and their wider implications for the treatment of cardiovascular diseases, focusing on two disease conditions: chronic heart failure and pulmonary arterial hypertension.

Does Gene Therapy in Beta Thalassemia Normalize Novel Markers of Ineffective Erythropoiesis and Iron Homeostasis?

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 816-816 ◽  
Author(s):  
Alexis A. Thompson ◽  
Tomas Ganz ◽  
Mary Therese Forsyth ◽  
Elizabeta Nemeth ◽  
Sherif M. Badawy
Keyword(s):  
Gene Therapy ◽  
Stem Cell ◽  
Iron Overload ◽  
Serum Ferritin ◽  
Research Funding ◽  
Iron Homeostasis ◽  
Beta Thalassemia ◽  
Ineffective Erythropoiesis ◽  
Liver Iron ◽  
Equity Ownership

BACKGROUND: Ineffective erythropoiesis in thalassemia alters iron homeostasis, predisposing to systemic iron overload. Successful allogeneic hematopoietic stem cell transplantation (HSCT) in thalassemia major corrects anemia, should eliminate ineffective erythropoiesis (IE) and normalize iron homeostasis (IH). Whether gene therapy (GT) will fully correct IE and IH is not known. This cross-sectional observational study evaluated the iron status of patients with beta thalassemia following HSCT or GT, and compared them with cohorts of patients with thalassemia intermedia (TI) or transfusion-dependent thalassemia (TDT) using recently introduced biomarkers along with imaging studies and other clinical assessments to better understand and characterize IE and IH across groups. METHODS: We evaluated a convenience sample of 29 participants with beta thalassemia (median age 25 years, IQR 21-35; females 55%; Asian 52%). Participants in the HSCT (n=6) and GT (n=10) groups were evaluated on average 116.5 and 46.9 months following cell infusion, respectively. TDT patients (n= 9) were evaluated pre-transfusion and off iron chelation for at least 7 days, and TI (n=4) were un-transfused or not transfused in &gt;3 years. Clinical lab assessments and MRI R2*/ T2* to assess heart and liver iron burden including post-processing, were performed using local clinical protocols. ELISAs for hepcidin, erythroferrone (Erfe) and GDF-15 were performed in a blinded manner. RESULTS: Median values for all IE and IH parameters tested were normal in the HSCT group, and were significantly lower than in all other groups. There were significant differences among all groups for hemoglobin (p=0.003), erythropoietin (Epo) (p=0.03), serum ferritin (SF) (p=0.01), transferrin (p=0.006), soluble transferrin receptor (sTfR) (p=0.02), serum hepcidin: serum ferritin (H:F) ratio (p=0.006), Erfe (p=0.001), GDF15 (p=0.003), and liver iron content (LIC) by MRI R2* (p=0.02). H:F ratio, a surrogate for predisposition to systemic iron loading, inversely correlated with Erfe (rs= -0.85, p&lt;0.0001), GDF15 (rs= -0.69, p=0.0001) and liver R2* (rs= -0.66, p=0.0004). In a multivariate analysis, adjusted for gender and race, H:F ratio and Epo levels predicted Erfe and GDF15 (p=0.05 and p=0.06; p=0.01 and p=0.05), respectively. Even after excluding GT patients that are not transfusion independent (N=2), SF, Epo, sTfR and hepcidin remain abnormal in the GT group, and there were no significant differences in these parameters between GT and TDT. However, novel biomarkers of IH and IE suggested lower ineffective erythropoiesis in GT compared to TDT (median (IQR) Erfe, 12 (11.6-25.2) vs. 39.6 (24.5-54.7), p=0.03; GDF15, 1909.9 (1389-4431) vs. 8906 (4421-12331), p=0.02), respectively. Erfe and GDF15 were also lower in GT compared to TI, however these differences did not reach statistical significance. There were no differences in hepcidin, ferritin, or H:F by race, however Erfe and GDF15 were significantly lower in Asians compared to non-Asians (p=0.006 and p=0.02, respectively). CONCLUSION: Nearly 4 years post infusion, most subjects with TDT treated with GT are transfusion independent with near normal hemoglobin, however, studies in this limited cohort using conventional measures suggest IE and IH improve, particularly when transfusion support is no longer needed, however they remain abnormal compared to HSCT recipients, who using these parameters appear to be cured. STfR did not detect differences, however GDF15 and Erfe were more sensitive assays that could demonstrate significant improvement in IE and IH with GT compared to TDT. Contribution to IE by uncorrected stem cell populations post GT cannot be determined. Transduction enhancement and other recent improvements to GT may yield different results. Longitudinal studies are needed to determine if thalassemia patients treated with GT will have ongoing IE predisposing to systemic iron overload. Disclosures Thompson: bluebird bio, Inc.: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Baxalta: Research Funding. Ganz:Intrinsic LifeSciences: Consultancy, Equity Ownership. Nemeth:Intrinsic LifeSciences: Consultancy, Equity Ownership; Silarus Therapeutics: Consultancy, Equity Ownership; Keryx: Consultancy; Ionis Pharmaceuticals: Consultancy; La Jolla Pharma: Consultancy; Protagonist: Consultancy.

Down Regulation of Hepcidin and Interleukin 1-Alpha in Pbmc from Patients with Beta thalassemia

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 2880-2880
Author(s):  
Maria-Eliana Lai ◽  
Stefania Vacquer ◽  
Maria Paola Carta ◽  
Claudia Mulas ◽  
Pierluigi Cocco ◽  
...  
Keyword(s):  
Iron Overload ◽  
Iron Homeostasis ◽  
Mononuclear Cells ◽  
Interleukin 1 ◽  
Diagnostic Tools ◽  
Beta Thalassemia ◽  
Blood Transfusions ◽  
Mrna Levels ◽  
Down Regulation ◽  
Hepcidin Mrna

Abstract Thalassemia is an inherited blood disease characterized by low levels or absence of normal globin chains. Severe forms of thalassemia, thalassemia major (TM), require regular blood transfusions, the main cause of secondary hemosyderosis. However, iron overload is a potential complication, even in patients (pts) with thalassemia intermedia (TI), who do not require transfusions. Among them, iron overload is mainly the result of an excessive absorption of dietary iron, caused by a down-regulation of hepcidin, an hepatic hormone that acts as a major regulator of systemic iron homeostasis. Very low mRNA levels of hepcidin have been reported in urine as well as in liver biopsies from patients with TI. It has been also reported that, interleukin-1 alpha (IL-1α) stimulates hepcidin transcription, raising the question as to whether a down-regulation of this cytokine may be responsible, at least partially, for the excessive iron absorption occurring in patients with TI. Here, we assessed whether IL-1α was involved in hepcidin regulation in β-thalassemia. Peripheral blood mononuclear cells (PBMCs) were isolated from 6 TM pts, 8 TI pts and 6 controls. mRNA was obtained from PBMCs by RT-PCR. Hepcidin mRNA levels were reduced in both TM and TI pts when compared to the age matched normal controls. Neverthless, hepcidin mRNA levels were significantly lower in TI pts, as compared to TM pts receiving regular blood transfusions. Among TI pts lower hepcidin mRNA level was associated with lower level of IL-α. Tumor necrosis factor alpha (TNF-α) does not seem to be involved in the regulation of hepcidin transcription. Interestingly, the levels of mRNA expression of acyl-CoA-cholesterol acyltransferase (ACAT), the enzyme responsible for intracellular cholesterol ester accumulation, and thus, for atherosclerotic plaque formation were strongly induced in PBMCs in TI pts. These results suggest that PBMCs hepcidin and IL-1-α measurements could possibly be used in the future as simple, ease and sensible diagnostic tools for the detection of iron overload in patients with thalassemia. ACAT expression may even be used as therapeutic target in preventing atherosclerotic complications such as pulmonary thromboembolism, cerebral thrombosis, and leg ulcers. frequently occurring in such patients.

scholarly journals Iron-deficiency anemia from matriptase-2 inactivation is dependent on the presence of functional Bmp6

Blood ◽  
2011 ◽  
Vol 117 (2) ◽  
pp. 647-650 ◽  
Author(s):  
Anne Lenoir ◽  
Jean-Christophe Deschemin ◽  
Léon Kautz ◽  
Andrew J. Ramsay ◽  
Marie-Paule Roth ◽  
...  
Keyword(s):  
Iron Deficiency ◽  
Iron Overload ◽  
Serine Protease ◽  
Iron Deficiency Anemia ◽  
Iron Homeostasis ◽  
Deficiency Anemia ◽  
Hepatic Iron ◽  
Master Regulator ◽  
Liver Iron ◽  
The Relationship

Abstract Hepcidin is the master regulator of iron homeostasis. In the liver, iron-dependent hepcidin activation is regulated through Bmp6 and its membrane receptor hemojuvelin (Hjv), whereas, in response to iron deficiency, hepcidin repression seems to be controlled by a pathway involving the serine protease matriptase-2 (encoded by Tmprss6). To determine the relationship between Bmp6 and matriptase-2 pathways, Tmprss6−/− mice (characterized by increased hepcidin levels and anemia) and Bmp6−/− mice (exhibiting severe iron overload because of hepcidin deficiency) were intercrossed. We showed that loss of Bmp6 decreased hepcidin levels; increased hepatic iron; and, importantly, corrected hematologic abnormalities in Tmprss6−/− mice. This finding suggests that elevated hepcidin levels in patients with familial iron-refractory, iron-deficiency anemia are the result of excess signaling through the Bmp6/Hjv pathway.

scholarly journals Impaired lysosomal acidification triggers iron deficiency, necrotic cell death and inflammationin vivo

2019 ◽  
Author(s):  
King Faisal Yambire ◽  
Christine Rostosky ◽  
Takashi Watanabe ◽  
David Pacheu-Grau ◽  
Sylvia Torres-Odio ◽  
...  
Keyword(s):  
Cell Death ◽  
Iron Deficiency ◽  
Necrotic Cell Death ◽  
Primary Neurons ◽  
Resonance Imaging ◽  
Necrotic Cell ◽  
Cellular Iron ◽  
The Brain ◽  
Lysosomal Acidification

SUMMARYLysosomal acidification is a key feature of healthy cells. Inability to maintain lysosomal acidic pH is associated with aging and neurodegenerative diseases. However, the mechanisms elicited by impaired lysosomal acidification remain unknown. We show here that inhibition of lysosomal acidification triggers cellular iron deficiency, which results in impaired mitochondrial function and necrotic cell death. These effects are recovered by supplying iron via a lysosome-independent pathway. Notably, iron deficiency is sufficient to trigger inflammatory signaling in cultured primary neurons. Using a mouse model of impaired lysosomal acidification, we observed a robust iron deficiency response in the brain, verified byin vivomagnetic resonance imaging. Furthermore, the brains of these mice present a pervasive inflammatory signature associated with instability of mitochondrial DNA (mtDNA), both corrected by supplementation of the mice diet with iron. Our results highlight a novel mechanism linking lysosomal dysfunction, mitochondrial malfunction and inflammationin vivo.

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