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FLASH GENE

Symbol

FXN

contributors: mct/shn - updated : 29-01-2016

HGNC name	frataxin
HGNC id	3951

FLASH GENE DNA RNA EXPRESSION PROTEIN DISORDER ANIMAL & CELL MODELS

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
	PITRM1 regulates intermediate FXN levels
	HAX1 protein levels are indeed regulated through FXN modulation

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)

Type Gene Modification Chromosome rearrangement Protein expression Protein 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
	System Type Disorder Pubmed neurology ataxia   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 neurology ataxia   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 neurology ataxia   ectopic expression of enzymes that scavenge H2O2 in Drosophila FRDA model suppresses the deleterious phenotypes associated with frataxin deficiency neurology ataxia   genetic modulation of the PPARgamma pathway affects frataxin levels in vitro, supporting PPARgamma as a novel therapeutic target in FRDA neurology ataxia   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