Selected-GenAtlas references SOURCE GeneCards NCBI Gene Swiss-Prot Orphanet Ensembl
HGNC UniGene Nucleotide OMIM UCSC
Home Page
FLASH GENE
Symbol FXN contributors: mct/shn - updated : 29-01-2015
HGNC name frataxin
HGNC id 3951
Corresponding disease
FRDA Friedreich ataxia
Location 9q21.11      Physical location : 71.650.478 - 71.715.094
Synonym name
  • frataxin, putative protein
  • frataxin intermediate form
  • frataxin, mitochondrial
  • Synonym symbol(s) X25, FARR, FA, MGC57199, CyaY, FRDA
    EC.number 1.16.3.1
    DNA
    TYPE functioning gene
    STRUCTURE 64.62 kb     5 Exon(s)
    motif repetitive sequence
    text structure
  • repetitive sequence=GAA repeat (9 to 60 ) within the central A-rich sequence of Alu elements
  • severe deficiency of FXN transcript,is predominantly caused by epigenetic silencing of the FXN promoter
  • MAPPING cloned Y linked Y status confirmed
    Map cen - D9S1879 - D9S1787 - FXN - D9S1800 - D9S273 - qter
    RNA
    TRANSCRIPTS type messenger
    identificationnb exonstypebpproduct
    ProteinkDaAAspecific expressionYearPubmed
    5 splicing 7168 23.1 210 - 2011 21216878
  • precursor rapidly targeted to the mitochondria, and upon entrance into the mitochondria, the frataxin precursor undergoes a two-step proteolytic processing, mediated by the mitochondrial processing peptidase; the resulting mature frataxin is a 130 AAs globular polypeptide that mostly resides within the mitochondrial matrix
  • 5 splicing 7176 - 196 low expressed 2008 18697824
    insertion of 8 bp betwwen 4 and 5A exon sequence
    5 - 980 - 171 - 2009 19843162
    EXPRESSION
    Type widely
       expressed in (based on citations)
    organ(s)
    SystemOrgan level 1Organ level 2Organ level 3Organ level 4LevelPubmedSpeciesStageRna symbol
    Cardiovascularheart   highly Homo sapiens
    Digestiveliver   moderately Homo sapiens
     stomach   highly
    Endocrineparathyroid   highly
    Lymphoid/Immunespleen   moderately Homo sapiens
     thymus   moderately Homo sapiens
    Nervousbrainhindbraincerebellum moderately
     gangliasensory gangliadorsal root  
     spinal cord   moderately
    Reproductivefemale systemovary  highly
     male systemprostate  moderately
    Respiratorylung   moderately
    Urinarykidney   highly Homo sapiens
    tissue
    SystemTissueTissue level 1Tissue level 2LevelPubmedSpeciesStageRna symbol
    Blood / Hematopoieticbone marrow   
    Connectivebone   
    Epithelialsecretoryglandularendocrine 
    Muscularstriatumskeletal moderately Homo sapiens
    Nervouscentral   
    Nervousperipherous   
    cell lineage
    cell lines
    fluid/secretion
    at STAGE
    PROTEIN
    PHYSICAL PROPERTIES
    STRUCTURE
    motifs/domains
  • a well-characterized globular domain present in all species and preceded in eukaryotes by a non-conserved N-terminal tail that contains the mitochondrial import signal, region flexible and intrinsically unfolded, unlikely important for the conserved functions of the protein
  • frataxin-like domain
  • alpha/beta fold followed by the C-terminal region (CTR) with a nonperiodic structure that packs against the protein core
  • mono polymer monomer
    isoforms Precursor a 210 AA precursor that is rapidly targeted to the mitochondria (PMID: 21216878)
    HOMOLOGY
    interspecies ortholog to Fxn, Mus musculus
    ortholog to Fxn, Rattus norvegicus
    ortholog to FXN, Pan troglodytes
    ortholog to fxn, Danio rerio
    Homologene
    FAMILY
  • frataxin family
  • CATEGORY chaperone/stress , regulatory , storage , transport
    SUBCELLULAR LOCALIZATION     intracellular
    intracellular,cytoplasm,organelle,mitochondria,inner
    intracellular,cytoplasm,cytosolic
    text
  • strictly localized to the mitochondria, excluding the presence of a cytosolic pool in normal adult tissues
  • physiological role of extramitochondrial frataxin in the cytoplasmic compartment
  • basic FUNCTION
  • iron chaperone involved in the assembly of Fe-S clusters (ISC)
  • required not only for the biogenesis of mitochondrial containing iron-sulfur clusters(ISC) protein, but also for the biogenesis of cytoplasmic and nuclear ISC proteins
  • playing a role in regulating mitochondrial iron import/export in the stability of DNA structure, and in the maintenance of overall cellular homeostasis and protection from oxidative damage (protective role with regard to nuclear damage)
  • acts as an iron chaperone protein to modulate mitochondrial aconitase activity
  • playing a role in the maturation of both mitochondrial and cytosolic Fe/S proteins
  • may act as a mitochondrial tumor suppressor protein in mammals
  • key activator of mitochondrial energy conversion and oxidative phosphorylation
  • acting as an iron chaperone protein to modulate mitochondrial aconitase activity
  • directly involved in mitochondrial iron-binding and detoxification
  • detoxifies surplus iron thereby affording a critical anti-oxidant mechanism
  • iron detoxification, another function of frataxin relevant to anti-oxidant defense and cell longevity that could play a critical role in the metabolically demanding environment of non-dividing neuronal, cardiac and pancreatic beta cells
  • supports the functions of iron sulfur cluster insertion into apoproteins
  • mitochondrial frataxin acts as an iron-chaperone by providing ferrous iron (Fe2+) in a bioavailable form
  • potentially having a direct functionin the regulation of cytosolic aconitase/ACO1 activity
  • main role of FXN is to supply iron in a bioavailable form for mitochondrial Fe/S cluster synthesis
  • functions with Fe2+ as an allosteric activator that triggers sulfur delivery and Fe/S cluster assembly (
  • ISCU and FXN stimulate NFS1 and LYRM4 cysteine desulfurase activity
  • functions as an activator for human Fe/S cluster biosynthesis
  • modulates DNA-repair mechanisms
  • protects tumor cells against oxidative stress and apoptosis but also acts as a tumor suppressor
  • participates to the hypoxia-induced stress response in tumors, thus implying that modulation of its expression could have a critical role in tumor cell survival and/or progression
  • activation of apoptosis in frataxin-deficient mature neurons may contribute to neurodegeneration in FRDA
  • local unfolding of CTR may be a critical step for the global unfolding of FXN, and modulation of the CTR interactions may strongly affect FXN physiological function
  • CELLULAR PROCESS nucleotide, repair
    PHYSIOLOGICAL PROCESS development
    text
  • cellular iron homeostasis
  • involved in both heme and iron-sulfur cluster biosyntheses
  • PATHWAY
    metabolism
    signaling neurotransmission
    synaptic transmission
    a component
  • component of the Fe/S cluster assembly machinery, and of the electronic transport chain
  • complex SDU and SDUF comprised of NFS1, LYRM4, and ISCU and NFS1, LYRM4, ISCU, and FXN, respectively (SDUF is capable of synthesizing Fe/S cluster)
  • INTERACTION
    DNA
    RNA
    small molecule
    iron
    protein
  • mitochondrial processing peptidase beta, MPPbeta
  • interacting with aconitase in a citrate-dependent fashion
  • interacting with SDHA, SDHB
  • interacting with MTCP1
  • interacting with mortalin (GRP75), LYRM4 (binds the iron-sulfur biogenesis NFS1/ISCU complex through LYRM4, this interaction is nickel-dependent, and multiple consequences of frataxin deficiency are duplicated by LYRM4 deficiency)
  • extramitochondrial frataxin directly interacts with the ISC-dependent cytosolic aconitase/iron regulatory protein-1 (ACO1) bifunctional protein
  • HSCB could stabilize frataxin in the mitochondria, and frataxin significantly decrease in the HSCB-depleted cells
  • IFNG appears to act largely through a transcriptional mechanism on the FXN gene
  • accelerates persulfide formation on NFS1 and favors a helix-to-coil interconversion on ISCU that facilitates the transfer of sulfur from NFS1 to ISCU as an initial step in Fe-S cluster biosynthesis
  • cell & other
  • associated with mitochondrial membrane
  • REGULATION
    activated by interferon gamma (IFNG) in a variety of cell types, including primary cells derived from FRDA patients
    Other degraded by the ubiquitin–proteasome system and K147 is the the single lysine residue responsible for its ubiquitination and degradation
    ASSOCIATED DISORDERS
    corresponding disease(s) FRDA
    Other morbid association(s)
    TypeGene ModificationChromosome rearrangementProtein expressionProtein Function
    constitutional        
    detrimental effect of frataxin silencing, not only for astrocytes, but also for neuron-glia interactions, underlining the need to take into account the role of non-cell autonomous processes in FRDA
    constitutional     --low  
    induced mitochondrial dysfunction due to a bioenergetic deficit and abnormal Ca(2+) homeostasis in the mitochondria that were associated with oxidative and endoplasmic reticulum stresses
    tumoral     --over  
    in several tumor cell lines in response to hypoxic stress, a condition often associated with tumor progression
    Susceptibility diabetes (insulin resistance)
    Variant & Polymorphism
    Candidate gene
    Marker
    Therapy target
  • extramitochondrial frataxin can fully replace mitochondrial frataxin in promoting survival of frataxin cells
  • effects of frataxin knockdown in HeLa cells are rescued by expression mitochondrial ferritin
  • monitoring the methylation status may be a useful biomarker for tracking therapeutic benefit following administration of epigenetic drugs
  • SystemTypeDisorderPubmed
    neurologyataxia 
    therapeutic efforts should focus on an approach that combines iron removal from mitochondria with a treatment that increases cytosolic iron levels to maximize residual frataxin expression in FRDA patients
    neurologyataxia 
    the antioxidant Idebenone delays the cardiac disease onset, progression and death of frataxin deficient animals by 1 week, but does not correct the Fe-S enzyme deficiency suuporting its utilization for the treatment of FRDA
    neurologyataxia 
    ectopic expression of enzymes that scavenge H2O2 in Drosophila FRDA model suppresses the deleterious phenotypes associated with frataxin deficiency
    neurologyataxia 
    genetic modulation of the PPARgamma pathway affects frataxin levels in vitro, supporting PPARgamma as a novel therapeutic target in FRDA
    neurologyataxia 
    possibility of modulating frataxin stability through the use of small molecules designed to directly target K147, the single lysine residue responsible for its ubiquitination and degradation
    ANIMAL & CELL MODELS
  • deletion of exon 4 of the mouse Frda gene lead to embryonic lethality a few days after implantation whith no iron accumulation
  • striated muscle frataxin-deficient line and a neuron/cardiac muscle frataxin-deficient line display cardiac hypertrophy without skeletal muscle involvement, large sensory neuron dysfunction without alteration of the small sensory and motor neurons, and deficient activities of complexes I-III of the respiratory chain and of the aconitases
  • Mice carrying a hepatocyte-specific disruption of the frataxin gene develop multiple liver tumours
  • in mouse FRDA model the Fe-S enzyme deficiency occurs at 4 weeks of age prior to cardiac dilatation and concomitant development of left ventricular hypertrophy and the mitochondrial iron accumulation occurs at a terminal stage
  • suppression of the Drosophila frataxin confers distinct phenotypes in larvae and adults, leading to giant long-lived larvae and to conditional short-lived adults resulting to diminished activities of numerous heme- and iron-sulfur-containing enzymes, loss of intracellular iron homeostasis and increased susceptibility to iron toxicity
  • disruption of Fxn protein frataxin specifically in murine hepatocytes leads to reduced life span and development of multiple hepatic tumors, increased oxidative stress, impaired respiration and reduced ATP levels and reduced activity of iron-sulfur cluster
  • frataxin-deficient cells are more prone to undergo stress-induced mitochondrial damage and apoptosis, while the overexpression of frataxin confers protection to a variety of cell types
  • frataxin silencing in HeLa cells caused a reduction of growth, inhibition of the activity of aconitase and superoxide dismutase-2 and reduction of cytosolic ferritins without alteration of mitochondrial iron content
  • frataxin deficiency in murine liver is associated with increased basal levels of oxidative DNA base damage