Hereditary Ataxia: A Focus on Heme Metabolism and Fe-S Cluster Biogenesis

Chiabrando, Deborah; Bertino, Francesca; Tolosano, Emanuela

doi:10.3390/ijms21113760

Cited by 16 publications

(13 citation statements)

References 172 publications

(215 reference statements)

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“…A low FXN expression, primarily caused by an abnormal GAA triplet repeat expansion in the first intron of the frataxin gene, is associated with the neurodegenerative disease Friedreich’s ataxia (FRDA; OMIM 229300) [ 1 ]; in addition, several FXN point mutations including nonsense, missense, insertions and deletions have been associated with compound heterozygous FRDA patients [ 1 , 2 , 3 , 4 ]. The main biochemical feature of FRDA is a large depletion of proteins relying on iron-sulphur clusters (ISC) for function (such as those of the mitochondrial respiratory chain complexes I, II and III or aconitase) with an accompanying increase in mitochondrial iron and oxidative stress [ 5 , 6 , 7 , 8 ].…”

Section: Introductionmentioning

confidence: 99%

Effects of Fe2+/Fe3+ Binding to Human Frataxin and Its D122Y Variant, as Revealed by Site-Directed Spin Labeling (SDSL) EPR Complemented by Fluorescence and Circular Dichroism Spectroscopies

Doni

Passerini

Audran

et al. 2020

IJMS

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Frataxin is a highly conserved protein whose deficiency results in the neurodegenerative disease Friederich’s ataxia. Frataxin’s actual physiological function has been debated for a long time without reaching a general agreement; however, it is commonly accepted that the protein is involved in the biosynthetic iron-sulphur cluster (ISC) machinery, and several authors have pointed out that it also participates in iron homeostasis. In this work, we use site-directed spin labeling coupled to electron paramagnetic resonance (SDSL EPR) to add new information on the effects of ferric and ferrous iron binding on the properties of human frataxin in vitro. Using SDSL EPR and relating the results to fluorescence experiments commonly performed to study iron binding to FXN, we produced evidence that ferric iron causes reversible aggregation without preferred interfaces in a concentration-dependent fashion, starting at relatively low concentrations (micromolar range), whereas ferrous iron binds without inducing aggregation. Moreover, our experiments show that the ferrous binding does not lead to changes of protein conformation. The data reported in this study reveal that the currently reported binding stoichiometries should be taken with caution. The use of a spin label resistant to reduction, as well as the comparison of the binding effect of Fe2+ in wild type and in the pathological D122Y variant of frataxin, allowed us to characterize the Fe2+ binding properties of different protein sites and highlight the effect of the D122Y substitution on the surrounding residues. We suggest that both Fe2+ and Fe3+ might play a relevant role in the context of the proposed FXN physiological functions.

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Section: Introductionmentioning

confidence: 99%

Effects of Fe2+/Fe3+ Binding to Human Frataxin and Its D122Y Variant, as Revealed by Site-Directed Spin Labeling (SDSL) EPR Complemented by Fluorescence and Circular Dichroism Spectroscopies

Doni

Passerini

Audran

et al. 2020

IJMS

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“…The principal function of frataxin is still unknown; however, the involvement of the FXN protein in iron-sulphur clusters (Fe-S clusters), heme group biosynthesis [ 66 ], and mitochondriogenesis [ 67 ] has been reported, although only the role of the FXN protein in Fe-S cluster biogenesis seems to be more convincing and extensively proved [ 68 ]. The generation of iron-sulphur clusters and their insertion in apoproteins is a complex process that involves many players located in mitochondria and cytosol and divided into three sequential steps.…”

Section: Thioredoxins and Glutaredoxins In Friedreich’s Ataxiamentioning

confidence: 99%

“…All these processes in which TRX and GRX participate in Fe-S cluster biogenesis, assembly and function seem to be very relevant in FRDA. Their function could be essential in a disease in which frataxin is deficient, since this protein has been proven to be involved in Fe-S cluster biogenesis [ 143 ] Therefore, correct Fe-S cluster biogenesis in mitochondria is intimately linked to cellular iron homeostasis, and failure in the assembly of mitochondrial Fe-S proteins upon frataxin deficiency results in increased iron import, availability and accumulation in mitochondria after the activation of IRP1 [ 68 ].…”

Section: Thioredoxins and Glutaredoxins In Friedreich’s Ataxiamentioning

confidence: 99%

Thioredoxin and Glutaredoxin Systems as Potential Targets for the Development of New Treatments in Friedreich’s Ataxia

et al. 2020

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The thioredoxin family consists of a small group of redox proteins present in all organisms and composed of thioredoxins (TRXs), glutaredoxins (GLRXs) and peroxiredoxins (PRDXs) which are found in the extracellular fluid, the cytoplasm, the mitochondria and in the nucleus with functions that include antioxidation, signaling and transcriptional control, among others. The importance of thioredoxin family proteins in neurodegenerative diseases is gaining relevance because some of these proteins have demonstrated an important role in the central nervous system by mediating neuroprotection against oxidative stress, contributing to mitochondrial function and regulating gene expression. Specifically, in the context of Friedreich’s ataxia (FRDA), thioredoxin family proteins may have a special role in the regulation of Nrf2 expression and function, in Fe-S cluster metabolism, controlling the expression of genes located at the iron-response element (IRE) and probably regulating ferroptosis. Therefore, comprehension of the mechanisms that closely link thioredoxin family proteins with cellular processes affected in FRDA will serve as a cornerstone to design improved therapeutic strategies.

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“…In human erythroid cells, the loss of mitoferrin-1 could induce heme synthesis defects due to impaired mitochondrial iron uptake [ 194 , 198 , 199 ], causing erythropoietic protoporphyria [ 200 , 201 ]. Moreover, the knockdown of mitoferrin-2 resulted in a decreased mitochondrial iron content in human epithelial cell lines [ 64 ], and its depletion in murine fibroblasts affected heme synthesis and mitochondrial Fe/S cluster assembly [ 202 ]. A similar effect was also observed for mitoferrin-1 depletion, indicating that both isoforms contribute to mitochondrial iron transport in non-erythroid cells [ 202 ].…”

Section: Drosophila Melanogaster Vs Human Mitomentioning

confidence: 99%

“…Moreover, the knockdown of mitoferrin-2 resulted in a decreased mitochondrial iron content in human epithelial cell lines [ 64 ], and its depletion in murine fibroblasts affected heme synthesis and mitochondrial Fe/S cluster assembly [ 202 ]. A similar effect was also observed for mitoferrin-1 depletion, indicating that both isoforms contribute to mitochondrial iron transport in non-erythroid cells [ 202 ]. On the other hand, mitoferrin-2 was found to be unable to restore heme synthesis in developing erythroid cells.…”

Section: Drosophila Melanogaster Vs Human Mitomentioning

confidence: 99%

Drosophila melanogaster Mitochondrial Carriers: Similarities and Differences with the Human Carriers

Curcio

Lunetti

Zara

et al. 2020

IJMS

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Mitochondrial carriers are a family of structurally related proteins responsible for the exchange of metabolites, cofactors and nucleotides between the cytoplasm and mitochondrial matrix. The in silico analysis of the Drosophila melanogaster genome has highlighted the presence of 48 genes encoding putative mitochondrial carriers, but only 20 have been functionally characterized. Despite most Drosophila mitochondrial carrier genes having human homologs and sharing with them 50% or higher sequence identity, D. melanogaster genes display peculiar differences from their human counterparts: (1) in the fruit fly, many genes encode more transcript isoforms or are duplicated, resulting in the presence of numerous subfamilies in the genome; (2) the expression of the energy-producing genes in D. melanogaster is coordinated from a motif known as Nuclear Respiratory Gene (NRG), a palindromic 8-bp sequence; (3) fruit-fly duplicated genes encoding mitochondrial carriers show a testis-biased expression pattern, probably in order to keep a duplicate copy in the genome. Here, we review the main features, biological activities and role in the metabolism of the D. melanogaster mitochondrial carriers characterized to date, highlighting similarities and differences with their human counterparts. Such knowledge is very important for obtaining an integrated view of mitochondrial function in D. melanogaster metabolism.

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Hereditary Ataxia: A Focus on Heme Metabolism and Fe-S Cluster Biogenesis

Cited by 16 publications

References 172 publications

Effects of Fe2+/Fe3+ Binding to Human Frataxin and Its D122Y Variant, as Revealed by Site-Directed Spin Labeling (SDSL) EPR Complemented by Fluorescence and Circular Dichroism Spectroscopies

Effects of Fe2+/Fe3+ Binding to Human Frataxin and Its D122Y Variant, as Revealed by Site-Directed Spin Labeling (SDSL) EPR Complemented by Fluorescence and Circular Dichroism Spectroscopies

Thioredoxin and Glutaredoxin Systems as Potential Targets for the Development of New Treatments in Friedreich’s Ataxia

Drosophila melanogaster Mitochondrial Carriers: Similarities and Differences with the Human Carriers

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