scholarly journals Extra-mitochondrial mouse frataxin and its implications for mouse models of Friedreich’s ataxia

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Liwei Weng ◽  
Laurent Laboureur ◽  
Qingqing Wang ◽  
Lili Guo ◽  
Peining Xu ◽  
...  
Keyword(s):  
Mitochondrial Dysfunction ◽  
Mouse Models ◽  
Human Subjects ◽  
Friedreich’S Ataxia ◽  
Friedreich's Ataxia ◽  
Mouse Heart ◽  
Mitochondrial Enzymes ◽  
Iron Sulfur Cluster ◽  
Mouse Tissues ◽  
Mature Mouse

Abstract Mature frataxin is essential for the assembly of iron–sulfur cluster proteins including a number of mitochondrial enzymes. Reduced levels of mature frataxin (81-20) in human subjects caused by the genetic disease Friedreich’s ataxia results in decreased mitochondrial function, neurodegeneration, and cardiomyopathy. Numerous studies of mitochondrial dysfunction have been conducted using mouse models of frataxin deficiency. However, mouse frataxin that is reduced in these models, is assumed to be mature frataxin (78-207) by analogy with human mature frataxin (81-210). Using immunoaffinity purification coupled with liquid chromatography-high resolution tandem mass spectrometry, we have discovered that mature frataxin in mouse heart (77%), brain (86%), and liver (47%) is predominantly a 129-amino acid truncated mature frataxin (79-207) in which the N-terminal lysine residue has been lost. Mature mouse frataxin (78-207) only contributes 7–15% to the total frataxin protein present in mouse tissues. We have also found that truncated mature frataxin (79-207) is present primarily in the cytosol of mouse liver; whereas, frataxin (78-207) is primarily present in the mitochondria. These findings, which provide support for the role of extra-mitochondrial frataxin in the etiology of Friedreich’s ataxia, also have important implications for studies of mitochondrial dysfunction conducted in mouse models of frataxin deficiency.

Mitochondrial dysfunction in the neuro-degenerative and cardio-degenerative disease, Friedreich's ataxia

2018 ◽  
Vol 117 ◽  
pp. 35-48 ◽  
Author(s):  
Shannon Chiang ◽  
Danuta S. Kalinowski ◽  
Patric J. Jansson ◽  
Des R. Richardson ◽  
Michael L.-H. Huang
Keyword(s):  
Mitochondrial Dysfunction ◽  
Friedreich’S Ataxia ◽  
Friedreich's Ataxia ◽  
Degenerative Disease

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.

Oxidative stress, mitochondrial dysfunction and cellular stress response in Friedreich's ataxia

2005 ◽  
Vol 233 (1-2) ◽  
pp. 145-162 ◽  
Author(s):  
Vittorio Calabrese ◽  
Raffaele Lodi ◽  
Caterina Tonon ◽  
Velia D'Agata ◽  
Maria Sapienza ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Stress Response ◽  
Mitochondrial Dysfunction ◽  
Cellular Stress ◽  
Friedreich’S Ataxia ◽  
Friedreich's Ataxia ◽  
Cellular Stress Response

Friedreich's ataxia protein: phylogenetic evidence for mitochondrial dysfunction

1996 ◽  
Vol 19 (11) ◽  
pp. 465-468 ◽  
Author(s):  
Toby J. Gibson ◽  
Eugene V. Koonin ◽  
Giovanna Musco ◽  
Annalisa Pastore ◽  
Peer Bork
Keyword(s):  
Mitochondrial Dysfunction ◽  
Friedreich’S Ataxia ◽  
Friedreich's Ataxia

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 Targeting NRF2 for the Treatment of Friedreich’s Ataxia: A Comparison among Drugs

2019 ◽  
Vol 20 (20) ◽  
pp. 5211 ◽  
Author(s):  
Sara Petrillo ◽  
Jessica D’Amico ◽  
Piergiorgio La Rosa ◽  
Enrico Silvio Bertini ◽  
Fiorella Piemonte
Keyword(s):  
Dimethyl Fumarate ◽  
Friedreich’S Ataxia ◽  
Nerve Fibers ◽  
Friedreich's Ataxia ◽  
Related Factor ◽  
Iron Sulfur Cluster ◽  
Redox Active ◽  
Nrf2 Activation ◽  
Clinical Benefits ◽  
Skin Biopsies

NRF2 (Nuclear factor Erythroid 2-related Factor 2) signaling is impaired in Friedreich’s Ataxia (FRDA), an autosomal recessive disease characterized by progressive nervous system damage and degeneration of nerve fibers in the spinal cord and peripheral nerves. The loss of frataxin in patients results in iron sulfur cluster deficiency and iron accumulation in the mitochondria, making FRDA a fatal and debilitating condition. There are no currently approved therapies for the treatment of FRDA and molecules able to activate NRF2 have the potential to induce clinical benefits in patients. In this study, we compared the efficacy of six redox-active drugs, some already adopted in clinical trials, targeting NRF2 activation and frataxin expression in fibroblasts obtained from skin biopsies of FRDA patients. All of these drugs consistently increased NRF2 expression, but differential profiles of NRF2 downstream genes were activated. The Sulforaphane and N-acetylcysteine were particularly effective on genes involved in preventing inflammation and maintaining glutathione homeostasis, the dimethyl fumarate, omaxevolone, and EPI-743 in counteracting toxic products accumulation, the idebenone in mitochondrial protection. This study may contribute to develop synergic therapies, based on a combination of treatment molecules.

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