Affinage

FXN

Frataxin, mitochondrial · UniProt Q16595

Round 2 corrected
Length
210 aa
Mass
23.1 kDa
Annotated
2026-04-28
130 papers in source corpus 35 papers cited in narrative 35 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

Frataxin is an essential nuclear-encoded mitochondrial protein that functions as an allosteric activator of the NFS1/ISD11/ISCU cysteine desulfurase complex, dramatically increasing its catalytic efficiency for sulfur mobilization during iron-sulfur (Fe-S) cluster biosynthesis, and simultaneously serves as an iron chaperone that delivers ferrous iron to both the ISCU scaffold (for Fe-S cluster assembly) and ferrochelatase (for the terminal step of heme biosynthesis) (PMID:20873749, PMID:12785837, PMID:15123683). Frataxin also protects the [4Fe-4S] cluster of aconitase from oxidative inactivation and can reactivate the damaged [3Fe-4S] form, linking it to mitochondrial redox homeostasis (PMID:15247478). Loss-of-function caused by homozygous GAA trinucleotide repeat expansion in FXN intron 1—which silences transcription through R-loop-triggered heterochromatin formation (increased H3K9 methylation, decreased acetylation) and RNA polymerase II elongation block—causes Friedreich's ataxia, characterized by deficient Fe-S enzyme activities, mitochondrial iron accumulation, and oxidative damage (PMID:8596916, PMID:21745819, PMID:24787137, PMID:9326946).

Mechanistic history

Synthesis pass · year-by-year structured walk · 9 steps
  1. 1996 High

    Positional cloning identified FXN (X25) as the causative gene for Friedreich's ataxia, revealing that the majority of patients carry homozygous GAA trinucleotide repeat expansions in intron 1, establishing the molecular basis of the disease.

    Evidence Positional cloning, sequencing, and GAA repeat analysis in FRDA families

    PMID:8596916

    Open questions at the time
    • Protein function entirely unknown at this point
    • Mechanism by which GAA expansion causes disease not established
  2. 1997 High

    Frataxin was localized to mitochondria and its loss shown to cause mitochondrial iron accumulation and deficient Fe-S enzyme activities, establishing it as a mitochondrial iron homeostasis factor and Friedreich's ataxia as a mitochondrial disease.

    Evidence Immunocytofluorescence, immunoelectron microscopy, yeast YFH1 knockout, enzyme activity assays in patient tissue and yeast, cross-species complementation

    PMID:9180083 PMID:9241270 PMID:9302253 PMID:9326946

    Open questions at the time
    • Direct biochemical function of frataxin not yet defined
    • Whether iron accumulation is primary or secondary to Fe-S cluster deficiency not resolved
  3. 2000 High

    Crystal structures of human frataxin and its bacterial ortholog CyaY revealed a conserved αβ-sandwich fold with a contiguous anionic surface predicted to mediate iron binding and protein-protein interactions, providing a structural framework for understanding disease mutations.

    Evidence X-ray crystallography at 1.8 Å (human) and 1.4 Å (E. coli CyaY)

    PMID:10900192 PMID:10908679

    Open questions at the time
    • Iron binding stoichiometry and affinity not yet quantified
    • Identity of physiological protein partners not determined
  4. 2003 High

    Frataxin was shown to bind iron with defined stoichiometry and deliver it to the ISU scaffold protein to support [2Fe-2S] cluster assembly in vitro, establishing its role as an iron donor for Fe-S cluster biosynthesis.

    Evidence Isothermal titration calorimetry, fluorescence spectroscopy, in vitro reconstitution of Fe-S cluster assembly

    PMID:12785837

    Open questions at the time
    • Whether frataxin is solely an iron donor or also regulates the desulfurase was unknown
    • In vivo validation of iron chaperone function in mammalian cells not yet performed
  5. 2004 High

    Frataxin was demonstrated to function as an iron chaperone for both aconitase (protecting and reactivating its [4Fe-4S] cluster) and ferrochelatase (delivering iron for heme biosynthesis), broadening its role beyond Fe-S cluster assembly to general mitochondrial iron utilization.

    Evidence Co-immunoprecipitation, in vitro reconstitution of aconitase reactivation, ferrochelatase iron delivery assays

    PMID:15123683 PMID:15247478

    Open questions at the time
    • Relative physiological importance of iron chaperone versus regulatory roles not resolved
    • RNAi in human cells showed Fe-S deficiency but no heme deficiency, questioning in vivo relevance of ferrochelatase delivery
  6. 2010 High

    A paradigm shift established frataxin as an allosteric activator of the NFS1/ISD11/ISCU cysteine desulfurase complex, increasing catalytic efficiency ~300-fold, resolving the apparent contradiction between bacterial CyaY (inhibitor) and eukaryotic frataxin function.

    Evidence In vitro enzyme kinetics with reconstituted human NFS1/ISD11/ISCU complex ± frataxin

    PMID:20873749

    Open questions at the time
    • Structural basis for how frataxin binding allosterically activates NFS1 not defined
    • Why bacterial CyaY inhibits while human frataxin activates the same reaction remains mechanistically unexplained
  7. 2011 High

    The silencing mechanism of expanded GAA repeats was dissected: R-loops form at the expanded repeat, triggering heterochromatin formation (H3K9me2) that blocks RNA Pol II elongation rather than transcription initiation, establishing the epigenetic cascade underlying FXN silencing in Friedreich's ataxia.

    Evidence ChIP for RNA Pol II, H3K9me2, and R-loop immunofluorescence in patient cells; GFP reporter with 560 GAA repeats; pharmacological perturbation with camptothecin

    PMID:18045775 PMID:21745819 PMID:24787137

    Open questions at the time
    • Whether therapeutic reversal of R-loops or heterochromatin can restore frataxin levels in patients
    • Contribution of DNA methylation versus histone modifications to silencing not fully deconvolved
  8. 2017 High

    The crystal structure of the complete NFS1-ISD11-ACP-ISCU complex defined the 3D architecture into which frataxin integrates, and protein replacement therapy with TAT-delivered frataxin rescued Fe-S enzyme activity and extended lifespan in FRDA mouse models, providing proof-of-concept for therapeutic frataxin restoration.

    Evidence X-ray crystallography and SAXS of the biosynthetic complex; TAT-MTScs-FXN protein delivery in mouse models with biochemical and survival endpoints

    PMID:28980774 PMID:29097656

    Open questions at the time
    • Cryo-EM or crystal structure of frataxin bound within the complete biosynthetic complex not yet reported
    • Scalability and pharmacokinetics of protein replacement therapy for human translation unknown
  9. 2020 Medium

    Post-transcriptional regulation of FXN was established through identification of multiple miRNAs (miR-124, miR-145, miR-224-5p) that directly target the FXN 3'-UTR, with miR-224-5p levels mechanistically linked to the GAA expansion itself.

    Evidence Luciferase reporter assays, miRNA sequencing, ZFN-mediated GAA excision in FRDA cells

    PMID:23382970 PMID:26717909 PMID:32291635

    Open questions at the time
    • Relative contribution of miRNA-mediated versus transcriptional silencing to frataxin deficiency in patients not quantified
    • Therapeutic potential of anti-miR strategies not tested in vivo

Open questions

Synthesis pass · forward-looking unresolved questions
  • A high-resolution structure of frataxin bound within the complete NFS1/ISD11/ACP/ISCU complex is needed to explain the molecular basis of allosteric activation, and the physiological hierarchy among frataxin's iron chaperone, Fe-S assembly activator, and potential iron storage functions remains unresolved.
  • No atomic-resolution structure of frataxin engaged with the full biosynthetic complex
  • Mechanistic basis for opposing effects of bacterial CyaY (inhibition) versus human frataxin (activation) on desulfurase not structurally resolved
  • In vivo relevance of frataxin oligomerization and iron storage function unclear

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0008289 lipid binding 3 GO:0140104 molecular carrier activity 3 GO:0060090 molecular adaptor activity 2 GO:0098772 molecular function regulator activity 2
Localization
GO:0005739 mitochondrion 3
Pathway
R-HSA-1430728 Metabolism 6 R-HSA-1643685 Disease 4
Partners
ACO2FECHISCUISD11NFS1
Complex memberships
NFS1/ISD11/ACP/ISCU Fe-S cluster biosynthetic complex

Evidence

Reading pass · 35 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1996 The FXN gene (X25) encodes a 210-amino acid protein, frataxin, and the majority of Friedreich's ataxia patients are homozygous for an unstable GAA trinucleotide repeat expansion in its first intron, with a minority carrying point mutations; frataxin has homologs in C. elegans and yeast. Positional cloning, sequencing, GAA repeat analysis, cross-species homology Science High 8596916
1997 Frataxin is a mitochondrial protein; immunocytofluorescence and immunoelectron microscopy localize it to mitochondrial membranes and crests, and the first 20 amino acids encode the mitochondrial targeting sequence that is cleaved during maturation to produce an 18 kDa processed form severely reduced in FRDA patients. Immunocytofluorescence, immunoelectron microscopy, Western blot with monoclonal antibodies, truncation expression experiments Human molecular genetics High 9302253
1997 Frataxin deficiency results in deficient activity of Fe-S cluster-containing subunits of mitochondrial respiratory complexes I, II, and III, and of aconitase, in endomyocardial biopsies of FRDA patients; disruption of yeast YFH1 (frataxin homolog) causes the same Fe-S enzyme deficiencies, linking frataxin to Fe-S cluster biogenesis. Enzyme activity assays on patient biopsy tissue and yeast YFH1 knockout Nature genetics High 9326946
1997 The yeast frataxin homolog YFH1 encodes a mitochondrial protein required for mitochondrial iron homeostasis and respiratory function; YFH1 deletion causes mitochondrial iron accumulation; the YFH1-homologous domain of human frataxin can functionally substitute in yeast, and a disease-associated missense mutation reduces this function. Yeast genetics (gene deletion, complementation), mitochondrial iron measurement, respiratory growth assays, domain swapping Science High 9180083
1997 Mouse and yeast frataxin homologs contain mitochondrial targeting sequences in their N-terminal domains; disruption of the yeast gene causes mitochondrial dysfunction; human frataxin co-localizes with a mitochondrial marker in tagging experiments, confirming Friedreich's ataxia as a mitochondrial disease from a nuclear gene mutation. In situ hybridization, yeast gene disruption, mitochondrial co-localization tagging Nature genetics High 9241270
1997 YFH1-deleted yeast lose mitochondrial DNA and respiratory function; the YFH1 protein localizes to mitochondria and is required for maintenance of mitochondrial DNA; a disease-associated missense mutation in the YFH1-homologous domain reduces function. Yeast genetics, mitochondrial DNA analysis, respiratory assays, localization Nature genetics High 9241271
2000 Crystal structure of human frataxin at 1.8 Å resolution reveals a novel alphabeta sandwich fold: a five-stranded antiparallel beta-sheet supporting two parallel alpha-helices; a cluster of 12 acidic residues forms a contiguous anionic surface predicted to mediate iron and protein-protein binding; disease-associated mutations map to this anionic patch, a second conserved surface, or the hydrophobic core. X-ray crystallography at 1.8 Å resolution The Journal of biological chemistry High 10900192
2000 Crystal structure of E. coli frataxin ortholog CyaY at 1.4 Å resolution reveals the same conserved fold (six-stranded antiparallel beta-sheet flanked by two alpha-helices), establishing that this fold is shared across the frataxin family and providing a framework for interpreting disease mutations. X-ray crystallography at 1.4 Å resolution Proceedings of the National Academy of Sciences of the United States of America High 10908679
2001 Frataxin expression rescue in FRDA lymphoblasts restores mitochondrial membrane potential and reduces elevated filtrable mitochondrial iron; FRDA cells are hypersensitive to oxidative stress from free iron/H2O2 (Fenton mechanism), and this sensitivity is rescued by frataxin overexpression; aconitase and isocitrate dehydrogenase activities are also rescued, supporting frataxin's role in mitochondrial iron homeostasis. Transfection/rescue experiments, mitochondrial membrane potential measurement, mitochondrial iron measurement, enzyme activity assays, oxidative stress challenge Human molecular genetics High 11590127
2002 Human frataxin expressed in E. coli assembles into stable ~1 MDa homopolymers that bind ~10 iron atoms per frataxin molecule; iron-loaded polymers are detectable on non-denaturing gels; in yeast, mature frataxin partitions into monomeric and high-molecular-weight (>600 kDa) pools with ~5 Fe atoms per molecule, and similar high-MW pools exist in mouse heart, suggesting iron storage function. Gel filtration, electron microscopy, non-denaturing PAGE, iron staining, radiolabeled iron immunoprecipitation Human molecular genetics High 11823441
2003 Human frataxin binds 6–7 ferric iron ions (Kd ~10–12 µM for Fe3+; ~55 µM for Fe2+) and forms a sub-micromolar complex with the scaffold protein ISU (only when iron-loaded; apo-frataxin does not bind ISU); holo-frataxin donates iron to ISU to support [2Fe-2S] cluster assembly with NifS as sulfur donor, establishing frataxin as an iron donor for Fe-S cluster biosynthesis. Isothermal titration calorimetry, fluorescence spectroscopy, UV-vis and CD spectroscopy, reconstitution of [2Fe-2S] cluster assembly in vitro Journal of the American Chemical Society High 12785837
2004 Human frataxin acts as an iron chaperone for aconitase: frataxin interacts with aconitase in a citrate-dependent manner, reduces oxidant-induced inactivation of the [4Fe-4S] cluster, and converts inactive [3Fe-4S]1+ aconitase to the active [4Fe-4S]2+ form. Co-immunoprecipitation, enzyme activity assays, in vitro reconstitution of aconitase reactivation Science High 15247478
2004 Human holo-frataxin is a high-affinity binding partner for ferrochelatase and delivers iron to ferrochelatase to support the terminal step of heme biosynthesis (insertion of ferrous iron into protoporphyrin IX); distinct binding affinities of holo-frataxin for ferrochelatase versus ISU allow discrimination between heme and Fe-S cluster biosynthesis pathways. Protein-protein interaction assay, in vitro iron delivery and heme biosynthesis reconstitution The Journal of biological chemistry High 15123683
2004 Solution structure of bacterial frataxin CyaY solved by NMR; iron binding mapped to a highly anionic surface of the molecule conserved across the frataxin family; this surface hosts both Fe2+ and Fe3+ with defined stoichiometry without requiring aggregation; the corresponding region of human frataxin also binds iron but with weaker affinity; secondary binding sites on CyaY but not human frataxin hint at a polymerization mechanism. NMR solution structure determination, site-directed mutagenesis, iron binding assays Structure High 15530368
2004 CyaY (E. coli frataxin) binds at least two Fe2+ per monomer (Kd ~4 µM by ITC); bound Fe2+ is oxidized slowly by O2 but rapidly by H2O2 without producing hydroxyl radicals (complete H2O2 reduction to H2O); up to 6 Fe3+ bind per monomer after oxidation, and CyaY attenuates iron-catalyzed Fenton chemistry; Fe2+ addition causes tetramer formation; excess iron causes aggregation. Isothermal titration calorimetry, EPR spin trapping, UV-vis/fluorescence spectroscopy, analytical ultracentrifugation Journal of molecular biology High 15276847
2004 Frataxin depletion by RNAi in human HeLa cells decreases activities of mitochondrial Fe-S proteins (aconitase, succinate dehydrogenase) and reduces Fe-S cluster association with cytosolic iron-regulatory protein 1, while non-Fe-S protein activities, iron uptake, total iron content, and heme formation are unaffected; mitochondrial iron deposits are absent, indicating iron accumulation is a late consequence of frataxin deficiency. RNAi knockdown in HeLa cells, enzyme activity assays, iron uptake measurement, heme assay Human molecular genetics High 15509595
2007 The Friedreich's ataxia GAA repeat expansion in intron 1 of FXN induces epigenetic changes in brain, cerebellum, and heart tissues: upstream CpG sites become hypermethylated, downstream CpG sites become hypomethylated, with differential methylation also at the FXN promoter and exon 1; chromatin immunoprecipitation shows decreased H3K9 acetylation and increased H3K9 methylation in FRDA brain tissue; a YAC transgenic mouse model recapitulates these epigenetic changes. Bisulfite sequencing, chromatin immunoprecipitation (ChIP), YAC transgenic mouse model Human molecular genetics High 18045775
2007 CyaY is localized in the cytoplasm (not membrane-associated) of E. coli, as demonstrated by Western blot and live-cell GFP imaging; complex I is fully assembled and active in a cyaY mutant but its amount is reduced by one third, indicating CyaY plays a non-essential, non-structural role in complex I assembly. Western blot, live-cell GFP imaging, complex I activity assay, assembly analysis BMC biochemistry Medium 17650323
2007 CyaY expressed in mitochondria-targeted form in yeast lacking YFH1 (yfh1Δ) largely complements loss of Fe-S cluster enzyme activities and heme synthesis and restores respiratory growth; CyaY also effectively protects yfh1Δ from H2O2-induced oxidative damage, demonstrating partial functional conservation between bacterial and eukaryotic frataxins. Mitochondria-targeted heterologous expression in yeast, Fe-S enzyme activity assays, heme synthesis assay, oxidative stress survival assay FEMS yeast research High 17727661
2009 Bacterial frataxin CyaY inhibits Fe-S cluster formation in an iron-dependent manner by binding to the desulfurase IscS through its iron-binding surface (conserved across the frataxin family); CyaY functions as an iron sensor/regulator that fine-tunes Fe-S cluster formation to available iron concentrations, rather than as a simple iron donor. Biochemical and biophysical assays (IscS binding, cluster formation kinetics), site-directed mutagenesis of iron-binding surface Nature structural & molecular biology High 19305405
2010 Human frataxin binds to a preformed NFS1/Isd11/Isu2 (cysteine desulfurase) complex and acts as an allosteric activator: frataxin binding decreases the KM for cysteine from 0.59 to 0.011 mM and increases catalytic efficiency (kcat/KM) from 25 to 7900 M⁻¹s⁻¹; ferrous iron further stimulates this activity, while oxidizing conditions diminish complex formation and activation. In vitro enzyme kinetics, complex formation assays, biochemical reconstitution Biochemistry High 20873749
2011 Mammalian frataxin's main endogenous interactors are ISCU, NFS1, and ISD11 (the core Fe-S assembly complex), demonstrated by immunoprecipitation; frataxin interacts with the preformed complex rather than individual components; the quaternary complex is ~190 kDa; the mature FXN81-210 form is the essential functional form in vivo. Co-immunoprecipitation, heterologous expression, gel filtration, in vivo complementation PloS one High 21298097
2011 Hyperexpanded GAA repeats in FXN intron 1 block productive transcription elongation (not initiation) in FRDA cells: ChIP analysis shows similar FXN pre-mRNA levels upstream of the GAA tract but heterochromatin-like histone modifications specifically downstream, near the GAA repeat region; these chromatin changes are independent of transcription initiation and elongation. Chromatin immunoprecipitation (ChIP), quantitative PCR, GFP reporter construct with 560 GAA repeats Nucleic acids research High 21745819
2011 Spectroscopic characterization of CyaY's effect on cluster formation on IscU: CyaY (bacterial frataxin ortholog) slows down enzymatic Fe-S cluster formation without altering the relative ratio of [2Fe-2S]2+ to [4Fe-4S]2+ products, directly affecting IscS enzymatic activity. Multiple spectroscopies (UV-vis, EPR, Mössbauer, resonance Raman) monitoring cluster formation kinetics PloS one High 21799759
2011 R-loops (RNA/DNA hybrids) form on expanded GAA repeats in patient cells at the endogenous FXN locus; these R-loops co-localize with repressive H3K9me2 chromatin marks and impede RNA Pol II transcription; increasing R-loop levels with camptothecin up-regulates repressive chromatin marks causing FXN silencing; R-loops act as an initial trigger upstream of heterochromatin formation. R-loop immunofluorescence/ChIP, H3K9me2 ChIP, RNA Pol II ChIP, topoisomerase inhibitor treatment PLoS genetics High 24787137
2013 FXN 3'-UTR harbors SNPs that create or abolish miRNA target sites affecting frataxin expression; a specific FRDA-associated 3'-UTR haplotype confers ~1.2-fold decreased reporter expression; miR-124 was specifically demonstrated to down-regulate FXN via the 3'-UTR, establishing post-transcriptional regulation of frataxin through miRNA targeting. 3'-UTR sequencing in FRDA cohorts, reporter gene assays, miRNA target validation PloS one Medium 23382970
2013 FXN promoter/intron 1 region shows increased 5-hydroxymethylcytosine (5hmC) rather than 5-methylcytosine (5mC) as the predominant DNA modification in FRDA cerebellum and heart tissues; CTCF occupancy at the FXN 5' UTR is decreased in FRDA cerebellum tissues, suggesting loss of insulator binding as part of the silencing mechanism. MethylScreen restriction enzyme digestion/qPCR distinguishing 5hmC from 5mC, ChIP for CTCF PloS one Medium 24023969
2015 CyaY and IscX compete for binding to the same surface on IscS desulfurase; IscX modulates CyaY's inhibitory properties by competing for the IscS binding site, rescuing CyaY-inhibited cluster formation rates; this competition is iron-concentration dependent (stronger at low iron, negligible at high iron), establishing a dual regulatory mechanism for Fe-S cluster biogenesis. NMR, small angle X-ray scattering (SAXS), biochemical binding and activity assays Frontiers in molecular biosciences High 29457004
2015 CyaY potentiates E. coli fitness and participates in ISC-mediated Fe-S cluster biogenesis in vivo, requiring iron-rich conditions for its contribution to be significant; genetic interaction between cyaY and iscX shows additive effects on Fe-S cluster protein maturation; a cyaY mutation reduces Salmonella virulence in mice. Gene knockout, genetic interaction analysis, Fe-S enzyme activity assays, mouse virulence model Molecular microbiology Medium 25430730
2015 MiRNA-145 directly binds the 3'-UTR of FXN and negatively regulates its expression; through targeting FXN, miRNA-145 regulates apoptosis and mitochondrial function in cell lines, and FXN was identified as the most differentially expressed key gene in congenital heart disease by microarray analysis. TargetScan prediction, luciferase reporter 3'-UTR assay, real-time PCR, functional apoptosis/mitochondria assays in cell lines Pediatric cardiology Medium 26717909
2017 Crystal structure of the NFS1-ISD11-ACP complex with and without ISCU, combined with SAXS, defines the 3D architecture of the complete mitochondrial Fe-S cluster biosynthetic complex; frataxin's role is placed within this structural context: catalytic center involves NFS1 active-site Cys and conserved Cys/Asp/His of ISCU; ISD11-ACP have regulatory rather than catalytic roles linking Fe-S synthesis to mitochondrial lipid synthesis. X-ray crystallography, SAXS, biochemical assays Nature communications High 29097656
2017 FXN81-210 and CyaY both form ring-shaped oligomers in the presence of iron under aerobic conditions; FXN81-210 oligomers are unstable (dissociate ~24 h) while CyaY oligomers are stable, explained by more acidic residues at the monomer interface; monomers pack head-to-tail with iron-binding sites at interfaces; CyaY oligomers can be dissociated by iron chelators deferiprone, DFO (ferric), and BIPY (ferrous); deferiprone/DFO stimulate FXN81-210 oligomerization while BIPY does not, indicating FXN81-210 oligomerization is primarily driven by ferric iron. Dynamic light scattering, SAXS, electron microscopy, cross-linking mass spectrometry, iron chelator experiments PloS one Medium 29200434
2017 TAT-MTScs-FXN fusion protein (frataxin coupled to a cell-penetrating TAT peptide and mitochondrial targeting sequence) penetrates muscle mitochondria in FRDA mouse models, restores succinate dehydrogenase activity, increases cell survival and reduces apoptotic markers (α-fodrin cleavage, caspase 9 activation) in frataxin-deficient DRG neurons, and produces significant lifespan extension in mice. Protein delivery in primary DRG neurons and mouse models, mitochondrial fractionation, enzyme activity assay, apoptosis markers, survival assay Journal of cellular and molecular medicine Medium 28980774
2019 Computational and experimental assessment of FXN missense variants: thermodynamic measurements (far-UV circular dichroism, intrinsic fluorescence) of eight amino acid substitutions determine unfolding free energy changes; variants in the hydrophobic core predominantly affect protein stability; surface residue mutations affect interactions with Fe-S cluster assembly and heme biosynthetic proteins. Far-UV circular dichroism, intrinsic fluorescence spectroscopy, computational stability prediction benchmarking Human mutation Medium 31209948
2020 miRNA-224-5p directly targets the FXN transcript, decreasing FXN mRNA and protein levels; validated by luciferase reporter assay; ZFN-mediated excision of expanded GAA repeats in FRDA cells decreases miRNA-224-5p levels, providing a mechanistic link between GAA expansion and miRNA-mediated post-transcriptional regulation of frataxin. miRNAseq/RNAseq integrated analysis, luciferase reporter assay, qRT-PCR, immunoblotting, ZFN-mediated GAA repeat excision Molecular neurobiology Medium 32291635

Source papers

Stage 0 corpus · 130 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1996 Friedreich's ataxia: autosomal recessive disease caused by an intronic GAA triplet repeat expansion. Science (New York, N.Y.) 2292 8596916
2002 Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. Proceedings of the National Academy of Sciences of the United States of America 1479 12477932
2020 A reference map of the human binary protein interactome. Nature 849 32296183
1997 Aconitase and mitochondrial iron-sulphur protein deficiency in Friedreich ataxia. Nature genetics 820 9326946
1997 Regulation of mitochondrial iron accumulation by Yfh1p, a putative homolog of frataxin. Science (New York, N.Y.) 763 9180083
2011 Phylogenetic-based propagation of functional annotations within the Gene Ontology consortium. Briefings in bioinformatics 656 21873635
1997 Frataxin is reduced in Friedreich ataxia patients and is associated with mitochondrial membranes. Human molecular genetics 619 9302253
2006 A protein-protein interaction network for human inherited ataxias and disorders of Purkinje cell degeneration. Cell 610 16713569
2004 The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). Genome research 438 15489334
2016 Widespread Expansion of Protein Interaction Capabilities by Alternative Splicing. Cell 423 26871637
1997 Studies of human, mouse and yeast homologues indicate a mitochondrial function for frataxin. Nature genetics 397 9241270
2004 Frataxin acts as an iron chaperone protein to modulate mitochondrial aconitase activity. Science (New York, N.Y.) 310 15247478
2003 Iron-sulfur cluster biosynthesis. Characterization of frataxin as an iron donor for assembly of [2Fe-2S] clusters in ISU-type proteins. Journal of the American Chemical Society 295 12785837
1997 Respiratory deficiency due to loss of mitochondrial DNA in yeast lacking the frataxin homologue. Nature genetics 292 9241271
2014 R-loops associated with triplet repeat expansions promote gene silencing in Friedreich ataxia and fragile X syndrome. PLoS genetics 287 24787137
1999 Friedreich's ataxia: point mutations and clinical presentation of compound heterozygotes. Annals of neurology 286 9989622
2007 Rimonabant reduces obesity-associated hepatic steatosis and features of metabolic syndrome in obese Zucker fa/fa rats. Hepatology (Baltimore, Md.) 245 17526015
2021 Quantitative high-confidence human mitochondrial proteome and its dynamics in cellular context. Cell metabolism 239 34800366
2010 Human frataxin is an allosteric switch that activates the Fe-S cluster biosynthetic complex. Biochemistry 231 20873749
2004 Frataxin-mediated iron delivery to ferrochelatase in the final step of heme biosynthesis. The Journal of biological chemistry 226 15123683
2007 hORFeome v3.1: a resource of human open reading frames representing over 10,000 human genes. Genomics 222 17207965
2016 Mitochondrial Protein Interaction Mapping Identifies Regulators of Respiratory Chain Function. Molecular cell 220 27499296
2013 Friedreich ataxia: neuropathology revised. Journal of neuropathology and experimental neurology 210 23334592
2009 Bacterial frataxin CyaY is the gatekeeper of iron-sulfur cluster formation catalyzed by IscS. Nature structural & molecular biology 207 19305405
2007 The Friedreich ataxia GAA repeat expansion mutation induces comparable epigenetic changes in human and transgenic mouse brain and heart tissues. Human molecular genetics 205 18045775
2018 The roles of free ammonia (FA) in biological wastewater treatment processes: A review. Environment international 189 30481673
2011 Mammalian frataxin: an essential function for cellular viability through an interaction with a preformed ISCU/NFS1/ISD11 iron-sulfur assembly complex. PloS one 189 21298097
2000 Crystal structure of human frataxin. The Journal of biological chemistry 185 10900192
2007 Repeat-induced epigenetic changes in intron 1 of the frataxin gene and its consequences in Friedreich ataxia. Nucleic acids research 169 17478498
2002 Assembly and iron-binding properties of human frataxin, the protein deficient in Friedreich ataxia. Human molecular genetics 169 11823441
2009 Gene-centric association signals for lipids and apolipoproteins identified via the HumanCVD BeadChip. American journal of human genetics 164 19913121
2017 Structure and functional dynamics of the mitochondrial Fe/S cluster synthesis complex. Nature communications 160 29097656
2004 Iron-sulfur protein maturation in human cells: evidence for a function of frataxin. Human molecular genetics 154 15509595
1990 Exercise training increases glucose transporter protein GLUT-4 in skeletal muscle of obese Zucker (fa/fa) rats. FEBS letters 149 2200706
1998 Leptin receptor signal transduction: OBRa and OBRb of fa type. Biochemical and biophysical research communications 127 9618284
1996 Phenotype-linked amino acid alteration in leptin receptor cDNA from Zucker fatty (fa/fa) rat. Biochemical and biophysical research communications 121 8630068
2005 Soy protein reduces hepatic lipotoxicity in hyperinsulinemic obese Zucker fa/fa rats. Journal of lipid research 119 15995177
2016 Compound heterozygous FXN mutations and clinical outcome in friedreich ataxia. Annals of neurology 118 26704351
2004 Solution structure of the bacterial frataxin ortholog, CyaY: mapping the iron binding sites. Structure (London, England : 1993) 113 15530368
1995 Increased neuropeptide Y secretion in the hypothalamic paraventricular nucleus of obese (fa/fa) Zucker rats. Brain research 107 8535835
2004 Iron binding and oxidation kinetics in frataxin CyaY of Escherichia coli. Journal of molecular biology 103 15276847
2000 Crystal structure of Escherichia coli CyaY protein reveals a previously unidentified fold for the evolutionarily conserved frataxin family. Proceedings of the National Academy of Sciences of the United States of America 97 10908679
2009 CHK1 inhibition as a strategy for targeting Fanconi Anemia (FA) DNA repair pathway deficient tumors. Molecular cancer 96 19371427
1994 Late onset Friedreich's disease: clinical features and mapping of mutation to the FRDA locus. Journal of neurology, neurosurgery, and psychiatry 95 8057123
2012 FXN methylation predicts expression and clinical outcome in Friedreich ataxia. Annals of neurology 93 22522441
1997 Postnatal development of the ob gene system: elevated leptin levels in suckling fa/fa rats. The American journal of physiology 76 9249584
2001 Frataxin expression rescues mitochondrial dysfunctions in FRDA cells. Human molecular genetics 74 11590127
1979 Consumption of O2 and early detection of fa/fa genotype in rats. Metabolism: clinical and experimental 72 491972
2007 The Fanconi anemia (FA) pathway confers glioma resistance to DNA alkylating agents. Journal of molecular medicine (Berlin, Germany) 71 17221219
2005 Physiological difference between obese (fa/fa) Zucker rats and lean Zucker rats concerning adiponectin. Metabolism: clinical and experimental 69 16092047
2011 Hyperexpansion of GAA repeats affects post-initiation steps of FXN transcription in Friedreich's ataxia. Nucleic acids research 64 21745819
1978 Adaptive responses of enzymes of carbohydrate and lipid metabolism to dietary alteration in genetically obese Zucker rats (fa/fa). European journal of biochemistry 64 710395
1999 Knock-out of the cyaY gene in Escherichia coli does not affect cellular iron content and sensitivity to oxidants. FEBS letters 61 10452520
2003 Characterization of bone structure in leptin receptor-deficient Zucker (fa/fa) rats. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research 59 12968669
2003 Upregulation of expression from the FRDA genomic locus for the therapy of Friedreich ataxia. The journal of gene medicine 57 12516053
1992 Vanadate treatment markedly increases glucose utilization in muscle of insulin-resistant fa/fa rats without modifying glucose transporter expression. Endocrinology 50 1612011
2007 Dynamics of insulin sensitivity, -cell function, and -cell mass during the development of diabetes in fa/fa rats. American journal of physiology. Endocrinology and metabolism 49 17895283
1980 Genetic and physical characterization of lambda transducing phages (lambda frdA) containing the fumarate reductase gene of Escherichia coli K12. Molecular & general genetics : MGG 49 6446651
2018 Causes and solutions to "globesity": The new fa(s)t alarming global epidemic. Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association 46 30176311
2011 Both FA- and mPEG-conjugated chitosan nanoparticles for targeted cellular uptake and enhanced tumor tissue distribution. Nanoscale research letters 46 22027239
2006 Anti-dsDNA antibody testing by Farr and ELISA techniques is not equivalent. The Journal of rheumatology 46 16924691
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