FXN

Existing Annotations Review

GO Term	Evidence	Action	Reason
GO:0016226 iron-sulfur cluster assembly	IBA GO_REF:0000033	ACCEPT	Summary: Iron-sulfur cluster assembly is the core biological process for FXN. FXN functions within the mitochondrial ISC assembly complex to promote de novo [2Fe-2S] cluster synthesis. This annotation is well-supported by phylogenetic inference and extensive experimental evidence. Reason: FXN is a key component of the mitochondrial iron-sulfur cluster assembly machinery. Multiple studies demonstrate its role in accelerating persulfide transfer from NFS1 to ISCU during [2Fe-2S] cluster assembly (PMID:12785837, PMID:24971490, PMID:29576242). The IBA annotation correctly reflects the conserved function across eukaryotes. Supporting Evidence: PMID:12785837 Provision of holo frataxin and inorganic sulfide is sufficient for cluster assembly in up to 70% yield. PMID:24971490 FXN accelerates the accumulation of sulfur on ISCU2 and that the resulting persulfide species is viable in the subsequent synthesis of Fe-S clusters. file:human/FXN/FXN-deep-research-falcon.md model: Edison Scientific Literature
GO:0008198 ferrous iron binding	IBA GO_REF:0000033	ACCEPT	Summary: Ferrous iron binding is a well-established molecular function of frataxin. FXN tightly binds a single Fe2+ ion but not Fe3+, and this iron is released during Fe-S cluster assembly. Reason: FXN binds Fe2+ with high affinity. NMR and ITC studies demonstrate specific binding of Fe2+ (K_D approximately 55 microM) but not Fe3+ (PMID:12785837, PMID:29576242). The iron-binding site is located on the alpha1-beta1 face of the protein. Supporting Evidence: PMID:29576242 FXN tightly binds a single Fe2+ but not Fe3+. PMID:12785837 Iron binding to frataxin has been quantitated by iron-dependent fluorescence measurements [K(D)(Fe(3+)) approximately 11.7 microM; (K(D)(Fe(2+)) approximately 55.0 microM] and isothermal titration calorimetry (ITC) [K(D)(Fe(3+)) approximately 10.2 microM]
GO:0005739 mitochondrion	IBA GO_REF:0000033	ACCEPT	Summary: Mitochondrial localization is strongly supported. FXN is synthesized as a precursor with an N-terminal targeting sequence and processed to the mature form in mitochondria. Reason: Multiple experimental studies confirm mitochondrial localization (PMID:9302253, PMID:9241270, PMID:21298097). The protein is processed by mitochondrial processing peptidase in two steps to yield the mature mitochondrial form. Supporting Evidence: PMID:21298097 The main interactors from mitochondrial HeLa cell extract of a C-terminal or N-terminal tagged human mature frataxin (hFXN81-210) are the core components of the de novo Fe-S cluster biosynthesis, ISCU, NFS1 and ISD11.
GO:0008199 ferric iron binding	IBA GO_REF:0000033	MARK AS OVER ANNOTATED	Summary: Ferric iron binding by FXN is controversial. Recent NMR studies show FXN binds Fe2+ but not Fe3+, though earlier studies reported Fe3+ binding. Reason: While earlier studies suggested FXN binds both Fe2+ and Fe3+ (PMID:12785837), more recent NMR studies (PMID:29576242) demonstrate that FXN binds Fe2+ but not Fe3+. When Fe2+ is oxidized to Fe3+, it dissociates from FXN. The physiologically relevant form appears to be Fe2+-bound FXN. Supporting Evidence: PMID:29576242 FXN tightly binds a single Fe2+ but not Fe3+... the addition of a 5-fold excess of FeCl3 did not lead to significant chemical shift perturbations... oxidized Fe2+ lost affinity to FXN.
GO:0034986 iron chaperone activity	IBA GO_REF:0000033	ACCEPT	Summary: Iron chaperone activity is a core molecular function of FXN. The protein delivers iron to multiple targets including ISCU for Fe-S cluster assembly and ferrochelatase for heme biosynthesis. Reason: FXN functions as an iron chaperone, delivering Fe2+ to the ISC assembly complex and to ferrochelatase for heme biosynthesis (PMID:15123683, PMID:12785837). Iron is released from FXN only when cysteine desulfurase is activated by both L-cysteine and reductant. Supporting Evidence: PMID:15123683 Herein we demonstrate Hs holofrataxin to be a high affinity iron binding partner for Hs ferrochelatase that is capable of both delivering iron to ferrochelatase and mediating the terminal step in mitochondrial heme biosynthesis PMID:29576242 Although the present results do not prove that the released iron is picked up by ISCU and used for Fe-S cluster formation, we have shown that Fe2+-FXN can serve as the sole iron donor for this process in vitro
GO:0051537 2 iron, 2 sulfur cluster binding	IBA GO_REF:0000033	UNDECIDED	Summary: Evidence for [2Fe-2S] cluster binding by FXN is limited. FXN is involved in [2Fe-2S] cluster assembly on ISCU but whether it binds the cluster itself is uncertain. Reason: While PMID:12785837 reported some evidence for [2Fe-2S] binding, the primary function of FXN is to deliver iron and activate sulfur transfer for cluster assembly on ISCU, not to bind the assembled cluster. More evidence would be needed to confirm this annotation.
GO:0004322 ferroxidase activity	IEA GO_REF:0000120	ACCEPT	Summary: Ferroxidase activity has been demonstrated for the oligomeric form of FXN in vitro. The monomeric form does not have this activity. Reason: The oligomeric form of human FXN has ferroxidase activity (EC 1.16.3.1) that catalyzes oxidation of Fe2+ to Fe3+, which may help detoxify redox-active iron (PMID:15641778). However, the physiological relevance is uncertain as the monomer is likely the predominant form. Supporting Evidence: PMID:15641778 The assembled protein has ferroxidase activity and detoxifies redox-active iron by sequestering it in a protein-protected compartment.
GO:0005739 mitochondrion	IEA GO_REF:0000120	ACCEPT	Summary: Redundant with IBA annotation for mitochondrion. Reason: Correct localization, supported by multiple experimental studies.
GO:0005829 cytosol	IEA GO_REF:0000044	ACCEPT	Summary: An extramitochondrial form of frataxin exists in the cytosol. This form modulates the RNA-binding activity of cytosolic aconitase (ACO1/IRP1). Reason: Extramitochondrial frataxin has been detected and characterized (PMID:20053667, PMID:16608849). It may contribute to oxidative stress resistance and regulate the cytosolic aconitase/IRP1 switch. Supporting Evidence: PMID:20053667 Molecular control of the cytosolic aconitase/IRP1 switch by extramitochondrial frataxin.
GO:0006783 heme biosynthetic process	IEA GO_REF:0000043	KEEP AS NON CORE	Summary: FXN delivers iron to ferrochelatase for the terminal step of heme biosynthesis. This is a secondary function to its primary role in Fe-S cluster assembly. Reason: FXN functions as an iron donor for ferrochelatase in the final step of heme biosynthesis (PMID:15123683). However, this appears to be a secondary function; the primary role is in Fe-S cluster assembly. Supporting Evidence: PMID:15123683 A general regulatory mechanism for mitochondrial iron metabolism is described that defines frataxin involvement in both heme and iron-sulfur cluster biosyntheses.
GO:0006811 monoatomic ion transport	IEA GO_REF:0000043	MARK AS OVER ANNOTATED	Summary: This is a very general term. FXN does not function as a transporter but as an iron chaperone that delivers iron within the mitochondrial matrix. Reason: FXN functions as an iron chaperone, not an ion transporter. The term monoatomic ion transport is too general and misleading for FXN's actual function.
GO:0006826 iron ion transport	IEA GO_REF:0000043	MODIFY	Summary: FXN is an iron chaperone rather than a transporter. It delivers iron within the mitochondrial matrix to target proteins. Reason: FXN delivers iron to ISCU and ferrochelatase but does not transport iron across membranes. A more appropriate term would be iron chaperone activity (GO:0034986), which is already annotated. Proposed replacements: iron chaperone activity
GO:0006879 intracellular iron ion homeostasis	IEA GO_REF:0000002	KEEP AS NON CORE	Summary: FXN deficiency leads to mitochondrial iron accumulation and dysregulation of iron homeostasis. However, this is a downstream consequence rather than a direct function. Reason: FXN loss leads to disrupted iron homeostasis and mitochondrial iron accumulation (PMID:18160053). However, iron homeostasis regulation is an indirect consequence of FXN's role in Fe-S cluster assembly rather than a direct molecular function. Supporting Evidence: PMID:18160053 The effects of frataxin silencing in HeLa cells are rescued by the expression of human mitochondrial ferritin.
GO:0007005 mitochondrion organization	IEA GO_REF:0000117	MARK AS OVER ANNOTATED	Summary: Mitochondrial organization is affected by FXN deficiency, but this is a downstream consequence of impaired Fe-S cluster biogenesis. Reason: While FXN deficiency affects mitochondrial structure, this is a secondary consequence of impaired Fe-S cluster assembly affecting respiratory chain complexes rather than a direct function of FXN in mitochondrial organization.
GO:0008199 ferric iron binding	IEA GO_REF:0000002	MARK AS OVER ANNOTATED	Summary: Duplicate of IBA annotation. Evidence for Fe3+ binding is weak. Reason: Recent NMR evidence shows FXN binds Fe2+ but not Fe3+ (PMID:29576242). Earlier reports of Fe3+ binding may reflect oxidation of bound Fe2+.
GO:0016226 iron-sulfur cluster assembly	IEA GO_REF:0000002	ACCEPT	Summary: Duplicate of IBA annotation. Core function well supported. Reason: Core biological process for FXN, well supported by multiple studies.
GO:0016491 oxidoreductase activity	IEA GO_REF:0000043	ACCEPT	Summary: FXN has ferroxidase activity (EC 1.16.3.1) in its oligomeric form, which is a type of oxidoreductase activity. Reason: The oligomeric form of FXN has ferroxidase activity (PMID:15641778), which catalyzes the oxidation of Fe2+ to Fe3+. This is an oxidoreductase activity.
GO:0030003 intracellular monoatomic cation homeostasis	IEA GO_REF:0000117	MARK AS OVER ANNOTATED	Summary: This is a general term. FXN's effect on iron homeostasis is indirect through its role in Fe-S cluster assembly. Reason: Very general term; effect on homeostasis is indirect.
GO:0046872 metal ion binding	IEA GO_REF:0000043	ACCEPT	Summary: Correct but overly general. FXN specifically binds ferrous iron. More specific terms (ferrous iron binding) are already annotated. Reason: Correct that FXN binds metal ions (specifically Fe2+), but the more specific term ferrous iron binding (GO:0008198) is preferable.
GO:0098771 inorganic ion homeostasis	IEA GO_REF:0000117	MARK AS OVER ANNOTATED	Summary: Very general term, indirect effect. Reason: Very general term; FXN's effect on ion homeostasis is indirect through Fe-S cluster assembly.
GO:0005515 protein binding	IPI PMID:32296183 A reference map of the human binary protein interactome.	MARK AS OVER ANNOTATED	Summary: Generic protein binding term from high-throughput interactome study. FXN binds specific partners including NFS1, ISCU, ISD11, and ferrochelatase. Reason: Protein binding is too generic. FXN has specific, functionally relevant interactions with the ISC assembly complex components (NFS1, ISD11, ISCU) and ferrochelatase. Supporting Evidence: PMID:32296183 Apr 8. A reference map of the human binary protein interactome.
GO:0005515 protein binding	IPI PMID:32814053 Interactome Mapping Provides a Network of Neurodegenerative ...	MARK AS OVER ANNOTATED	Summary: Generic protein binding from interactome study. Reason: Protein binding is too generic and uninformative for FXN. Supporting Evidence: PMID:32814053 Interactome Mapping Provides a Network of Neurodegenerative Disease Proteins and Uncovers Widespread Protein Aggregation in Affected Brains.
GO:0044572 [4Fe-4S] cluster assembly	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: FXN is directly involved in [2Fe-2S] cluster assembly on ISCU. The [4Fe-4S] clusters are formed downstream by combination of [2Fe-2S] clusters. Reason: FXN's direct role is in [2Fe-2S] cluster assembly. [4Fe-4S] cluster formation occurs downstream and depends on prior [2Fe-2S] cluster synthesis, so FXN acts upstream of this process. Supporting Evidence: PMID:29576242 Our current model of the mechanism of mitochondrial Fe-S cluster assembly consists of the following steps
GO:0099128 mitochondrial [2Fe-2S] assembly complex	IEA GO_REF:0000107	ACCEPT	Summary: FXN is a component of the mitochondrial [2Fe-2S] assembly complex. Multiple cryo-EM and biochemical studies confirm this. Reason: FXN is a confirmed component of the SDUF complex (NFS1-ISD11-ACP-ISCU-FXN) that assembles [2Fe-2S] clusters (PMID:31101807, PMID:21298097). Supporting Evidence: PMID:31101807 Structure of the human frataxin-bound iron-sulfur cluster assembly complex provides insight into its activation mechanism. PMID:21298097 the essential function of mammalian frataxin consists in interacting with the preformed ISCU/NFS1/ISD11 complex
GO:0005739 mitochondrion	IDA GO_REF:0000052	ACCEPT	Summary: Mitochondrial localization confirmed by immunofluorescence. Reason: Well-established mitochondrial localization.
GO:0005829 cytosol	IDA GO_REF:0000052	ACCEPT	Summary: Cytosolic localization of extramitochondrial frataxin confirmed. Reason: An extramitochondrial form of frataxin exists in the cytosol (PMID:20053667, PMID:16608849).
GO:0016226 iron-sulfur cluster assembly	TAS Reactome:R-HSA-1362409	ACCEPT	Summary: Reactome annotation for mitochondrial iron-sulfur cluster biogenesis. Reason: Core function well supported by Reactome pathway curation.
GO:0034551 mitochondrial respiratory chain complex III assembly	TAS Reactome:R-HSA-9865881	KEEP AS NON CORE	Summary: FXN contributes to Complex III assembly by providing Fe-S clusters. This is a downstream effect of its Fe-S cluster assembly function. Reason: FXN contributes to Complex III assembly indirectly through its role in Fe-S cluster biosynthesis. The Rieske protein (UQCRFS1) requires a [2Fe-2S] cluster.
GO:0005739 mitochondrion	NAS PMID:27519411 Architecture of the Human Mitochondrial Iron-Sulfur Cluster ...	ACCEPT	Summary: Mitochondrial localization from structural study of ISC complex. Reason: Well-established mitochondrial localization. Supporting Evidence: PMID:27519411 Epub 2016 Aug 12. Architecture of the Human Mitochondrial Iron-Sulfur Cluster Assembly Machinery.
GO:0016226 iron-sulfur cluster assembly	NAS PMID:29097656 Structure and functional dynamics of the mitochondrial Fe/S ...	ACCEPT	Summary: Fe-S cluster assembly role from structural study. Reason: Core function confirmed by structural studies. Supporting Evidence: PMID:29097656 Structure and functional dynamics of the mitochondrial Fe/S cluster synthesis complex.
GO:0008198 ferrous iron binding	TAS Reactome:R-HSA-1362416	ACCEPT	Summary: Reactome annotation for frataxin binding iron. Reason: Core molecular function well supported.
GO:0016226 iron-sulfur cluster assembly	IDA PMID:12785837 Iron-sulfur cluster biosynthesis. Characterization of fratax...	ACCEPT	Summary: Direct experimental evidence from Yoon and Cowan demonstrating FXN as iron donor for [2Fe-2S] cluster assembly on ISU-type proteins. Reason: Key primary study demonstrating FXN's role in Fe-S cluster assembly with direct biochemical assays. Supporting Evidence: PMID:12785837 Holo frataxin is also shown to mediate the transfer of iron from holo frataxin to nucleation sites for [2Fe-2S] cluster formation on ISU.
GO:0006783 heme biosynthetic process	IDA PMID:15123683 Frataxin-mediated iron delivery to ferrochelatase in the fin...	KEEP AS NON CORE	Summary: Direct evidence that FXN delivers iron to ferrochelatase for heme biosynthesis. Reason: FXN serves as iron donor for ferrochelatase, but this is secondary to its primary role in Fe-S cluster assembly. Supporting Evidence: PMID:15123683 Herein we demonstrate Hs holofrataxin to be a high affinity iron binding partner for Hs ferrochelatase that is capable of both delivering iron to ferrochelatase and mediating the terminal step in mitochondrial heme biosynthesis
GO:0008047 enzyme activator activity	IDA PMID:15123683 Frataxin-mediated iron delivery to ferrochelatase in the fin...	ACCEPT	Summary: FXN activates ferrochelatase by delivering iron. It also activates the cysteine desulfurase NFS1 in the ISC complex. Reason: FXN activates both ferrochelatase (PMID:15123683) and the cysteine desulfurase NFS1 (PMID:24971490, PMID:28634302). This allosteric activation is a core function. Supporting Evidence: PMID:24971490 Previous in vitro results revealed a role for human FXN in activating the cysteine desulfurase and Fe-S cluster biosynthesis activities of the Fe-S assembly complex. PMID:15123683 2004 Apr 27. Frataxin-mediated iron delivery to ferrochelatase in the final step of heme biosynthesis.
GO:0051604 protein maturation	IMP PMID:15509595 Iron-sulfur protein maturation in human cells - evidence for...	KEEP AS NON CORE	Summary: FXN is required for maturation of Fe-S proteins. This reflects its role in Fe-S cluster assembly and transfer. Reason: FXN contributes to Fe-S protein maturation through its role in cluster assembly, but protein maturation is not its direct molecular function. Supporting Evidence: PMID:15509595 Oct 27. Iron-sulfur protein maturation in human cells: evidence for a function of frataxin.
GO:0008047 enzyme activator activity	IDA PMID:28634302 Structure of human Fe-S assembly subcomplex reveals unexpect...	ACCEPT	Summary: Structural evidence for FXN activating cysteine desulfurase. Reason: FXN functions as an allosteric activator of the cysteine desulfurase complex, accelerating sulfur transfer from NFS1 to ISCU. Supporting Evidence: PMID:28634302 Structure of human Fe-S assembly subcomplex reveals unexpected cysteine desulfurase architecture and acyl-ACP-ISD11 interactions.
GO:0008047 enzyme activator activity	IDA PMID:38627381 Mechanism and structural dynamics of sulfur transfer during ...	ACCEPT	Summary: Recent structural study showing FXN's activating role in sulfur transfer. Reason: Recent cryo-EM study demonstrates FXN optimally positions residues for rapid persulfide transfer from NFS1 to ISCU. Supporting Evidence: PMID:38627381 Mechanism and structural dynamics of sulfur transfer during de novo [2Fe-2S] cluster assembly on ISCU2.
GO:0044571 [2Fe-2S] cluster assembly	IDA PMID:29491838 Iron Sulfur and Molybdenum Cofactor Enzymes Regulate the Dro...	ACCEPT	Summary: This annotation is from FlyBase citing PMID:29491838, which is about Drosophila Fe-S cluster metabolism. The annotation to human FXN may be an inference from fly data. Reason: While the reference is about Drosophila, the annotation of human FXN's role in [2Fe-2S] cluster assembly is well-supported by other studies (PMID:24971490, PMID:29576242). FXN is a core component of the ISC complex required for [2Fe-2S] cluster synthesis. Supporting Evidence: PMID:24971490 FXN accelerates the accumulation of sulfur on ISCU2 and that the resulting persulfide species is viable in the subsequent synthesis of Fe-S clusters. PMID:29491838 Iron Sulfur and Molybdenum Cofactor Enzymes Regulate the Drosophila Life Cycle by Controlling Cell Metabolism.
GO:0044571 [2Fe-2S] cluster assembly	IDA PMID:38627381 Mechanism and structural dynamics of sulfur transfer during ...	ACCEPT	Summary: Recent structural study of [2Fe-2S] cluster assembly mechanism. Reason: Core function demonstrated by recent high-resolution structural studies. Supporting Evidence: PMID:38627381 Mechanism and structural dynamics of sulfur transfer during de novo [2Fe-2S] cluster assembly on ISCU2.
GO:0005739 mitochondrion	HTP PMID:34800366 Quantitative high-confidence human mitochondrial proteome an...	ACCEPT	Summary: High-throughput proteomics confirming mitochondrial localization. Reason: Well-established mitochondrial localization. Supporting Evidence: PMID:34800366 Epub 2021 Nov 19. Quantitative high-confidence human mitochondrial proteome and its dynamics in cellular context.
GO:0005759 mitochondrial matrix	IC PMID:29491838 Iron Sulfur and Molybdenum Cofactor Enzymes Regulate the Dro...	ACCEPT	Summary: FXN functions in the mitochondrial matrix as part of the ISC assembly complex. Reason: The ISC assembly complex operates in the mitochondrial matrix, and FXN is a component of this complex. Supporting Evidence: PMID:29491838 Iron Sulfur and Molybdenum Cofactor Enzymes Regulate the Drosophila Life Cycle by Controlling Cell Metabolism.
GO:0005515 protein binding	IPI PMID:31101807 Structure of the human frataxin-bound iron-sulfur cluster as...	ACCEPT	Summary: Interaction with ISCU and NFS1 demonstrated in structural study. This represents functionally relevant binding. Reason: This annotation reflects the specific, functionally important interactions of FXN with ISCU (Q9H1K1) and NFS1 (Q9Y697) demonstrated by cryo-EM. Supporting Evidence: PMID:31101807 Structure of the human frataxin-bound iron-sulfur cluster assembly complex provides insight into its activation mechanism.
GO:0099128 mitochondrial [2Fe-2S] assembly complex	IDA PMID:29491838 Iron Sulfur and Molybdenum Cofactor Enzymes Regulate the Dro...	ACCEPT	Summary: FXN is a component of the mitochondrial [2Fe-2S] assembly complex. Reason: Core cellular component for FXN, well established by multiple studies. Supporting Evidence: PMID:29491838 Iron Sulfur and Molybdenum Cofactor Enzymes Regulate the Drosophila Life Cycle by Controlling Cell Metabolism.
GO:0034986 iron chaperone activity	TAS Reactome:R-HSA-9866272	ACCEPT	Summary: Reactome annotation for iron chaperone function in cluster assembly. Reason: Core molecular function well supported.
GO:0099128 mitochondrial [2Fe-2S] assembly complex	IDA PMID:31101807 Structure of the human frataxin-bound iron-sulfur cluster as...	ACCEPT	Summary: Cryo-EM structure confirms FXN as component of ISC complex. Reason: High-resolution cryo-EM structure demonstrates FXN binding to the ISC complex. Supporting Evidence: PMID:31101807 Structure of the human frataxin-bound iron-sulfur cluster assembly complex provides insight into its activation mechanism.
GO:0044571 [2Fe-2S] cluster assembly	IDA PMID:24971490 Human frataxin activates Fe-S cluster biosynthesis by facili...	ACCEPT	Summary: Direct biochemical evidence that FXN accelerates [2Fe-2S] cluster assembly by facilitating sulfur transfer. Reason: Key study demonstrating FXN's allosteric activation of sulfur transfer from NFS1 to ISCU for [2Fe-2S] cluster assembly. Supporting Evidence: PMID:24971490 FXN accelerates the accumulation of sulfur on ISCU2 and that the resulting persulfide species is viable in the subsequent synthesis of Fe-S clusters.
GO:0008198 ferrous iron binding	IDA PMID:29576242 Interactions of iron-bound frataxin with ISCU and ferredoxin...	ACCEPT	Summary: NMR evidence for specific Fe2+ binding. Reason: Detailed NMR study demonstrating specific binding of Fe2+ (but not Fe3+) to FXN. Supporting Evidence: PMID:29576242 FXN tightly binds a single Fe2+ but not Fe3+.
GO:0044571 [2Fe-2S] cluster assembly	IDA PMID:29576242 Interactions of iron-bound frataxin with ISCU and ferredoxin...	ACCEPT	Summary: NMR study demonstrating FXN's role in [2Fe-2S] cluster assembly. Reason: Core biological process well supported. Supporting Evidence: PMID:29576242 Epub 2018 Mar 15. Interactions of iron-bound frataxin with ISCU and ferredoxin on the cysteine desulfurase complex leading to Fe-S cluster assembly.
GO:0044572 [4Fe-4S] cluster assembly	IDA PMID:29576242 Interactions of iron-bound frataxin with ISCU and ferredoxin...	KEEP AS NON CORE	Summary: FXN contributes to [4Fe-4S] cluster assembly indirectly through [2Fe-2S] cluster synthesis. Reason: FXN's direct role is in [2Fe-2S] cluster assembly. [4Fe-4S] clusters form downstream by combination of [2Fe-2S] clusters. Supporting Evidence: PMID:29576242 Epub 2018 Mar 15. Interactions of iron-bound frataxin with ISCU and ferredoxin on the cysteine desulfurase complex leading to Fe-S cluster assembly.
GO:0044572 [4Fe-4S] cluster assembly	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: Inferred from mouse ortholog. Reason: Indirect contribution through [2Fe-2S] cluster synthesis.
GO:0005739 mitochondrion	IDA PMID:21298097 Mammalian frataxin - an essential function for cellular viab...	ACCEPT	Summary: Experimental evidence for mitochondrial localization. Reason: Well-established mitochondrial localization. Supporting Evidence: PMID:21298097 Mammalian frataxin: an essential function for cellular viability through an interaction with a preformed ISCU/NFS1/ISD11 iron-sulfur assembly complex.
GO:0099128 mitochondrial [2Fe-2S] assembly complex	IDA PMID:21298097 Mammalian frataxin - an essential function for cellular viab...	ACCEPT	Summary: Key study demonstrating FXN interacts with preformed ISCU/NFS1/ISD11 complex. Reason: Comprehensive study showing FXN is a component of the ISC assembly complex. Supporting Evidence: PMID:21298097 Our results demonstrate that frataxin interacts with a preformed ISCU/NFS1/ISD11 complex rather than with the individual components to form a stable quaternary complex.
GO:0005515 protein binding	IPI PMID:26702583 Mitochondrial Hspa9/Mortalin regulates erythroid differentia...	ACCEPT	Summary: Interaction with HSPA9/mortalin demonstrated. Reason: HSPA9 is a mitochondrial chaperone involved in Fe-S cluster transfer. The interaction with FXN is functionally relevant. Supporting Evidence: PMID:26702583 Dec 17. Mitochondrial Hspa9/Mortalin regulates erythroid differentiation via iron-sulfur cluster assembly.
GO:0005759 mitochondrial matrix	TAS Reactome:R-HSA-1362408	ACCEPT	Summary: Reactome annotation for mitochondrial matrix localization. Reason: The ISC complex operates in the mitochondrial matrix.
GO:0005759 mitochondrial matrix	TAS Reactome:R-HSA-1362416	ACCEPT	Summary: Duplicate Reactome annotation. Reason: Correct localization.
GO:0005759 mitochondrial matrix	TAS Reactome:R-HSA-9854405	ACCEPT	Summary: Reactome annotation for frataxin transferring Fe2+ to ACO2. Reason: Correct localization.
GO:0005759 mitochondrial matrix	TAS Reactome:R-HSA-9854984	ACCEPT	Summary: Reactome annotation for Fe-S cluster transfer to SDHB. Reason: Correct localization.
GO:0005759 mitochondrial matrix	TAS Reactome:R-HSA-9866272	ACCEPT	Summary: Reactome annotation for [2Fe-2S] insertion in UQCRFS1. Reason: Correct localization.
GO:0004322 ferroxidase activity	IDA PMID:15641778 Assembly of human frataxin is a mechanism for detoxifying re...	ACCEPT	Summary: Direct demonstration of ferroxidase activity for oligomeric FXN. Reason: The oligomeric form of FXN has ferroxidase activity that may help detoxify redox-active iron, though the monomer is likely the predominant functional form. Supporting Evidence: PMID:15641778 The assembled protein has ferroxidase activity and detoxifies redox-active iron by sequestering it in a protein-protected compartment.
GO:0051349 positive regulation of lyase activity	IDA PMID:20053667 Molecular control of the cytosolic aconitase/IRP1 switch by ...	KEEP AS NON CORE	Summary: Extramitochondrial frataxin modulates cytosolic aconitase (ACO1) activity. Reason: This activity of extramitochondrial frataxin is a secondary function. The primary role is in mitochondrial Fe-S cluster assembly. Supporting Evidence: PMID:20053667 Molecular control of the cytosolic aconitase/IRP1 switch by extramitochondrial frataxin.
GO:0070301 cellular response to hydrogen peroxide	IDA PMID:15641778 Assembly of human frataxin is a mechanism for detoxifying re...	KEEP AS NON CORE	Summary: Oligomeric FXN can detoxify redox-active iron and protect against oxidative stress. Reason: Protection against oxidative stress is a secondary consequence of FXN's iron sequestration activity. Supporting Evidence: PMID:15641778 However, the monomer is unable to prevent iron-catalyzed radical reactions and the formation of insoluble ferric iron oxides
GO:0043066 negative regulation of apoptotic process	IMP PMID:16608849 A pool of extramitochondrial frataxin that promotes cell sur...	KEEP AS NON CORE	Summary: Extramitochondrial frataxin contributes to cell survival and inhibits apoptosis. Reason: Anti-apoptotic function is associated with extramitochondrial frataxin and represents a secondary function. Supporting Evidence: PMID:16608849 2006 Apr 11. A pool of extramitochondrial frataxin that promotes cell survival.
GO:0090201 negative regulation of release of cytochrome c from mitochondria	IMP PMID:16608849 A pool of extramitochondrial frataxin that promotes cell sur...	KEEP AS NON CORE	Summary: FXN prevents cytochrome c release from mitochondria. Reason: This anti-apoptotic effect is a secondary consequence of FXN function. Supporting Evidence: PMID:16608849 2006 Apr 11. A pool of extramitochondrial frataxin that promotes cell survival.
GO:0034986 iron chaperone activity	IDA PMID:15123683 Frataxin-mediated iron delivery to ferrochelatase in the fin...	ACCEPT	Summary: Direct demonstration of iron chaperone activity - FXN delivers iron to ferrochelatase. Reason: Iron chaperone activity is a core molecular function of FXN, delivering iron to both ferrochelatase and the ISC assembly complex. Supporting Evidence: PMID:15123683 Herein we demonstrate Hs holofrataxin to be a high affinity iron binding partner for Hs ferrochelatase that is capable of both delivering iron to ferrochelatase and mediating the terminal step in mitochondrial heme biosynthesis
GO:0005759 mitochondrial matrix	ISS GO_REF:0000024	ACCEPT	Summary: Inferred from yeast ortholog. Reason: Correct localization based on conserved function.
GO:0005759 mitochondrial matrix	NAS PMID:17285345 N-terminal iron-mediated self-cleavage of human frataxin - r...	ACCEPT	Summary: Mitochondrial matrix localization from iron-binding study. Reason: Correct localization. Supporting Evidence: PMID:17285345 2007 Feb 7. N-terminal iron-mediated self-cleavage of human frataxin: regulation of iron binding and complex formation with target proteins.
GO:0008198 ferrous iron binding	IDA PMID:12785837 Iron-sulfur cluster biosynthesis. Characterization of fratax...	ACCEPT	Summary: Initial characterization of iron binding to frataxin. Reason: Core molecular function well demonstrated. Supporting Evidence: PMID:12785837 In this paper we demonstrate human frataxin to bind from six to seven iron ions.
GO:0008198 ferrous iron binding	IDA PMID:17285345 N-terminal iron-mediated self-cleavage of human frataxin - r...	ACCEPT	Summary: Iron binding study with N-terminal self-cleavage characterization. Reason: Core molecular function. Supporting Evidence: PMID:17285345 2007 Feb 7. N-terminal iron-mediated self-cleavage of human frataxin: regulation of iron binding and complex formation with target proteins.
GO:0008199 ferric iron binding	IDA PMID:12785837 Iron-sulfur cluster biosynthesis. Characterization of fratax...	MARK AS OVER ANNOTATED	Summary: Early study reporting ferric iron binding. Later NMR studies (PMID:29576242) show FXN preferentially binds Fe2+ not Fe3+. Reason: More recent NMR evidence demonstrates FXN binds Fe2+ but not Fe3+ (PMID:29576242). The earlier reports of Fe3+ binding may reflect oxidation of bound Fe2+. Supporting Evidence: PMID:12785837 Iron-sulfur cluster biosynthesis.
GO:0016540 protein autoprocessing	IDA PMID:12785837 Iron-sulfur cluster biosynthesis. Characterization of fratax...	REMOVE	Summary: FXN precursor undergoes two-step proteolytic processing by MPP to yield mature form. This is not autoprocessing but processing by mitochondrial processing peptidase. Reason: FXN is processed by mitochondrial processing peptidase (MPP), not by autoprocessing. The term is incorrect for FXN maturation. Supporting Evidence: PMID:12785837 Iron-sulfur cluster biosynthesis.
GO:0051537 2 iron, 2 sulfur cluster binding	IDA PMID:12785837 Iron-sulfur cluster biosynthesis. Characterization of fratax...	UNDECIDED	Summary: Some evidence for [2Fe-2S] binding was reported, but FXN's primary role is to facilitate cluster assembly on ISCU rather than to bind clusters itself. Reason: The evidence for [2Fe-2S] cluster binding by FXN is limited. More recent studies emphasize FXN's role in delivering iron and activating sulfur transfer rather than binding assembled clusters. Supporting Evidence: PMID:12785837 Iron-sulfur cluster biosynthesis.
GO:0005515 protein binding	IPI PMID:15123683 Frataxin-mediated iron delivery to ferrochelatase in the fin...	ACCEPT	Summary: Interaction with ferrochelatase (FECH/P22830) demonstrated. Reason: Functionally relevant interaction with ferrochelatase for iron delivery in heme biosynthesis. Supporting Evidence: PMID:15123683 Herein we demonstrate Hs holofrataxin to be a high affinity iron binding partner for Hs ferrochelatase that is capable of both delivering iron to ferrochelatase and mediating the terminal step in mitochondrial heme biosynthesis
GO:0005739 mitochondrion	IDA PMID:17468497 In vivo maturation of human frataxin.	ACCEPT	Summary: Experimental evidence for mitochondrial localization in vivo. Reason: Well-established mitochondrial localization. Supporting Evidence: PMID:17468497 Apr 27. In vivo maturation of human frataxin.
GO:0005829 cytosol	IDA PMID:17468497 In vivo maturation of human frataxin.	ACCEPT	Summary: Evidence for cytosolic localization of some FXN forms. Reason: Extramitochondrial frataxin exists in the cytosol. Supporting Evidence: PMID:17468497 Apr 27. In vivo maturation of human frataxin.
GO:0006879 intracellular iron ion homeostasis	IMP PMID:18160053 The effects of frataxin silencing in HeLa cells are rescued ...	KEEP AS NON CORE	Summary: FXN silencing disrupts iron homeostasis, rescued by mitochondrial ferritin expression. Reason: Effect on iron homeostasis is indirect through disrupted Fe-S cluster assembly. Supporting Evidence: PMID:18160053 The effects of frataxin silencing in HeLa cells are rescued by the expression of human mitochondrial ferritin.
GO:0008198 ferrous iron binding	IDA PMID:15123683 Frataxin-mediated iron delivery to ferrochelatase in the fin...	ACCEPT	Summary: Fe2+ binding demonstrated in context of ferrochelatase delivery. Reason: Core molecular function. Supporting Evidence: PMID:15123683 2004 Apr 27. Frataxin-mediated iron delivery to ferrochelatase in the final step of heme biosynthesis.
GO:0008199 ferric iron binding	IDA PMID:18537827 Dynamics, stability and iron-binding activity of frataxin cl...	MARK AS OVER ANNOTATED	Summary: Study of FRDA clinical mutants and iron binding. Reason: More recent NMR evidence (PMID:29576242) shows FXN binds Fe2+ but not Fe3+. Supporting Evidence: PMID:18537827 Dynamics, stability and iron-binding activity of frataxin clinical mutants.
GO:0010039 response to iron ion	IMP PMID:18424449 Iron-dependent regulation of frataxin expression - implicati...	KEEP AS NON CORE	Summary: FXN expression is regulated by iron levels. Reason: FXN is regulated by iron, but this describes regulation of FXN rather than its function. Supporting Evidence: PMID:18424449 Apr 17. Iron-dependent regulation of frataxin expression: implications for treatment of Friedreich ataxia.
GO:0005515 protein binding	IPI PMID:15961414 Frataxin interacts functionally with mitochondrial electron ...	ACCEPT	Summary: Interaction with succinate dehydrogenase subunits SDHA (P31040) and SDHB (P21912) demonstrated. Reason: Functionally relevant interactions with respiratory chain proteins containing Fe-S clusters. Supporting Evidence: PMID:15961414 Frataxin interacts functionally with mitochondrial electron transport chain proteins.

Gene Description

Existing Annotations Review

Core Functions

FXN functions as an allosteric activator of the cysteine desulfurase NFS1, accelerating persulfide formation and sulfur transfer to ISCU. Recent cryo-EM structures show FXN optimally positions ISCU assembly-site residues to enable rapid sulfur transfer.

FXN binds ferrous iron (Fe2+) with high affinity but does not bind ferric iron (Fe3+). The iron-binding site is located on the alpha1-beta1 face of the protein. Iron binding is essential for FXN's iron chaperone function.

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