Iron in Friedreich Ataxia: A Central Role in the Pathophysiology or an Epiphenomenon?

Alsina, David; Purroy, Rosa; Ros, Joaquim; Tamarit, Jordi

doi:10.3390/ph11030089

Cited by 35 publications

(35 citation statements)

References 97 publications

(123 reference statements)

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“…Friedrich's Ataxia is probably the most common form of this type of neurological diseases. Friedreich ataxia is a genetic disease caused by the deficiency of frataxin, a mitochondrial protein supposed to work such as a metal chaperone and iron storage protein [116]. Frataxin-deficient cells were often observed to be highly sensitive to oxidizing agents [117,118].…”

Section: Ros and Ataxiamentioning

confidence: 99%

“…However, looking at the mitochondrial iron pools, no differences were observed between controls or Friedrick's ataxia in human lymphoblasts or fibroblasts [119]. Nevertheless, some authors have suggested that oxidative stress could occur upstream (and not be the consequence) of iron-sulfur deficiency [116]. Undoubtedly, frataxin deficiency is reported to affect cell physiology at several levels, such as oxidative stress causing protein and DNA dysfunctions.…”

Section: Ros and Ataxiamentioning

confidence: 99%

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Role of Mesenchymal Stem Cells in Counteracting Oxidative Stress—Related Neurodegeneration

Angeloni

Gatti

Prata

et al. 2020

IJMS

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Neurodegenerative diseases include a variety of pathologies such as Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, amyotrophic lateral sclerosis, and so forth, which share many common characteristics such as oxidative stress, glycation, abnormal protein deposition, inflammation, and progressive neuronal loss. The last century has witnessed significant research to identify mechanisms and risk factors contributing to the complex etiopathogenesis of neurodegenerative diseases, such as genetic, vascular/metabolic, and lifestyle-related factors, which often co-occur and interact with each other. Apart from several environmental or genetic factors, in recent years, much evidence hints that impairment in redox homeostasis is a common mechanism in different neurological diseases. However, from a pharmacological perspective, oxidative stress is a difficult target, and antioxidants, the only strategy used so far, have been ineffective or even provoked side effects. In this review, we report an analysis of the recent literature on the role of oxidative stress in Alzheimer’s and Parkinson’s diseases as well as in amyotrophic lateral sclerosis, retinal ganglion cells, and ataxia. Moreover, the contribution of stem cells has been widely explored, looking at their potential in neuronal differentiation and reporting findings on their application in fighting oxidative stress in different neurodegenerative diseases. In particular, the exposure to mesenchymal stem cells or their secretome can be considered as a promising therapeutic strategy to enhance antioxidant capacity and neurotrophin expression while inhibiting pro-inflammatory cytokine secretion, which are common aspects of neurodegenerative pathologies. Further studies are needed to identify a tailored approach for each neurodegenerative disease in order to design more effective stem cell therapeutic strategies to prevent a broad range of neurodegenerative disorders.

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Section: Ros and Ataxiamentioning

confidence: 99%

Section: Ros and Ataxiamentioning

confidence: 99%

Role of Mesenchymal Stem Cells in Counteracting Oxidative Stress—Related Neurodegeneration

Angeloni

Gatti

Prata

et al. 2020

IJMS

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“…The results shown here reveal that FDX1 levels are significantly below of those found in normal DRG neurons or in FA lymphoblastoid cells (Figs, 1 and S1) thus supporting the rationale that calcitriol supplementation should be able to recover cell survival after frataxin depletion. Although we are aware that the explanation on how frataxin deficiency results in decreased FDX1 levels remains to be answered, deficiency in Fe/S cluster-containing proteins has been observed in several models of the disease [51,52].…”

Section: Discussionmentioning

confidence: 99%

Calcitriol increases frataxin levels and restores altered markers in cell models of Friedreich Ataxia

Britti¹,

Delaspre²,

Medina-Carbonero³

et al. 2020

Preprint

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Friedreich Ataxia (FA) is a neurodegenerative disease caused by the deficiency of frataxin, a mitochondrial protein. In primary cultures of dorsal root ganglia neurons, we showed that frataxin depletion resulted in decreased levels of the mitochondrial calcium exchanger NCLX, neurite degeneration and apoptotic cell death. Here we describe that frataxin-deficient dorsal root ganglia neurons display low levels of ferredoxin 1, a mitochondrial Fe/S cluster-containing protein that interacts with frataxin and, interestingly, is essential for the synthesis of calcitriol, the active form of vitamin D. We provide data that calcitriol supplementation, used at nanomolar concentrations, is able to reverse the molecular and cellular markers altered in DRG neurons. Calcitriol is able to recover both ferredoxin 1 and NCLX levels and restores mitochondrial membrane potential. Accordingly, apoptotic markers and neurite degeneration are reduced resulting in cell survival recovery with calcitriol supplementation. All these beneficial effects would be explained by the finding that calcitriol is able to increase the mature frataxin levels in both, frataxin-deficient DRG neurons and cardiomyocytes;remarkably, this increase also occurs in lymphoblastoid cell lines derived from FA patients. In conclusion, these results provide molecular bases to consider calcitriol for an easy and affordable therapeutic approach for FA patients.

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“…Indeed, although a decrease in heme synthesis has been reported in yeast and mouse frataxin mutants [ 104 , 105 ], no alterations were observed in FA erythroid progenitor stem cells, thus suggesting alternative mechanisms able to overcome the frataxin-related defects [ 106 ]. Despite this, to date, the frataxin involvement in the ISC biosynthesis remains the most credited function of the protein [ 107 ]. Frataxin would directly interact with the complex formed by the cysteine desulfurase NSF1 and the iron–sulfur cluster assembly enzyme ISCU (the major components of the ISC synthesis machinery) [ 108 ], although it is not clear whether frataxin may act as iron donor [ 109 ] or as an allosteric regulator [ 110 ].…”

Section: Ferroptosis In Neurodegeneration and In Friedreich’s Ataxmentioning

confidence: 99%

Ferroptosis in Friedreich’s Ataxia: A Metal-Induced Neurodegenerative Disease

et al. 2020

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Ferroptosis is an iron-dependent form of regulated cell death, arising from the accumulation of lipid-based reactive oxygen species when glutathione-dependent repair systems are compromised. Lipid peroxidation, mitochondrial impairment and iron dyshomeostasis are the hallmark of ferroptosis, which is emerging as a crucial player in neurodegeneration. This review provides an analysis of the most recent advances in ferroptosis, with a special focus on Friedreich’s Ataxia (FA), the most common autosomal recessive neurodegenerative disease, caused by reduced levels of frataxin, a mitochondrial protein involved in iron–sulfur cluster synthesis and antioxidant defenses. The hypothesis is that the iron-induced oxidative damage accumulates over time in FA, lowering the ferroptosis threshold and leading to neuronal cell death and, at last, to cardiac failure. The use of anti-ferroptosis drugs combined with treatments able to activate the antioxidant response will be of paramount importance in FA therapy, such as in many other neurodegenerative diseases triggered by oxidative stress.

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Iron in Friedreich Ataxia: A Central Role in the Pathophysiology or an Epiphenomenon?

Cited by 35 publications

References 97 publications

Role of Mesenchymal Stem Cells in Counteracting Oxidative Stress—Related Neurodegeneration

Role of Mesenchymal Stem Cells in Counteracting Oxidative Stress—Related Neurodegeneration

Calcitriol increases frataxin levels and restores altered markers in cell models of Friedreich Ataxia

Ferroptosis in Friedreich’s Ataxia: A Metal-Induced Neurodegenerative Disease

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