Defective palmitoylation of transferrin receptor triggers iron overload in Friedreich's ataxia fibroblasts

Blood ◽  
2021 ◽  
Author(s):  
Floriane Petit ◽  
Anthony Drecourt ◽  
Michaël Dussiot ◽  
Coralie Zangarelli ◽  
Olivier Hermine ◽  
...  
Keyword(s):  
Iron Overload ◽  
Transferrin Receptor ◽  
Iron Homeostasis ◽  
Mitochondrial Protein ◽  
Friedreich’S Ataxia ◽  
Friedreich's Ataxia ◽  
Gene Encoding ◽  
Iron Sulfur Cluster ◽  
The Road ◽  
Cellular Iron

Friedreich's ataxia (FRDA) is a frequent autosomal recessive disease caused by a GAA repeat expansion in the FXN gene encoding frataxin, a mitochondrial protein involved in iron-sulfur cluster (ISC) biogenesis. Resulting frataxin deficiency affects ISC-containing proteins and causes iron to accumulate in the brain and heart of FRDA patients. Here we report on abnormal cellular iron homeostasis in FRDA fibroblasts inducing a massive iron overload in the cytosol and mitochondria. We observe membrane transferrin receptor 1 (TfR1) accumulation, increased TfR1 endocytosis, and delayed transferrin recycling, ascribing this to impaired TfR1 palmitoylation. Frataxin deficiency is shown to reduce coenzyme A (CoA) availability for TfR1 palmitoylation. Finally, we demonstrate that artesunate, CoA, and dichloroacetate improve TfR1 palmitoylation and decrease iron overload, paving the road for evidence-based therapeutic strategies at the actionable level of TfR1 palmitoylation in FRDA.

scholarly journals Neurodegeneration in Friedreich’s Ataxia: From Defective Frataxin to Oxidative Stress

2013 ◽  
Vol 2013 ◽  
pp. 1-10 ◽  
Author(s):  
Cláudio M. Gomes ◽  
Renata Santos
Keyword(s):  
Oxidative Stress ◽  
Iron Homeostasis ◽  
Mitochondrial Protein ◽  
Friedreich’S Ataxia ◽  
Friedreich's Ataxia ◽  
Missense Mutations ◽  
Coding Region ◽  
Iron Sulfur Cluster ◽  
Central Nervous Systems ◽  
And Function

Friedreich’s ataxia is the most common inherited autosomal recessive ataxia and is characterized by progressive degeneration of the peripheral and central nervous systems and cardiomyopathy. This disease is caused by the silencing of theFXNgene and reduced levels of the encoded protein, frataxin. Frataxin is a mitochondrial protein that functions primarily in iron-sulfur cluster synthesis. This small protein with anα/βsandwich fold undergoes complex processing and imports into the mitochondria, generating isoforms with distinct N-terminal lengths which may underlie different functionalities, also in respect to oligomerization. Missense mutations in theFXNcoding region, which compromise protein folding, stability, and function, are found in 4% of FRDA heterozygous patients and are useful to understand how loss of functional frataxin impacts on FRDA physiopathology. In cells, frataxin deficiency leads to pleiotropic phenotypes, including deregulation of iron homeostasis and increased oxidative stress. Increasing amount of data suggest that oxidative stress contributes to neurodegeneration in Friedreich’s ataxia.

Frataxin and the molecular mechanism of mitochondrial iron-loading in Friedreich's ataxia

2016 ◽  
Vol 130 (11) ◽  
pp. 853-870 ◽  
Author(s):  
Shannon Chiang ◽  
Zaklina Kovacevic ◽  
Sumit Sahni ◽  
Darius J.R. Lane ◽  
Angelica M. Merlot ◽  
...  
Keyword(s):  
Iron Metabolism ◽  
Antioxidant Defense ◽  
Molecular Mechanisms ◽  
Mitochondrial Protein ◽  
Friedreich’S Ataxia ◽  
Friedreich's Ataxia ◽  
Iron Loading ◽  
Iron Sulfur Cluster ◽  
Cell Vitality ◽  
Mitochondrial Iron

The mitochondrion is a major site for the metabolism of the transition metal, iron, which is necessary for metabolic processes critical for cell vitality. The enigmatic mitochondrial protein, frataxin, is known to play a significant role in both cellular and mitochondrial iron metabolism due to its iron-binding properties and its involvement in iron–sulfur cluster (ISC) and heme synthesis. The inherited neuro- and cardio-degenerative disease, Friedreich's ataxia (FA), is caused by the deficient expression of frataxin that leads to deleterious alterations in iron metabolism. These changes lead to the accumulation of inorganic iron aggregates in the mitochondrial matrix that are presumed to play a key role in the oxidative damage and subsequent degenerative features of this disease. Furthermore, the concurrent dys-regulation of cellular antioxidant defense, which coincides with frataxin deficiency, exacerbates oxidative stress. Hence, the pathogenesis of FA underscores the importance of the integrated homeostasis of cellular iron metabolism and the cytoplasmic and mitochondrial redox environments. This review focuses on describing the pathogenesis of the disease, the molecular mechanisms involved in mitochondrial iron-loading and the dys-regulation of cellular antioxidant defense due to frataxin deficiency. In turn, current and emerging therapeutic strategies are also discussed.

scholarly journals The NRF2 Signaling Network Defines Clinical Biomarkers and Therapeutic Opportunity in Friedreich’s Ataxia

2020 ◽  
Vol 21 (3) ◽  
pp. 916 ◽  
Author(s):  
Piergiorgio La Rosa ◽  
Enrico Silvio Bertini ◽  
Fiorella Piemonte
Keyword(s):  
Cellular Response ◽  
Iron Homeostasis ◽  
Nuclear Translocation ◽  
Neurodegenerative Disorder ◽  
Mitochondrial Protein ◽  
Friedreich’S Ataxia ◽  
Friedreich's Ataxia ◽  
Signaling Network ◽  
Related Factor ◽  
Clinical Biomarkers

Friedreich’s ataxia (FA) is a trinucleotide repeats expansion neurodegenerative disorder, for which no cure or approved therapies are present. In most cases, GAA trinucleotide repetitions in the first intron of the FXN gene are the genetic trigger of FA, determining a strong reduction of frataxin, a mitochondrial protein involved in iron homeostasis. Frataxin depletion impairs iron–sulfur cluster biosynthesis and determines iron accumulation in the mitochondria. Mounting evidence suggests that these defects increase oxidative stress susceptibility and reactive oxygen species production in FA, where the pathologic picture is worsened by a defective regulation of the expression and signaling pathway modulation of the transcription factor NF-E2 p45-related factor 2 (NRF2), one of the fundamental mediators of the cellular antioxidant response. NRF2 protein downregulation and impairment of its nuclear translocation can compromise the adequate cellular response to the frataxin depletion-dependent redox imbalance. As NRF2 stability, expression, and activation can be modulated by diverse natural and synthetic compounds, efforts have been made in recent years to understand if regulating NRF2 signaling might ameliorate the pathologic defects in FA. Here we provide an analysis of the pharmaceutical interventions aimed at restoring the NRF2 signaling network in FA, elucidating specific biomarkers useful for monitoring therapeutic effectiveness, and developing new therapeutic tools.

scholarly journals Hepcidin in iron overload disorders

Blood ◽  
2005 ◽  
Vol 105 (10) ◽  
pp. 4103-4105 ◽  
Author(s):  
George Papanikolaou ◽  
Michalis Tzilianos ◽  
John I. Christakis ◽  
Dionisios Bogdanos ◽  
Konstantina Tsimirika ◽  
...  
Keyword(s):  
Iron Overload ◽  
Transferrin Receptor ◽  
Iron Homeostasis ◽  
Iron Absorption ◽  
Hereditary Hemochromatosis ◽  
Congenital Dyserythropoietic Anemia ◽  
Cellular Iron ◽  
Juvenile Hemochromatosis ◽  
Hepcidin Gene

Abstract Hepcidin is the principal regulator of iron absorption in humans. The peptide inhibits cellular iron efflux by binding to the iron export channel ferroportin and inducing its internalization and degradation. Either hepcidin deficiency or alterations in its target, ferroportin, would be expected to result in dysregulated iron absorption, tissue maldistribution of iron, and iron overload. Indeed, hepcidin deficiency has been reported in hereditary hemochromatosis and attributed to mutations in HFE, transferrin receptor 2, hemojuvelin, and the hepcidin gene itself. We measured urinary hepcidin in patients with other genetic causes of iron overload. Hepcidin was found to be suppressed in patients with thalassemia syndromes and congenital dyserythropoietic anemia type 1 and was undetectable in patients with juvenile hemochromatosis with HAMP mutations. Of interest, urine hepcidin levels were significantly elevated in 2 patients with hemochromatosis type 4. These findings extend the spectrum of iron disorders with hepcidin deficiency and underscore the critical importance of the hepcidin–ferroportin interaction in iron homeostasis.

scholarly journals Transferrin receptor is negatively modulated by the hemochromatosis protein HFE: Implications for cellular iron homeostasis

1999 ◽  
Vol 96 (10) ◽  
pp. 5434-5439 ◽  
Author(s):  
L. Salter-Cid ◽  
A. Brunmark ◽  
Y. Li ◽  
D. Leturcq ◽  
P. A. Peterson ◽  
...  
Keyword(s):  
Transferrin Receptor ◽  
Iron Homeostasis ◽  
Cellular Iron ◽  
Cellular Iron Homeostasis

scholarly journals SINEUP non-coding RNAs rescue defective frataxin expression and activity in a cellular model of Friedreich's Ataxia

2019 ◽  
Vol 47 (20) ◽  
pp. 10728-10743 ◽  
Author(s):  
Carlotta Bon ◽  
Riccardo Luffarelli ◽  
Roberta Russo ◽  
Silvia Fortuni ◽  
Bianca Pierattini ◽  
...  
Keyword(s):  
Genetic Defect ◽  
Friedreich’S Ataxia ◽  
Friedreich's Ataxia ◽  
Monogenic Disease ◽  
Transcriptional Level ◽  
Gene Encoding ◽  
Mitochondrial Aconitase ◽  
Non Coding Rnas ◽  
Gaa Repeats

Abstract Friedreich's ataxia (FRDA) is an untreatable disorder with neuro- and cardio-degenerative progression. This monogenic disease is caused by the hyper-expansion of naturally occurring GAA repeats in the first intron of the FXN gene, encoding for frataxin, a protein implicated in the biogenesis of iron-sulfur clusters. As the genetic defect interferes with FXN transcription, FRDA patients express a normal frataxin protein but at insufficient levels. Thus, current therapeutic strategies are mostly aimed to restore physiological FXN expression. We have previously described SINEUPs, natural and synthetic antisense long non-coding RNAs, which promote translation of partially overlapping mRNAs through the activity of an embedded SINEB2 domain. Here, by in vitro screening, we have identified a number of SINEUPs targeting human FXN mRNA and capable to up-regulate frataxin protein to physiological amounts acting at the post-transcriptional level. Furthermore, FXN-specific SINEUPs promote the recovery of disease-associated mitochondrial aconitase defects in FRDA-derived cells. In summary, we provide evidence that SINEUPs may be the first gene-specific therapeutic approach to activate FXN translation in FRDA and, more broadly, a novel scalable platform to develop new RNA-based therapies for haploinsufficient diseases.

scholarly journals New Insights into the Hepcidin-Ferroportin Axis and Iron Homeostasis in iPSC-Derived Cardiomyocytes from Friedreich’s Ataxia Patient

2019 ◽  
Vol 2019 ◽  
pp. 1-11 ◽  
Author(s):  
Alessandra Bolotta ◽  
Provvidenza Maria Abruzzo ◽  
Vito Antonio Baldassarro ◽  
Alessandro Ghezzo ◽  
Katia Scotlandi ◽  
...  
Keyword(s):  
Iron Homeostasis ◽  
Neurodegenerative Disorder ◽  
Cell Types ◽  
Friedreich’S Ataxia ◽  
Friedreich's Ataxia ◽  
Cardiac Cells ◽  
Cardiac Differentiation ◽  
Specific Cell ◽  
Differentiation Markers ◽  
Cardiac Iron

Iron homeostasis in the cardiac tissue as well as the involvement of the hepcidin-ferroportin (HAMP-FPN) axis in this process and in cardiac functionality are not fully understood. Imbalance of iron homeostasis occurs in several cardiac diseases, including iron-overload cardiomyopathies such as Friedreich’s ataxia (FRDA, OMIM no. 229300), a hereditary neurodegenerative disorder. Exploiting the induced pluripotent stem cells (iPSCs) technology and the iPSC capacity to differentiate into specific cell types, we derived cardiomyocytes of a FRDA patient and of a healthy control subject in order to study the cardiac iron homeostasis and the HAMP-FPN axis. Both CTR and FRDA iPSCs-derived cardiomyocytes express cardiac differentiation markers; in addition, FRDA cardiomyocytes maintain the FRDA-like phenotype. We found that FRDA cardiomyocytes show an increase in the protein expression of HAMP and FPN. Moreover, immunofluorescence analysis revealed for the first time an unexpected nuclear localization of FPN in both CTR and FRDA cardiomyocytes. However, the amount of the nuclear FPN was less in FRDA cardiomyocytes than in controls. These and other data suggest that iron handling and the HAMP-FPN axis regulation in FRDA cardiac cells are hampered and that FPN may have new, still not fully understood, functions. These findings underline the complexity of the cardiac iron homeostasis.

Deciphering Mitochondrial Iron Metabolism Using a Knockout Mouse.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 1995-1995
Author(s):  
Michael Huang ◽  
Erika Becker ◽  
Megan Whitnall ◽  
Yohan Suryo Rahmanto ◽  
Prem Ponka ◽  
...  
Keyword(s):  
Iron Metabolism ◽  
Iron Uptake ◽  
Knockout Mouse ◽  
Friedreich’S Ataxia ◽  
Friedreich's Ataxia ◽  
Down Regulation ◽  
Iron Sulfur Cluster ◽  
Sulfur Cluster ◽  
Iron Sulfur ◽  
Mitochondrial Iron

Abstract Abstract 1995 Poster Board I-1017 We utilized the muscle creatine kinase conditional frataxin knockout mouse to elucidate how frataxin-deficiency alters iron metabolism. This is of significance since frataxin-deficiency leads to the neuro- and cardio-degenerative disease, Friedreich's ataxia. Using cardiac tissues, we demonstrate that frataxin-deficiency leads to down-regulation of key molecules involved in three mitochondrial utilization pathways: iron-sulfur cluster (ISC) synthesis (iron-sulfur cluster scaffold protein1/2 and the cysteine desulferase, Nfs1); mitochondrial-iron storage (mitochondrial ferritin); and heme synthesis (5-aminolevulinate dehydratase, coproporphyrinogen oxidase, hydroxymethylbilane synthase, uroporphyrinogen III synthase and ferrochelatase). This marked decrease in mitochondrial-iron utilization and resultant reduced release of heme and ISC from the mitochondrion could contribute to the excess mitochondrial-iron observed. Indeed, this effect is compounded by increased iron availability for mitochondrial uptake through: (1) transferrin receptor1 up-regulation that increases iron uptake from transferrin; (2) decreased ferroportin1 expression, limiting iron export; (3) increased expression of the heme catabolism enzyme, heme oxygenase1, and down-regulation of ferritin-H and —L, both of which likely lead to increased “free iron” for mitochondrial uptake; and (4) increased expression of the mammalian exocyst protein, Sec15l1, and the mitochondrial-iron importer, mitoferrin-2 (Mfrn2), that facilitate cellular iron uptake and mitochondrial-iron influx, respectively. This study enables construction of a model explaining the cytosolic iron-deficiency and mitochondrial-iron-loading in the absence of frataxin that is important for understanding the pathogenesis of Friedreich's ataxia. Disclosures: No relevant conflicts of interest to declare.

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