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

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.

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

Blood ◽

10.1182/blood.2020006987 ◽

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.

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

Clinical Science ◽

10.1042/cs20160072 ◽

2016 ◽

Vol 130 (11) ◽

pp. 853-870 ◽

Cited By ~ 35

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.

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

International Journal of Molecular Sciences ◽

10.3390/ijms21030916 ◽

2020 ◽

Vol 21 (3) ◽

pp. 916 ◽

Cited By ~ 8

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.

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Oxidative stress modulates rearrangement of endoplasmic reticulum-mitochondria contacts and calcium dysregulation in a Friedreich's ataxia model

Redox Biology ◽

10.1016/j.redox.2020.101762 ◽

2020 ◽

Vol 37 ◽

pp. 101762

Author(s):

Laura R. Rodríguez ◽

Pablo Calap-Quintana ◽

Tamara Lapeña-Luzón ◽

Federico V. Pallardó ◽

Stephan Schneuwly ◽

...

Keyword(s):

Oxidative Stress ◽

Endoplasmic Reticulum ◽

Friedreich’S Ataxia ◽

Friedreich's Ataxia ◽

Calcium Dysregulation

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

Oxidative Medicine and Cellular Longevity ◽

10.1155/2019/7623023 ◽

2019 ◽

Vol 2019 ◽

pp. 1-11 ◽

Cited By ~ 2

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.

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Deciphering Mitochondrial Iron Metabolism Using a Knockout Mouse.

Blood ◽

10.1182/blood.v114.22.1995.1995 ◽

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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