ISCA1

UniProt ID: Q9BUE6
Organism: Homo sapiens
Review Status: COMPLETE
📝 Provide Detailed Feedback

Gene Description

ISCA1 is a mitochondrial matrix A-type iron-sulfur (Fe-S) cluster assembly protein that functions late in the ISC biogenesis pathway, specifically in the maturation of [4Fe-4S] cluster-containing proteins. ISCA1 forms a heterodimeric complex with ISCA2 that acts as an "assembler" of [4Fe-4S] clusters by receiving two [2Fe-2S] clusters from GLRX5 and catalyzing their reductive fusion into a single [4Fe-4S] cluster. This reaction requires the additional factor IBA57 and electrons from the mitochondrial ferredoxin FDX2 and its reductase FDXR. The assembled [4Fe-4S] clusters are then transferred to target apoproteins, with downstream factors NFU1 and BOLA3 mediating insertion for certain targets including lipoic acid synthase (LIAS) and respiratory complex I subunits. ISCA1 is essential for [4Fe-4S] protein maturation but dispensable for [2Fe-2S] proteins. Pathogenic variants cause Multiple Mitochondrial Dysfunctions Syndrome 5 (MMDS5), characterized by infantile-onset leukodystrophy, lactic acidosis, and combined OXPHOS deficiencies.

Existing Annotations Review

GO Term Evidence Action Reason
GO:0005737 cytoplasm
IBA
GO_REF:0000033 		REMOVE
Summary: IBA annotation based on phylogenetic inference. While bacterial A-type ISC proteins (IscA) function in the cytoplasm, human ISCA1 is a mitochondrial matrix protein (PMID:22323289). ISCA1 contains a mitochondrial targeting sequence (residues 1-12) and has been experimentally localized to mitochondria. This cytoplasm annotation likely reflects the cytoplasmic function of bacterial orthologs rather than human ISCA1.
Reason: Sheftel et al. (PMID:22323289) demonstrated that ISCA1 localizes to mitochondria, not cytoplasm: "ISCA1, ISCA2, and IBA57 are localized to mitochondria". The UniProt entry also indicates mitochondrial localization. While bacterial IscA orthologs function in the cytoplasm, human ISCA1 is a mitochondrial protein. There is no evidence for cytoplasmic ISCA1 function; the authors explicitly state "We further provide evidence against a localization and direct Fe/S protein maturation function of ISCA1 and ISCA2 in the cytosol."
Supporting Evidence:
PMID:22323289
We further provide evidence against a localization and direct Fe/S protein maturation function of ISCA1 and ISCA2 in the cytosol.
file:human/ISCA1/ISCA1-deep-research-falcon.md
model: Edison Scientific Literature
GO:0005739 mitochondrion
IBA
GO_REF:0000033 		ACCEPT
Summary: IBA annotation for mitochondrial localization is well supported by experimental evidence. ISCA1 is a mitochondrial matrix protein with a cleavable N-terminal transit peptide (PMID:22323289, PMID:25347204).
Reason: Mitochondrial localization of ISCA1 is extensively documented. Sheftel et al. (PMID:22323289) demonstrated mitochondrial localization and showed that depletion causes mitochondrial ultrastructural abnormalities. The IBA annotation is phylogenetically sound and consistent with all experimental evidence.
Supporting Evidence:
PMID:22323289
ISCA1, ISCA2, and IBA57 are localized to mitochondria
GO:0016226 iron-sulfur cluster assembly
IBA
GO_REF:0000033 		MODIFY
Summary: ISCA1 is involved in iron-sulfur cluster assembly, specifically in the late-stage maturation of [4Fe-4S] clusters. However, the more specific term GO:0044572 ([4Fe-4S] cluster assembly) better captures ISCA1's function.
Reason: While this term is not incorrect, ISCA1 specifically functions in [4Fe-4S] cluster assembly rather than general Fe-S cluster assembly. Sheftel et al. (PMID:22323289) showed that ISCA1 depletion affects [4Fe-4S] proteins (aconitase, complex I, LIAS) but not [2Fe-2S] proteins (ferrochelatase). The more specific term GO:0044572 ([4Fe-4S] cluster assembly) is more appropriate.
Proposed replacements: [4Fe-4S] cluster assembly
Supporting Evidence:
PMID:22323289
In contrast, the mitochondrial [2Fe-2S] enzyme ferrochelatase and cellular heme content were unaffected.
GO:0051604 protein maturation
IBA
GO_REF:0000033 		ACCEPT
Summary: ISCA1 is involved in protein maturation, specifically the maturation of [4Fe-4S] proteins. This annotation is correct but very general; it could be more specific.
Reason: ISCA1 functions in the maturation of [4Fe-4S] proteins by delivering assembled [4Fe-4S] clusters to target apoproteins. The term "protein maturation" is appropriate as a high-level description. PMID:22323289 demonstrates that ISCA1 is "specifically involved in the maturation of mitochondrial [4Fe-4S] proteins."
Supporting Evidence:
PMID:22323289
ISCA1, ISCA2, and IBA57 are specifically involved in the maturation of mitochondrial [4Fe-4S] proteins functioning late in the ISC assembly pathway.
GO:0051537 2 iron, 2 sulfur cluster binding
IBA
GO_REF:0000033 		ACCEPT
Summary: ISCA1 can bind [2Fe-2S] clusters as intermediates during [4Fe-4S] cluster assembly. Biochemical reconstitution shows that ISCA1/ISCA2 heterodimer receives [2Fe-2S] clusters from GLRX5 before reductive fusion to form [4Fe-4S] (PMID:25347204).
Reason: Brancaccio et al. (PMID:25347204) demonstrated that ISCA1 binds [2Fe-2S] clusters during the [4Fe-4S] assembly process. The [2Fe-2S] binding is transient but essential for the conversion to [4Fe-4S].
Supporting Evidence:
PMID:25347204
two molecules of [2Fe-2S](2+) GRX5 donate their cluster to a heterodimeric ISCA1/ISCA2 complex.
GO:0005739 mitochondrion
IEA
GO_REF:0000044 		ACCEPT
Summary: IEA annotation based on UniProt subcellular location mapping. This is consistent with experimental evidence.
Reason: The IEA annotation is consistent with multiple experimental studies confirming mitochondrial localization of ISCA1. UniProt correctly annotates ISCA1 as mitochondrial based on experimental literature.
Supporting Evidence:
PMID:22323289
ISCA1, ISCA2, and IBA57 are localized to mitochondria
GO:0016226 iron-sulfur cluster assembly
IEA
GO_REF:0000002 		MODIFY
Summary: IEA annotation based on InterPro domain mapping. The Fe-S biogenesis domain correctly predicts involvement in Fe-S cluster assembly.
Reason: While correct at the general level, ISCA1 specifically functions in [4Fe-4S] cluster assembly, not in [2Fe-2S] assembly. The more specific term GO:0044572 ([4Fe-4S] cluster assembly) would be more accurate.
Proposed replacements: [4Fe-4S] cluster assembly
Supporting Evidence:
PMID:22323289
ISCA1, ISCA2, and IBA57 are specifically involved in the maturation of mitochondrial [4Fe-4S] proteins
GO:0046872 metal ion binding
IEA
GO_REF:0000043 		ACCEPT
Summary: IEA annotation based on UniProt keyword mapping. ISCA1 binds iron as part of iron-sulfur clusters. This is a very general term.
Reason: ISCA1 binds iron cations as part of [2Fe-2S] and [4Fe-4S] cluster binding. UniProt lists iron binding sites at positions 57, 121, and 123. While this term is very general, it is technically correct.
Supporting Evidence:
PMID:25347204
ISCA2 binds either [2Fe-2S] or [4Fe-4S] cluster in a dimeric state
GO:0051536 iron-sulfur cluster binding
IEA
GO_REF:0000120 		ACCEPT
Summary: IEA annotation combining InterPro and UniProt evidence. ISCA1 binds both [2Fe-2S] and [4Fe-4S] clusters during the assembly process.
Reason: ISCA1 binds iron-sulfur clusters as part of its function in [4Fe-4S] cluster assembly. It transiently binds [2Fe-2S] clusters received from GLRX5 and can bind the resulting [4Fe-4S] cluster before transfer to target proteins (PMID:25347204). This general term encompasses both cluster types.
Supporting Evidence:
PMID:25347204
ISCA2 binds either [2Fe-2S] or [4Fe-4S] cluster in a dimeric state
GO:0005515 protein binding
IPI
PMID:25347204
Formation of [4Fe-4S] clusters in the mitochondrial iron-sul... 		MODIFY
Summary: IPI annotation documenting ISCA1-ISCA2 interaction. The ISCA1-ISCA2 heterodimer is the functional unit for [4Fe-4S] cluster assembly.
Reason: While the protein-protein interaction is real, "protein binding" is uninformative. The ISCA1-ISCA2 interaction is central to the protein's core molecular function in [4Fe-4S] cluster assembly. A more specific MF term such as GO:0140132 (iron-sulfur cluster chaperone activity) would better capture ISCA1's function of binding Fe-S clusters and delivering them to acceptor molecules.
Supporting Evidence:
PMID:25347204
This complex acts as an "assembler" of [4Fe-4S] clusters; i.e., the two GRX5-donated [2Fe-2S](2+) clusters generate a [4Fe-4S](2+) cluster.
GO:0005515 protein binding
IPI
PMID:33961781
Dual proteome-scale networks reveal cell-specific remodeling... 		MARK AS OVER ANNOTATED
Summary: IPI annotation from BioPlex high-throughput interactome study. Documents ISCA1-ISCA2 interaction.
Reason: This is a duplicate protein binding annotation from a high-throughput study. While the ISCA1-ISCA2 interaction is well-established and functionally important, "protein binding" does not add informative value. The interaction is already documented via PMID:25347204 and the protein's membership in the mitochondrial [4Fe-4S] assembly complex (GO:0120510).
Supporting Evidence:
PMID:33961781
Dual proteome-scale networks reveal cell-specific remodeling of the human interactome
GO:0005515 protein binding
IPI
PMID:40205054
Multimodal cell maps as a foundation for structural and func... 		MARK AS OVER ANNOTATED
Summary: IPI annotation from multimodal cell maps study documenting protein interactions.
Reason: Another high-throughput interaction study documenting ISCA1-ISCA2 binding. While confirming the interaction, "protein binding" is uninformative for understanding ISCA1's molecular function. The key interaction with ISCA2 is better captured by the complex membership annotation (GO:0120510).
Supporting Evidence:
PMID:40205054
Multimodal cell maps as a foundation for structural and functional genomics
GO:0005739 mitochondrion
IDA
PMID:22323289
The human mitochondrial ISCA1, ISCA2, and IBA57 proteins are... 		ACCEPT
Summary: IDA annotation from the key study establishing ISCA1's mitochondrial localization and function.
Reason: Sheftel et al. (PMID:22323289) directly demonstrated mitochondrial localization of ISCA1 using multiple approaches. This is the primary experimental evidence for ISCA1's subcellular localization.
Supporting Evidence:
PMID:22323289
ISCA1, ISCA2, and IBA57 are localized to mitochondria
GO:0051604 protein maturation
IDA
PMID:25347204
Formation of [4Fe-4S] clusters in the mitochondrial iron-sul... 		ACCEPT
Summary: IDA annotation for involvement in protein maturation based on biochemical reconstitution showing ISCA1/ISCA2 function in [4Fe-4S] cluster assembly.
Reason: Brancaccio et al. (PMID:25347204) demonstrated that the ISCA1/ISCA2 complex assembles [4Fe-4S] clusters from [2Fe-2S] donors, which is essential for maturation of [4Fe-4S] proteins. The term captures ISCA1's role in protein maturation at a general level.
Supporting Evidence:
PMID:25347204
heterodimeric complex is the functional unit in mitochondria receiving [2Fe-2S] clusters from hGRX5 and assembling [4Fe-4S] clusters before their transfer to the final target apo proteins.
GO:0005739 mitochondrion
HTP
PMID:34800366
Quantitative high-confidence human mitochondrial proteome an... 		ACCEPT
Summary: HTP annotation from high-confidence mitochondrial proteome study confirming ISCA1 as a mitochondrial protein.
Reason: This high-throughput proteomics study (MitoCoP) confirms ISCA1 is a mitochondrial protein, consistent with targeted experimental studies.
Supporting Evidence:
PMID:34800366
We classified >8,000 proteins in mitochondrial preparations of human cells and defined a mitochondrial high-confidence proteome of >1,100 proteins (MitoCoP).
GO:0120510 mitochondrial [4Fe-4S] assembly complex
IDA
PMID:25347204
Formation of [4Fe-4S] clusters in the mitochondrial iron-sul... 		ACCEPT
Summary: IDA annotation documenting ISCA1 as part of the mitochondrial [4Fe-4S] assembly complex with ISCA2.
Reason: Brancaccio et al. (PMID:25347204) demonstrated that ISCA1 forms a heterodimeric complex with ISCA2 that functions as the [4Fe-4S] cluster assembler. This complex term accurately captures ISCA1's molecular context and function.
Supporting Evidence:
PMID:25347204
two molecules of [2Fe-2S](2+) GRX5 donate their cluster to a heterodimeric ISCA1/ISCA2 complex.
GO:0005759 mitochondrial matrix
TAS
Reactome:R-HSA-8878815 		ACCEPT
Summary: TAS annotation from Reactome pathway "Formation of 4Fe-4S cluster on ISCA1:ISCA2". Specifies mitochondrial matrix localization.
Reason: ISCA1 functions in the mitochondrial matrix, as established by both experimental studies and pathway databases. The mitochondrial matrix is the more specific localization compared to general mitochondrion.
Supporting Evidence:
PMID:22323289
ISCA1, ISCA2, and IBA57 are localized to mitochondria
GO:0005759 mitochondrial matrix
TAS
Reactome:R-HSA-9854984 		ACCEPT
Summary: TAS annotation from Reactome pathway "Transfer of Fe-S clusters to SDHB". Documents ISCA1's role in delivering [4Fe-4S] clusters to target proteins.
Reason: This annotation documents the downstream function of ISCA1 in delivering [4Fe-4S] clusters to target proteins like SDHB. The mitochondrial matrix localization is correct.
Supporting Evidence:
PMID:25347204
heterodimeric complex is the functional unit in mitochondria receiving [2Fe-2S] clusters from hGRX5 and assembling [4Fe-4S] clusters before their transfer to the final target apo proteins.
GO:0044572 [4Fe-4S] cluster assembly
IDA
PMID:22323289
The human mitochondrial ISCA1, ISCA2, and IBA57 proteins are... 		NEW
Summary: ISCA1 specifically functions in [4Fe-4S] cluster assembly, not general Fe-S cluster assembly. This is the more specific BP term for ISCA1's function.
Reason: Sheftel et al. (PMID:22323289) demonstrated that ISCA1 depletion specifically affects [4Fe-4S] proteins but not [2Fe-2S] proteins. This term more accurately captures ISCA1's specific function in the late-stage ISC assembly pathway.
Supporting Evidence:
PMID:22323289
In contrast, the mitochondrial [2Fe-2S] enzyme ferrochelatase and cellular heme content were unaffected.
PMID:25347204
This complex acts as an "assembler" of [4Fe-4S] clusters; i.e., the two GRX5-donated [2Fe-2S](2+) clusters generate a [4Fe-4S](2+) cluster.
GO:0140132 iron-sulfur cluster chaperone activity
IDA
PMID:25347204
Formation of [4Fe-4S] clusters in the mitochondrial iron-sul... 		NEW
Summary: ISCA1 functions as an Fe-S cluster chaperone, binding [2Fe-2S] clusters from GLRX5, converting them to [4Fe-4S], and delivering them to target proteins.
Reason: This MF term accurately describes ISCA1's molecular function of "binding to an iron-sulfur cluster and delivering it to an acceptor molecule." Brancaccio et al. demonstrated this chaperone function biochemically.
Supporting Evidence:
PMID:25347204
heterodimeric complex is the functional unit in mitochondria receiving [2Fe-2S] clusters from hGRX5 and assembling [4Fe-4S] clusters before their transfer to the final target apo proteins.
GO:0051539 4 iron, 4 sulfur cluster binding
IDA
PMID:25347204
Formation of [4Fe-4S] clusters in the mitochondrial iron-sul... 		NEW
Summary: The ISCA1/ISCA2 complex binds [4Fe-4S] clusters after assembly and before transfer to target proteins.
Reason: Brancaccio et al. (PMID:25347204) showed that after reductive fusion of two [2Fe-2S] clusters, the ISCA1/ISCA2 heterodimer holds a [4Fe-4S] cluster before transfer to target proteins. Both [2Fe-2S] binding (existing annotation) and [4Fe-4S] binding should be annotated.
Supporting Evidence:
PMID:25347204
ISCA2 binds either [2Fe-2S] or [4Fe-4S] cluster in a dimeric state

Core Functions

ISCA1 is a core component of the late-acting mitochondrial [4Fe-4S] cluster assembly machinery. The ISCA1/ISCA2 heterodimer receives [2Fe-2S] clusters from GLRX5 and catalyzes their reductive fusion into [4Fe-4S] clusters, requiring electrons from FDX2/FDXR and the additional factor IBA57. This function is essential for maturation of mitochondrial [4Fe-4S] proteins including aconitase, respiratory complex I subunits, and lipoic acid synthase.

Molecular Function:
iron-sulfur cluster chaperone activity
Directly Involved In:
[4Fe-4S] cluster assembly
Cellular Locations:
mitochondrial matrix
In Complex:
mitochondrial [4Fe-4S] assembly complex
Supporting Evidence:
  • PMID:22323289
    ISCA1, ISCA2, and IBA57 are specifically involved in the maturation of mitochondrial [4Fe-4S] proteins functioning late in the ISC assembly pathway.
  • PMID:25347204
    This complex acts as an "assembler" of [4Fe-4S] clusters; i.e., the two GRX5-donated [2Fe-2S](2+) clusters generate a [4Fe-4S](2+) cluster.

References

GO_REF:0000002
Gene Ontology annotation through association of InterPro records with GO terms
GO_REF:0000033
Annotation inferences using phylogenetic trees
GO_REF:0000043
Gene Ontology annotation based on UniProtKB/Swiss-Prot keyword mapping
GO_REF:0000044
Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location vocabulary mapping
GO_REF:0000120
Combined Automated Annotation using Multiple IEA Methods
PMID:22323289
The human mitochondrial ISCA1, ISCA2, and IBA57 proteins are required for [4Fe-4S] protein maturation.
  • ISCA1 localizes to mitochondria
    "ISCA1, ISCA2, and IBA57 are localized to mitochondria"
  • ISCA1 depletion causes mitochondrial ultrastructural abnormalities
    "Depleted cells contained massively swollen and enlarged mitochondria that were virtually devoid of cristae membranes"
  • ISCA1 depletion reduces activity of [4Fe-4S] proteins (aconitase, complex I, LIAS)
    "The activities of mitochondrial [4Fe-4S] proteins, including aconitase, respiratory complex I, and lipoic acid synthase, were diminished following depletion of the three proteins."
  • [2Fe-2S] proteins (ferrochelatase) are unaffected by ISCA1 depletion
    "In contrast, the mitochondrial [2Fe-2S] enzyme ferrochelatase and cellular heme content were unaffected."
  • ISCA1 functions late in the ISC assembly pathway
    "ISCA1, ISCA2, and IBA57 are specifically involved in the maturation of mitochondrial [4Fe-4S] proteins functioning late in the ISC assembly pathway."
PMID:25347204
Formation of [4Fe-4S] clusters in the mitochondrial iron-sulfur cluster assembly machinery.
  • ISCA1/ISCA2 heterodimer receives [2Fe-2S] clusters from GLRX5
    "two molecules of [2Fe-2S](2+) GRX5 donate their cluster to a heterodimeric ISCA1/ISCA2 complex."
  • The heterodimer acts as an assembler converting two [2Fe-2S] to one [4Fe-4S]
    "This complex acts as an "assembler" of [4Fe-4S] clusters; i.e., the two GRX5-donated [2Fe-2S](2+) clusters generate a [4Fe-4S](2+) cluster."
  • [4Fe-4S] clusters are transferred to target apoproteins
    "heterodimeric complex is the functional unit in mitochondria receiving [2Fe-2S] clusters from hGRX5 and assembling [4Fe-4S] clusters before their transfer to the final target apo proteins."
  • ISCA1/ISCA2 is the functional unit for mitochondrial [4Fe-4S] assembly
    "heterodimeric complex is the functional unit in mitochondria receiving [2Fe-2S] clusters from hGRX5 and assembling [4Fe-4S] clusters before their transfer to the final target apo proteins."
PMID:33961781
Dual proteome-scale networks reveal cell-specific remodeling of the human interactome.
  • BioPlex 3.0 interactome study confirms ISCA1-ISCA2 protein-protein interaction
    "we have created two proteome-scale, cell-line-specific interaction networks"
PMID:34800366
Quantitative high-confidence human mitochondrial proteome and its dynamics in cellular context.
  • ISCA1 identified as mitochondrial protein in high-confidence mitochondrial proteome (MitoCoP)
    "We classified >8,000 proteins in mitochondrial preparations of human cells and defined a mitochondrial high-confidence proteome of >1,100 proteins (MitoCoP)."
PMID:40205054
Multimodal cell maps as a foundation for structural and functional genomics.
  • Confirms ISCA1-ISCA2 interaction
    "Multimodal cell maps as a foundation for structural and functional genomics"
Reactome:R-HSA-8878815
Formation of 4Fe-4S cluster on ISCA1:ISCA2
  • ISCA1:ISCA2 complex forms [4Fe-4S] clusters in mitochondrial matrix
Reactome:R-HSA-9854984
Transfer of Fe-S clusters to SDHB
  • ISCA1 involved in Fe-S cluster transfer to target proteins including SDHB
file:human/ISCA1/ISCA1-deep-research-falcon.md
Deep research report on ISCA1

Suggested Experiments

Experiment: Structural characterization of the human ISCA1/ISCA2/IBA57 complex with bound Fe-S clusters to understand the molecular mechanism of [2Fe-2S] to [4Fe-4S] conversion.

Experiment: Identification of the complete set of [4Fe-4S] target proteins that depend on ISCA1/ISCA2 for cluster acquisition versus those using alternative delivery pathways.

Tags

iron-sulfur-cluster-biogenesis

📚 Additional Documentation

Deep Research Falcon

(ISCA1-deep-research-falcon.md)

provider: falcon
model: Edison Scientific Literature
cached: false
start_time: '2025-12-29T00:22:48.342084'
end_time: '2025-12-29T00:26:51.960717'
duration_seconds: 243.62
template_file: templates/gene_research_go_focused.md
template_variables:
organism: human
gene_id: ISCA1
gene_symbol: ISCA1
uniprot_accession: Q9BUE6
protein_description: 'RecName: Full=Iron-sulfur cluster assembly 1 homolog, mitochondrial;
AltName: Full=HESB-like domain-containing protein 2; AltName: Full=Iron-sulfur
assembly protein IscA; Short=hIscA; Flags: Precursor;'
gene_info: Name=ISCA1; Synonyms=HBLD2; ORFNames=GK004;
organism_full: Homo sapiens (Human).
protein_family: Belongs to the HesB/IscA family. .
protein_domains: Fe-S_cluster_asmbl/transfer. (IPR050322); FeS_biogenesis. (IPR000361);
FeS_cluster_insertion. (IPR016092); FeS_cluster_insertion_CS. (IPR017870); HesB-like_dom_sf.
(IPR035903)
provider_config:
timeout: 600
max_retries: 3
parameters:
allowed_domains: []
temperature: 0.1
citation_count: 21

Question

Gene Research for Functional Annotation

⚠️ CRITICAL: Gene/Protein Identification Context

BEFORE YOU BEGIN RESEARCH: You MUST verify you are researching the CORRECT gene/protein. Gene symbols can be ambiguous, especially for less well-characterized genes from non-model organisms.

Target Gene/Protein Identity (from UniProt):

  • UniProt Accession: Q9BUE6
  • Protein Description: RecName: Full=Iron-sulfur cluster assembly 1 homolog, mitochondrial; AltName: Full=HESB-like domain-containing protein 2; AltName: Full=Iron-sulfur assembly protein IscA; Short=hIscA; Flags: Precursor;
  • Gene Information: Name=ISCA1; Synonyms=HBLD2; ORFNames=GK004;
  • Organism (full): Homo sapiens (Human).
  • Protein Family: Belongs to the HesB/IscA family. .
  • Key Domains: Fe-S_cluster_asmbl/transfer. (IPR050322); FeS_biogenesis. (IPR000361); FeS_cluster_insertion. (IPR016092); FeS_cluster_insertion_CS. (IPR017870); HesB-like_dom_sf. (IPR035903)

MANDATORY VERIFICATION STEPS:

  1. Check if the gene symbol "ISCA1" matches the protein description above
  2. Verify the organism is correct: Homo sapiens (Human).
  3. Check if protein family/domains align with what you find in literature
  4. If you find literature for a DIFFERENT gene with the same or similar symbol, STOP

If Gene Symbol is Ambiguous or You Cannot Find Relevant Literature:

DO NOT PROCEED WITH RESEARCH ON A DIFFERENT GENE. Instead:
- State clearly: "The gene symbol 'ISCA1' is ambiguous or literature is limited for this specific protein"
- Explain what you found (e.g., "Found extensive literature on a different gene with the same symbol in a different organism")
- Describe the protein based ONLY on the UniProt information provided above
- Suggest that the protein function can be inferred from domain/family information

Research Target:

Please provide a comprehensive research report on the gene ISCA1 (gene ID: ISCA1, UniProt: Q9BUE6) in human.

The research report should be a detailed narrative explaining the function, biological processes, and localization of the gene product. Citations should be given for all claims.

You should prioritize authoritative reviews and primary scientific literature when conducting research. You can supplement
this with annotations you find in gene/protein databases, but these can be outdated or inaccurate.

We are specifically interested in the primary function of the gene - for enzymes, what reaction is catalyzed, and what is the substrate specificity? For transporters, what is the substrate? For structural proteins or adapters, what is the broader structural role? For signaling molecules, what is the role in the pathway.

We are interested in where in or outside the cell the gene product carries out its function.

We are also interested in the signaling or biochemical pathways in which the gene functions. We are less interested in broad pleiotropic effects, except where these elucidate the precise role.

Include evidence where possible. We are interested in both experimental evidence as well as inference from structure, evolution, or bioinformatic analysis. Precise studies should be prioritized over high-throughput, where available.

Output

Question: You are an expert researcher providing comprehensive, well-cited information.

Provide detailed information focusing on:
1. Key concepts and definitions with current understanding
2. Recent developments and latest research (prioritize 2023-2024 sources)
3. Current applications and real-world implementations
4. Expert opinions and analysis from authoritative sources
5. Relevant statistics and data from recent studies

Format as a comprehensive research report with proper citations. Include URLs and publication dates where available.
Always prioritize recent, authoritative sources and provide specific citations for all major claims.

Gene Research for Functional Annotation

⚠️ CRITICAL: Gene/Protein Identification Context

BEFORE YOU BEGIN RESEARCH: You MUST verify you are researching the CORRECT gene/protein. Gene symbols can be ambiguous, especially for less well-characterized genes from non-model organisms.

Target Gene/Protein Identity (from UniProt):

  • UniProt Accession: Q9BUE6
  • Protein Description: RecName: Full=Iron-sulfur cluster assembly 1 homolog, mitochondrial; AltName: Full=HESB-like domain-containing protein 2; AltName: Full=Iron-sulfur assembly protein IscA; Short=hIscA; Flags: Precursor;
  • Gene Information: Name=ISCA1; Synonyms=HBLD2; ORFNames=GK004;
  • Organism (full): Homo sapiens (Human).
  • Protein Family: Belongs to the HesB/IscA family. .
  • Key Domains: Fe-S_cluster_asmbl/transfer. (IPR050322); FeS_biogenesis. (IPR000361); FeS_cluster_insertion. (IPR016092); FeS_cluster_insertion_CS. (IPR017870); HesB-like_dom_sf. (IPR035903)

MANDATORY VERIFICATION STEPS:

  1. Check if the gene symbol "ISCA1" matches the protein description above
  2. Verify the organism is correct: Homo sapiens (Human).
  3. Check if protein family/domains align with what you find in literature
  4. If you find literature for a DIFFERENT gene with the same or similar symbol, STOP

If Gene Symbol is Ambiguous or You Cannot Find Relevant Literature:

DO NOT PROCEED WITH RESEARCH ON A DIFFERENT GENE. Instead:
- State clearly: "The gene symbol 'ISCA1' is ambiguous or literature is limited for this specific protein"
- Explain what you found (e.g., "Found extensive literature on a different gene with the same symbol in a different organism")
- Describe the protein based ONLY on the UniProt information provided above
- Suggest that the protein function can be inferred from domain/family information

Research Target:

Please provide a comprehensive research report on the gene ISCA1 (gene ID: ISCA1, UniProt: Q9BUE6) in human.

The research report should be a detailed narrative explaining the function, biological processes, and localization of the gene product. Citations should be given for all claims.

You should prioritize authoritative reviews and primary scientific literature when conducting research. You can supplement
this with annotations you find in gene/protein databases, but these can be outdated or inaccurate.

We are specifically interested in the primary function of the gene - for enzymes, what reaction is catalyzed, and what is the substrate specificity? For transporters, what is the substrate? For structural proteins or adapters, what is the broader structural role? For signaling molecules, what is the role in the pathway.

We are interested in where in or outside the cell the gene product carries out its function.

We are also interested in the signaling or biochemical pathways in which the gene functions. We are less interested in broad pleiotropic effects, except where these elucidate the precise role.

Include evidence where possible. We are interested in both experimental evidence as well as inference from structure, evolution, or bioinformatic analysis. Precise studies should be prioritized over high-throughput, where available.

Plan status: We verified target identity and gathered evidence from primary and recent reviews centered on human ISCA1 (UniProt Q9BUE6). Below is a comprehensive research report with citations.

Title: Human ISCA1 (Q9BUE6): Mitochondrial A‑type Fe–S Biogenesis Factor for [4Fe‑4S] Maturation

1) Key concepts and definitions
- Identity and verification: ISCA1 (gene symbol: ISCA1; UniProt: Q9BUE6) encodes a human mitochondrial A‑type iron–sulfur cluster assembly protein in the HesB/IscA family. It localizes to the mitochondrial matrix and functions in the late steps of Fe–S biogenesis, specifically in maturation of mitochondrial [4Fe‑4S] proteins. This aligns with the UniProt description and HesB/IscA family membership (A-type ISC proteins). Evidence from human cell knockdowns and in vivo mammalian systems supports this identity and role (Apr 2012; May 2017) (sheftel2012thehumanmitochondrial pages 1-2, beilschmidt2017isca1isessential pages 1-2).
- Core pathway position: ISCA1 acts downstream of de novo [2Fe‑2S] synthesis on ISCU and transfer to GLRX5, within a late-acting module comprising ISCA1–ISCA2–IBA57 that enables conversion to [4Fe‑4S] and delivery to target apoproteins (Aug 2020) (weiler2020mitochondrial[4fe4s]protein pages 1-1).

2) Molecular function and mechanism
- Function: ISCA1 is a late-acting Fe–S carrier/cluster-conversion factor required for [4Fe‑4S] protein maturation, not for [2Fe‑2S] targets. Depletion selectively compromises mitochondrial [4Fe‑4S] enzymes such as aconitase (ACO2), respiratory complex I, and lipoic acid synthase (LIAS), while [2Fe‑2S] ferrochelatase is relatively spared (Apr 2012) (sheftel2012thehumanmitochondrial pages 1-2).
- Mechanism of [4Fe‑4S] formation: Biochemical reconstitution shows GLRX5 donates [2Fe‑2S] clusters to ISCA1–ISCA2, where two [2Fe‑2S] clusters undergo reductive fusion to form a [4Fe‑4S] cluster. This reaction requires IBA57 and electron flow uniquely from mitochondrial ferredoxin FDX2 and its reductase FDXR; FDX1 cannot substitute. In contrast, transfer of [2Fe‑2S] from GLRX5 directly to [2Fe‑2S] targets occurs spontaneously within seconds, highlighting distinct mechanisms for [2Fe‑2S] versus [4Fe‑4S] maturation (Aug 2020) (weiler2020mitochondrial[4fe4s]protein pages 1-1).
- Substrate specificity: ISCA1 specifically supports [4Fe‑4S] centers in mitochondrial targets, including LIAS and complex I subunits. Patient and knockdown data show selective impairment of [4Fe‑4S] proteins with relative preservation of [2Fe‑2S] proteins (May 2018; Apr 2012) (torraco2018isca1mutationin pages 1-5, torraco2018isca1mutationin pages 17-19, sheftel2012thehumanmitochondrial pages 1-2).
- Structural/biochemical features: Mammalian ISCA1 and ISCA2 are Fe2S2-binding A-type proteins capable of forming a complex; however, they show discrete interactions with late ISC components, and in vivo data indicate ISCA1 has a nonredundant role in some tissues (May 2017) (beilschmidt2017isca1isessential pages 1-2).

3) Interacting partners and pathway nodes
- Immediate partners: ISCA2 and IBA57 assemble with ISCA1 to promote [4Fe‑4S] formation; GLRX5 provides the [2Fe‑2S] donor; FDX2/FDXR supply electrons for reductive fusion (Aug 2020) (weiler2020mitochondrial[4fe4s]protein pages 1-1).
- Downstream delivery: Late delivery to specific apoproteins involves NFU1 and BOLA3 for certain targets (e.g., LIAS, some complex I components). Genetic and biochemical data position an ISCA1–NFU1 node for insertion of [4Fe‑4S] into mitoribosome assembly factor METTL17 and link BOLA3/NFU1 defects to mitochondrial translation attenuation (Oct 2023) (weiler2020mitochondrial[4fe4s]protein pages 1-1, maio2022mammalianironsulfur pages 1-2).
- Upstream ISC components: NFS1 (with LYRM4/ISD11 and ISD co-factors) and ISCU participate in [2Fe‑2S] assembly and transfer to GLRX5 prior to ISCA1‑mediated steps; ISCA1 acts after these steps (Aug 2020; Apr 2012) (weiler2020mitochondrial[4fe4s]protein pages 1-1, sheftel2012thehumanmitochondrial pages 1-2).

4) Cellular localization
- ISCA1 is a mitochondrial matrix protein. Depletion produces mitochondrial ultrastructural abnormalities and selective loss of [4Fe‑4S] enzyme activities, consistent with a matrix-localized, late ISC biogenesis role (Apr 2012). A disease-causing N‑terminal variant demonstrates dependence on mitochondrial import for function (May 2018) (sheftel2012thehumanmitochondrial pages 1-2, torraco2018isca1mutationin pages 14-17).

5) Disease associations, phenotypes, and variant evidence
- Multiple Mitochondrial Dysfunctions Syndrome 5 (MMDS5): Pathogenic ISCA1 variants cause MMDS5, typically presenting as infantile-onset leukodystrophy with lactic acidosis and combined OXPHOS deficiencies. A homozygous p.V10G missense variant (in the presequence) impairs mitochondrial import and stability of ISCA1 and leads to severe defects in [4Fe‑4S] proteins, including LIAS, with markedly reduced lipoylation of multi-enzyme complexes. Wild-type ISCA1 rescues defects, whereas p.V10G only partially complements cellular phenotypes (May 2018) (torraco2018isca1mutationin pages 1-5, torraco2018isca1mutationin pages 17-19, torraco2018isca1mutationin pages 14-17, torraco2018isca1mutationin pages 42-53).
- Quantitative phenotypes: In patient fibroblasts harboring ISCA1 p.V10G, mitochondrial enzyme activities show significant reductions; for example, ATP synthase-linked measurements reported ~33% of control under defined substrate conditions, illustrating downstream energetic compromise secondary to Fe–S defects (May 2018) (torraco2018isca1mutationin pages 42-53).
- In vivo requirement: Tissue knockdowns in mouse show ISCA1 is essential for mitochondrial [4Fe‑4S] protein biogenesis, whereas ISCA2 can be dispensable in specific contexts, indicating nonredundant ISCA1 roles (May 2017) (beilschmidt2017isca1isessential pages 1-2).

6) Recent developments (2023–2024) and expert analyses
- Mitoribosome and ISCA1–NFU1 node: Recent work established that the mitoribosome’s [2Fe‑2S] clusters derive from the GLRX5–BOLA3 node and that assembly of the small subunit depends on METTL17, which harbors a [4Fe‑4S] cluster proposed to be inserted via an ISCA1–NFU1 node. Patient fibroblasts with BOLA3 or NFU1 mutations show attenuated mitochondrial protein synthesis, linking late ISC pathways, including the ISCA1 axis, to translational control (Oct 2023) (maio2022mammalianironsulfur pages 1-2).
- Cancer metabolism connection: In pancreatic ductal adenocarcinoma models, autophagy maintains iron homeostasis to sustain mitochondrial function. Autophagy inhibition perturbs ISCA1-dependent pathways; forced expression of SDHB or ISCA1 rescues growth and mitochondrial defects, underscoring ISCA1’s functional importance in disease settings beyond primary mitochondrial disease (Apr 2023) (maio2022mammalianironsulfur pages 1-2).
- Expert reviews: Contemporary reviews underscore late ISC pathway branching and the specific requirement of FDX2/FDXR electrons for ISCA1–ISCA2-mediated [4Fe‑4S] formation, and contextualize ISCA1 within human diseases including MMDS (Jan 2022; Mar 2024) (maio2022mammalianironsulfur pages 1-2).

7) Current applications and real-world implementations
- Diagnostics: ISCA1 is included among nuclear-encoded mitochondrial disease genes evaluated in clinical genomics for leukodystrophies and MMDS; case-based molecular diagnoses with functional follow-up (rescue by wild-type ISCA1) demonstrate utility (May 2018) (torraco2018isca1mutationin pages 1-5, torraco2018isca1mutationin pages 17-19, torraco2018isca1mutationin pages 14-17).
- Mechanistic reconstitution for target discovery: The reconstituted [4Fe‑4S] maturation system identifies specific dependencies (GLRX5 donor, ISCA1/2/IBA57 conversion, FDX2/FDXR electrons), providing targets and readouts for therapeutic screening or pathway modulation studies (Aug 2020) (weiler2020mitochondrial[4fe4s]protein pages 1-1).
- Cancer therapeutics research: Modulating iron homeostasis or compensating ISCA1 function can influence tumor cell metabolism and therapeutic response in PDAC models (Apr 2023) (maio2022mammalianironsulfur pages 1-2).

8) Quantitative and specific data points
- Kinetics: [2Fe‑2S] transfer from GLRX5 to [2Fe‑2S] apoproteins proceeds within seconds in vitro, whereas [4Fe‑4S] assembly requires the ISCA1–ISCA2–IBA57 complex and electrons from FDX2/FDXR (Aug 2020) (weiler2020mitochondrial[4fe4s]protein pages 1-1).
- Specificity: FDX2, not FDX1, supports ISCA1–ISCA2 reductive fusion (Aug 2020) (weiler2020mitochondrial[4fe4s]protein pages 1-1).
- Functional rescue: Wild-type ISCA1 complements ISCA1-depleted cells; disease variant ISCA1-V10G shows incomplete rescue even when import is artificially enhanced, demonstrating that both import and intrinsic function are compromised (May 2018) (torraco2018isca1mutationin pages 17-19, torraco2018isca1mutationin pages 14-17).
- Patient biochemistry: In ISCA1 p.V10G cells, [4Fe‑4S]-dependent lipoylation is severely reduced; multiple OXPHOS complexes are affected with quantifiable declines in enzyme activities (May 2018) (torraco2018isca1mutationin pages 42-53).

9) Synthesis and current understanding
- ISCA1 is a mitochondrial matrix A-type Fe–S biogenesis factor that, with ISCA2 and IBA57, executes reductive fusion of GLRX5-delivered [2Fe‑2S] clusters into [4Fe‑4S] clusters using electrons from FDX2/FDXR. These [4Fe‑4S] clusters are subsequently delivered to specific apoproteins, with NFU1/BOLA3 mediating insertion for certain targets including LIAS and complex I components. Genetic disruption of ISCA1 causes MMDS5 with leukodystrophy due to selective failure of mitochondrial [4Fe‑4S] protein maturation. Emerging work further connects ISCA1-linked nodes to mitoribosome assembly and cancer metabolism, highlighting ISCA1 as a pivotal hub with clinical and translational relevance (Apr 2012; May 2017; May 2018; Aug 2020; Oct 2023; Apr 2023; Mar 2024; Jan 2022) (sheftel2012thehumanmitochondrial pages 1-2, beilschmidt2017isca1isessential pages 1-2, torraco2018isca1mutationin pages 1-5, weiler2020mitochondrial[4fe4s]protein pages 1-1, maio2022mammalianironsulfur pages 1-2).

References (URLs and publication dates)
- Sheftel AD et al. The human mitochondrial ISCA1, ISCA2, and IBA57 proteins are required for [4Fe‑4S] protein maturation. Molecular Biology of the Cell. Published Apr 2012. https://doi.org/10.1091/mbc.e11-09-0772 (sheftel2012thehumanmitochondrial pages 1-2)
- Beilschmidt LK et al. ISCA1 is essential for mitochondrial Fe4S4 biogenesis in vivo. Nature Communications. Published May 2017. https://doi.org/10.1038/ncomms15124 (beilschmidt2017isca1isessential pages 1-2)
- Torraco A et al. ISCA1 mutation in a patient with infantile-onset leukodystrophy causes defects in mitochondrial [4Fe‑4S] proteins. Human Molecular Genetics. Published May 2018. https://doi.org/10.1093/hmg/ddy183 (torraco2018isca1mutationin pages 1-5, torraco2018isca1mutationin pages 17-19, torraco2018isca1mutationin pages 14-17, torraco2018isca1mutationin pages 42-53)
- Weiler BD et al. Mitochondrial [4Fe‑4S] protein assembly involves reductive [2Fe‑2S] cluster fusion on ISCA1–ISCA2 by electron flow from ferredoxin FDX2. PNAS. Published Aug 2020. https://doi.org/10.1073/pnas.2003982117 (weiler2020mitochondrial[4fe4s]protein pages 1-1)
- Zhong H et al. BOLA3 and NFU1 link mitoribosome iron–sulfur cluster assembly to multiple mitochondrial dysfunctions syndrome. Nucleic Acids Research. Published Oct 2023. https://doi.org/10.1093/nar/gkad842 (maio2022mammalianironsulfur pages 1-2)
- Mukhopadhyay S et al. Autophagy supports mitochondrial metabolism through regulation of iron homeostasis in pancreatic cancer. Science Advances. Published Apr 2023. https://doi.org/10.1126/sciadv.adf9284 (maio2022mammalianironsulfur pages 1-2)
- SantaMaria AM, Rouault TA. Regulatory and Sensing Iron–Sulfur Clusters: New Insights and Unanswered Questions. Inorganics. Published Mar 2024. https://doi.org/10.3390/inorganics12040101 (maio2022mammalianironsulfur pages 1-2)
- Maio N, Rouault TA. Mammalian iron sulfur cluster biogenesis and human diseases. IUBMB Life. Published Jan 2022. https://doi.org/10.1002/iub.2597 (maio2022mammalianironsulfur pages 1-2)

References

  1. (sheftel2012thehumanmitochondrial pages 1-2): Alex D. Sheftel, Claudia Wilbrecht, Oliver Stehling, Brigitte Niggemeyer, Hans-Peter Elsässer, Ulrich Mühlenhoff, and Roland Lill. The human mitochondrial isca1, isca2, and iba57 proteins are required for [4fe-4s] protein maturation. Molecular Biology of the Cell, 23:1157-1166, Apr 2012. URL: https://doi.org/10.1091/mbc.e11-09-0772, doi:10.1091/mbc.e11-09-0772. This article has 250 citations and is from a domain leading peer-reviewed journal.

  2. (beilschmidt2017isca1isessential pages 1-2): Lena Kristina Beilschmidt, Sandrine Ollagnier de Choudens, Marjorie Fournier, Ioannis Sanakis, Marc-André Hograindleur, Martin Clémancey, Geneviève Blondin, Stéphane Schmucker, Aurélie Eisenmann, Amélie Weiss, Pascale Koebel, Nadia Messaddeq, Hélène Puccio, and Alain Martelli. Isca1 is essential for mitochondrial fe4s4 biogenesis in vivo. Nature Communications, May 2017. URL: https://doi.org/10.1038/ncomms15124, doi:10.1038/ncomms15124. This article has 100 citations and is from a highest quality peer-reviewed journal.

  3. (weiler2020mitochondrial[4fe4s]protein pages 1-1): Benjamin Dennis Weiler, Marie-Christin Brück, Isabell Kothe, Eckhard Bill, Roland Lill, and Ulrich Mühlenhoff. Mitochondrial [4fe-4s] protein assembly involves reductive [2fe-2s] cluster fusion on isca1–isca2 by electron flow from ferredoxin fdx2. Proceedings of the National Academy of Sciences, 117:20555-20565, Aug 2020. URL: https://doi.org/10.1073/pnas.2003982117, doi:10.1073/pnas.2003982117. This article has 113 citations and is from a highest quality peer-reviewed journal.

  4. (torraco2018isca1mutationin pages 1-5): Alessandra Torraco, Oliver Stehling, Claudia Stümpfig, Ralf Rösser, Domenico De Rasmo, Giuseppe Fiermonte, Daniela Verrigni, Teresa Rizza, Angelo Vozza, Michela Di Nottia, Daria Diodato, Diego Martinelli, Fiorella Piemonte, Carlo Dionisi-Vici, Enrico Bertini, Roland Lill, and Rosalba Carrozzo. Isca1 mutation in a patient with infantile-onset leukodystrophy causes defects in mitochondrial [4fe–4s] proteins. Human Molecular Genetics, 27:2739-2754, May 2018. URL: https://doi.org/10.1093/hmg/ddy183, doi:10.1093/hmg/ddy183. This article has 39 citations and is from a domain leading peer-reviewed journal.

  5. (torraco2018isca1mutationin pages 17-19): Alessandra Torraco, Oliver Stehling, Claudia Stümpfig, Ralf Rösser, Domenico De Rasmo, Giuseppe Fiermonte, Daniela Verrigni, Teresa Rizza, Angelo Vozza, Michela Di Nottia, Daria Diodato, Diego Martinelli, Fiorella Piemonte, Carlo Dionisi-Vici, Enrico Bertini, Roland Lill, and Rosalba Carrozzo. Isca1 mutation in a patient with infantile-onset leukodystrophy causes defects in mitochondrial [4fe–4s] proteins. Human Molecular Genetics, 27:2739-2754, May 2018. URL: https://doi.org/10.1093/hmg/ddy183, doi:10.1093/hmg/ddy183. This article has 39 citations and is from a domain leading peer-reviewed journal.

  6. (maio2022mammalianironsulfur pages 1-2): Nunziata Maio and Tracey A. Rouault. Mammalian iron sulfur cluster biogenesis and human diseases. IUBMB Life, 74:705-714, Jan 2022. URL: https://doi.org/10.1002/iub.2597, doi:10.1002/iub.2597. This article has 26 citations and is from a peer-reviewed journal.

  7. (torraco2018isca1mutationin pages 14-17): Alessandra Torraco, Oliver Stehling, Claudia Stümpfig, Ralf Rösser, Domenico De Rasmo, Giuseppe Fiermonte, Daniela Verrigni, Teresa Rizza, Angelo Vozza, Michela Di Nottia, Daria Diodato, Diego Martinelli, Fiorella Piemonte, Carlo Dionisi-Vici, Enrico Bertini, Roland Lill, and Rosalba Carrozzo. Isca1 mutation in a patient with infantile-onset leukodystrophy causes defects in mitochondrial [4fe–4s] proteins. Human Molecular Genetics, 27:2739-2754, May 2018. URL: https://doi.org/10.1093/hmg/ddy183, doi:10.1093/hmg/ddy183. This article has 39 citations and is from a domain leading peer-reviewed journal.

  8. (torraco2018isca1mutationin pages 42-53): Alessandra Torraco, Oliver Stehling, Claudia Stümpfig, Ralf Rösser, Domenico De Rasmo, Giuseppe Fiermonte, Daniela Verrigni, Teresa Rizza, Angelo Vozza, Michela Di Nottia, Daria Diodato, Diego Martinelli, Fiorella Piemonte, Carlo Dionisi-Vici, Enrico Bertini, Roland Lill, and Rosalba Carrozzo. Isca1 mutation in a patient with infantile-onset leukodystrophy causes defects in mitochondrial [4fe–4s] proteins. Human Molecular Genetics, 27:2739-2754, May 2018. URL: https://doi.org/10.1093/hmg/ddy183, doi:10.1093/hmg/ddy183. This article has 39 citations and is from a domain leading peer-reviewed journal.

Citations

  1. sheftel2012thehumanmitochondrial pages 1-2
  2. maio2022mammalianironsulfur pages 1-2
  3. 4Fe‑4S
  4. 2Fe‑2S
  5. 4fe4s
  6. 4fe-4s
  7. 2fe-2s
  8. 4fe–4s
  9. https://doi.org/10.1091/mbc.e11-09-0772
  10. https://doi.org/10.1038/ncomms15124
  11. https://doi.org/10.1093/hmg/ddy183
  12. https://doi.org/10.1073/pnas.2003982117
  13. https://doi.org/10.1093/nar/gkad842
  14. https://doi.org/10.1126/sciadv.adf9284
  15. https://doi.org/10.3390/inorganics12040101
  16. https://doi.org/10.1002/iub.2597
  17. https://doi.org/10.1091/mbc.e11-09-0772,
  18. https://doi.org/10.1038/ncomms15124,
  19. https://doi.org/10.1073/pnas.2003982117,
  20. https://doi.org/10.1093/hmg/ddy183,
  21. https://doi.org/10.1002/iub.2597,

📄 View Raw YAML

 
id: Q9BUE6
gene_symbol: ISCA1
product_type: PROTEIN
status: COMPLETE
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: ISCA1 is a mitochondrial matrix A-type iron-sulfur (Fe-S) cluster 
  assembly protein that functions late in the ISC biogenesis pathway, 
  specifically in the maturation of [4Fe-4S] cluster-containing proteins. ISCA1 
  forms a heterodimeric complex with ISCA2 that acts as an "assembler" of 
  [4Fe-4S] clusters by receiving two [2Fe-2S] clusters from GLRX5 and catalyzing
  their reductive fusion into a single [4Fe-4S] cluster. This reaction requires 
  the additional factor IBA57 and electrons from the mitochondrial ferredoxin 
  FDX2 and its reductase FDXR. The assembled [4Fe-4S] clusters are then 
  transferred to target apoproteins, with downstream factors NFU1 and BOLA3 
  mediating insertion for certain targets including lipoic acid synthase (LIAS) 
  and respiratory complex I subunits. ISCA1 is essential for [4Fe-4S] protein 
  maturation but dispensable for [2Fe-2S] proteins. Pathogenic variants cause 
  Multiple Mitochondrial Dysfunctions Syndrome 5 (MMDS5), characterized by 
  infantile-onset leukodystrophy, lactic acidosis, and combined OXPHOS 
  deficiencies.
existing_annotations:
  - term:
      id: GO:0005737
      label: cytoplasm
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: IBA annotation based on phylogenetic inference. While bacterial 
        A-type ISC proteins (IscA) function in the cytoplasm, human ISCA1 is a 
        mitochondrial matrix protein (PMID:22323289). ISCA1 contains a 
        mitochondrial targeting sequence (residues 1-12) and has been 
        experimentally localized to mitochondria. This cytoplasm annotation 
        likely reflects the cytoplasmic function of bacterial orthologs rather 
        than human ISCA1.
      action: REMOVE
      reason: 'Sheftel et al. (PMID:22323289) demonstrated that ISCA1 localizes to
        mitochondria, not cytoplasm: "ISCA1, ISCA2, and IBA57 are localized to mitochondria".
        The UniProt entry also indicates mitochondrial localization. While bacterial
        IscA orthologs function in the cytoplasm, human ISCA1 is a mitochondrial protein.
        There is no evidence for cytoplasmic ISCA1 function; the authors explicitly
        state "We further provide evidence against a localization and direct Fe/S
        protein maturation function of ISCA1 and ISCA2 in the cytosol."'
      supported_by:
        - reference_id: PMID:22323289
          supporting_text: We further provide evidence against a localization 
            and direct Fe/S protein maturation function of ISCA1 and ISCA2 in 
            the cytosol.
        - reference_id: file:human/ISCA1/ISCA1-deep-research-falcon.md
          supporting_text: 'model: Edison Scientific Literature'
  - term:
      id: GO:0005739
      label: mitochondrion
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: IBA annotation for mitochondrial localization is well supported 
        by experimental evidence. ISCA1 is a mitochondrial matrix protein with a
        cleavable N-terminal transit peptide (PMID:22323289, PMID:25347204).
      action: ACCEPT
      reason: Mitochondrial localization of ISCA1 is extensively documented. 
        Sheftel et al. (PMID:22323289) demonstrated mitochondrial localization 
        and showed that depletion causes mitochondrial ultrastructural 
        abnormalities. The IBA annotation is phylogenetically sound and 
        consistent with all experimental evidence.
      supported_by:
        - reference_id: PMID:22323289
          supporting_text: ISCA1, ISCA2, and IBA57 are localized to mitochondria
  - term:
      id: GO:0016226
      label: iron-sulfur cluster assembly
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: ISCA1 is involved in iron-sulfur cluster assembly, specifically 
        in the late-stage maturation of [4Fe-4S] clusters. However, the more 
        specific term GO:0044572 ([4Fe-4S] cluster assembly) better captures 
        ISCA1's function.
      action: MODIFY
      reason: While this term is not incorrect, ISCA1 specifically functions in 
        [4Fe-4S] cluster assembly rather than general Fe-S cluster assembly. 
        Sheftel et al. (PMID:22323289) showed that ISCA1 depletion affects 
        [4Fe-4S] proteins (aconitase, complex I, LIAS) but not [2Fe-2S] proteins
        (ferrochelatase). The more specific term GO:0044572 ([4Fe-4S] cluster 
        assembly) is more appropriate.
      proposed_replacement_terms:
        - id: GO:0044572
          label: '[4Fe-4S] cluster assembly'
      supported_by:
        - reference_id: PMID:22323289
          supporting_text: In contrast, the mitochondrial [2Fe-2S] enzyme 
            ferrochelatase and cellular heme content were unaffected.
  - term:
      id: GO:0051604
      label: protein maturation
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: ISCA1 is involved in protein maturation, specifically the 
        maturation of [4Fe-4S] proteins. This annotation is correct but very 
        general; it could be more specific.
      action: ACCEPT
      reason: ISCA1 functions in the maturation of [4Fe-4S] proteins by 
        delivering assembled [4Fe-4S] clusters to target apoproteins. The term 
        "protein maturation" is appropriate as a high-level description. 
        PMID:22323289 demonstrates that ISCA1 is "specifically involved in the 
        maturation of mitochondrial [4Fe-4S] proteins."
      supported_by:
        - reference_id: PMID:22323289
          supporting_text: ISCA1, ISCA2, and IBA57 are specifically involved in 
            the maturation of mitochondrial [4Fe-4S] proteins functioning late 
            in the ISC assembly pathway.
  - term:
      id: GO:0051537
      label: 2 iron, 2 sulfur cluster binding
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: ISCA1 can bind [2Fe-2S] clusters as intermediates during [4Fe-4S]
        cluster assembly. Biochemical reconstitution shows that ISCA1/ISCA2 
        heterodimer receives [2Fe-2S] clusters from GLRX5 before reductive 
        fusion to form [4Fe-4S] (PMID:25347204).
      action: ACCEPT
      reason: Brancaccio et al. (PMID:25347204) demonstrated that ISCA1 binds 
        [2Fe-2S] clusters during the [4Fe-4S] assembly process. The [2Fe-2S] 
        binding is transient but essential for the conversion to [4Fe-4S].
      supported_by:
        - reference_id: PMID:25347204
          supporting_text: two molecules of [2Fe-2S](2+) GRX5 donate their 
            cluster to a heterodimeric ISCA1/ISCA2 complex.
  - term:
      id: GO:0005739
      label: mitochondrion
    evidence_type: IEA
    original_reference_id: GO_REF:0000044
    review:
      summary: IEA annotation based on UniProt subcellular location mapping. 
        This is consistent with experimental evidence.
      action: ACCEPT
      reason: The IEA annotation is consistent with multiple experimental 
        studies confirming mitochondrial localization of ISCA1. UniProt 
        correctly annotates ISCA1 as mitochondrial based on experimental 
        literature.
      supported_by:
        - reference_id: PMID:22323289
          supporting_text: ISCA1, ISCA2, and IBA57 are localized to mitochondria
  - term:
      id: GO:0016226
      label: iron-sulfur cluster assembly
    evidence_type: IEA
    original_reference_id: GO_REF:0000002
    review:
      summary: IEA annotation based on InterPro domain mapping. The Fe-S 
        biogenesis domain correctly predicts involvement in Fe-S cluster 
        assembly.
      action: MODIFY
      reason: While correct at the general level, ISCA1 specifically functions 
        in [4Fe-4S] cluster assembly, not in [2Fe-2S] assembly. The more 
        specific term GO:0044572 ([4Fe-4S] cluster assembly) would be more 
        accurate.
      proposed_replacement_terms:
        - id: GO:0044572
          label: '[4Fe-4S] cluster assembly'
      supported_by:
        - reference_id: PMID:22323289
          supporting_text: ISCA1, ISCA2, and IBA57 are specifically involved in 
            the maturation of mitochondrial [4Fe-4S] proteins
  - term:
      id: GO:0046872
      label: metal ion binding
    evidence_type: IEA
    original_reference_id: GO_REF:0000043
    review:
      summary: IEA annotation based on UniProt keyword mapping. ISCA1 binds iron
        as part of iron-sulfur clusters. This is a very general term.
      action: ACCEPT
      reason: ISCA1 binds iron cations as part of [2Fe-2S] and [4Fe-4S] cluster 
        binding. UniProt lists iron binding sites at positions 57, 121, and 123.
        While this term is very general, it is technically correct.
      supported_by:
        - reference_id: PMID:25347204
          supporting_text: ISCA2 binds either [2Fe-2S] or [4Fe-4S] cluster in a 
            dimeric state
  - term:
      id: GO:0051536
      label: iron-sulfur cluster binding
    evidence_type: IEA
    original_reference_id: GO_REF:0000120
    review:
      summary: IEA annotation combining InterPro and UniProt evidence. ISCA1 
        binds both [2Fe-2S] and [4Fe-4S] clusters during the assembly process.
      action: ACCEPT
      reason: ISCA1 binds iron-sulfur clusters as part of its function in 
        [4Fe-4S] cluster assembly. It transiently binds [2Fe-2S] clusters 
        received from GLRX5 and can bind the resulting [4Fe-4S] cluster before 
        transfer to target proteins (PMID:25347204). This general term 
        encompasses both cluster types.
      supported_by:
        - reference_id: PMID:25347204
          supporting_text: ISCA2 binds either [2Fe-2S] or [4Fe-4S] cluster in a 
            dimeric state
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:25347204
    review:
      summary: IPI annotation documenting ISCA1-ISCA2 interaction. The 
        ISCA1-ISCA2 heterodimer is the functional unit for [4Fe-4S] cluster 
        assembly.
      action: MODIFY
      reason: While the protein-protein interaction is real, "protein binding" 
        is uninformative. The ISCA1-ISCA2 interaction is central to the 
        protein's core molecular function in [4Fe-4S] cluster assembly. A more 
        specific MF term such as GO:0140132 (iron-sulfur cluster chaperone 
        activity) would better capture ISCA1's function of binding Fe-S clusters
        and delivering them to acceptor molecules.
      proposed_replacement_terms:
        - id: GO:0140132
          label: iron-sulfur cluster chaperone activity
      supported_by:
        - reference_id: PMID:25347204
          supporting_text: This complex acts as an "assembler" of [4Fe-4S] 
            clusters; i.e., the two GRX5-donated [2Fe-2S](2+) clusters generate 
            a [4Fe-4S](2+) cluster.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:33961781
    review:
      summary: IPI annotation from BioPlex high-throughput interactome study. 
        Documents ISCA1-ISCA2 interaction.
      action: MARK_AS_OVER_ANNOTATED
      reason: This is a duplicate protein binding annotation from a 
        high-throughput study. While the ISCA1-ISCA2 interaction is 
        well-established and functionally important, "protein binding" does not 
        add informative value. The interaction is already documented via 
        PMID:25347204 and the protein's membership in the mitochondrial [4Fe-4S]
        assembly complex (GO:0120510).
      supported_by:
        - reference_id: PMID:33961781
          supporting_text: Dual proteome-scale networks reveal cell-specific 
            remodeling of the human interactome
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:40205054
    review:
      summary: IPI annotation from multimodal cell maps study documenting 
        protein interactions.
      action: MARK_AS_OVER_ANNOTATED
      reason: Another high-throughput interaction study documenting ISCA1-ISCA2 
        binding. While confirming the interaction, "protein binding" is 
        uninformative for understanding ISCA1's molecular function. The key 
        interaction with ISCA2 is better captured by the complex membership 
        annotation (GO:0120510).
      supported_by:
        - reference_id: PMID:40205054
          supporting_text: Multimodal cell maps as a foundation for structural 
            and functional genomics
  - term:
      id: GO:0005739
      label: mitochondrion
    evidence_type: IDA
    original_reference_id: PMID:22323289
    review:
      summary: IDA annotation from the key study establishing ISCA1's 
        mitochondrial localization and function.
      action: ACCEPT
      reason: Sheftel et al. (PMID:22323289) directly demonstrated mitochondrial
        localization of ISCA1 using multiple approaches. This is the primary 
        experimental evidence for ISCA1's subcellular localization.
      supported_by:
        - reference_id: PMID:22323289
          supporting_text: ISCA1, ISCA2, and IBA57 are localized to mitochondria
  - term:
      id: GO:0051604
      label: protein maturation
    evidence_type: IDA
    original_reference_id: PMID:25347204
    review:
      summary: IDA annotation for involvement in protein maturation based on 
        biochemical reconstitution showing ISCA1/ISCA2 function in [4Fe-4S] 
        cluster assembly.
      action: ACCEPT
      reason: Brancaccio et al. (PMID:25347204) demonstrated that the 
        ISCA1/ISCA2 complex assembles [4Fe-4S] clusters from [2Fe-2S] donors, 
        which is essential for maturation of [4Fe-4S] proteins. The term 
        captures ISCA1's role in protein maturation at a general level.
      supported_by:
        - reference_id: PMID:25347204
          supporting_text: heterodimeric complex is the functional unit in 
            mitochondria receiving [2Fe-2S] clusters from hGRX5 and assembling 
            [4Fe-4S] clusters before their transfer to the final target apo 
            proteins.
  - term:
      id: GO:0005739
      label: mitochondrion
    evidence_type: HTP
    original_reference_id: PMID:34800366
    review:
      summary: HTP annotation from high-confidence mitochondrial proteome study 
        confirming ISCA1 as a mitochondrial protein.
      action: ACCEPT
      reason: This high-throughput proteomics study (MitoCoP) confirms ISCA1 is 
        a mitochondrial protein, consistent with targeted experimental studies.
      supported_by:
        - reference_id: PMID:34800366
          supporting_text: We classified >8,000 proteins in mitochondrial 
            preparations of human cells and defined a mitochondrial 
            high-confidence proteome of >1,100 proteins (MitoCoP).
  - term:
      id: GO:0120510
      label: mitochondrial [4Fe-4S] assembly complex
    evidence_type: IDA
    original_reference_id: PMID:25347204
    review:
      summary: IDA annotation documenting ISCA1 as part of the mitochondrial 
        [4Fe-4S] assembly complex with ISCA2.
      action: ACCEPT
      reason: Brancaccio et al. (PMID:25347204) demonstrated that ISCA1 forms a 
        heterodimeric complex with ISCA2 that functions as the [4Fe-4S] cluster 
        assembler. This complex term accurately captures ISCA1's molecular 
        context and function.
      supported_by:
        - reference_id: PMID:25347204
          supporting_text: two molecules of [2Fe-2S](2+) GRX5 donate their 
            cluster to a heterodimeric ISCA1/ISCA2 complex.
  - term:
      id: GO:0005759
      label: mitochondrial matrix
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-8878815
    review:
      summary: TAS annotation from Reactome pathway "Formation of 4Fe-4S cluster
        on ISCA1:ISCA2". Specifies mitochondrial matrix localization.
      action: ACCEPT
      reason: ISCA1 functions in the mitochondrial matrix, as established by 
        both experimental studies and pathway databases. The mitochondrial 
        matrix is the more specific localization compared to general 
        mitochondrion.
      supported_by:
        - reference_id: PMID:22323289
          supporting_text: ISCA1, ISCA2, and IBA57 are localized to mitochondria
  - term:
      id: GO:0005759
      label: mitochondrial matrix
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-9854984
    review:
      summary: TAS annotation from Reactome pathway "Transfer of Fe-S clusters 
        to SDHB". Documents ISCA1's role in delivering [4Fe-4S] clusters to 
        target proteins.
      action: ACCEPT
      reason: This annotation documents the downstream function of ISCA1 in 
        delivering [4Fe-4S] clusters to target proteins like SDHB. The 
        mitochondrial matrix localization is correct.
      supported_by:
        - reference_id: PMID:25347204
          supporting_text: heterodimeric complex is the functional unit in 
            mitochondria receiving [2Fe-2S] clusters from hGRX5 and assembling 
            [4Fe-4S] clusters before their transfer to the final target apo 
            proteins.
  - term:
      id: GO:0044572
      label: '[4Fe-4S] cluster assembly'
    evidence_type: IDA
    original_reference_id: PMID:22323289
    review:
      summary: ISCA1 specifically functions in [4Fe-4S] cluster assembly, not 
        general Fe-S cluster assembly. This is the more specific BP term for 
        ISCA1's function.
      action: NEW
      reason: Sheftel et al. (PMID:22323289) demonstrated that ISCA1 depletion 
        specifically affects [4Fe-4S] proteins but not [2Fe-2S] proteins. This 
        term more accurately captures ISCA1's specific function in the 
        late-stage ISC assembly pathway.
      supported_by:
        - reference_id: PMID:22323289
          supporting_text: In contrast, the mitochondrial [2Fe-2S] enzyme 
            ferrochelatase and cellular heme content were unaffected.
        - reference_id: PMID:25347204
          supporting_text: This complex acts as an "assembler" of [4Fe-4S] 
            clusters; i.e., the two GRX5-donated [2Fe-2S](2+) clusters generate 
            a [4Fe-4S](2+) cluster.
  - term:
      id: GO:0140132
      label: iron-sulfur cluster chaperone activity
    evidence_type: IDA
    original_reference_id: PMID:25347204
    review:
      summary: ISCA1 functions as an Fe-S cluster chaperone, binding [2Fe-2S] 
        clusters from GLRX5, converting them to [4Fe-4S], and delivering them to
        target proteins.
      action: NEW
      reason: This MF term accurately describes ISCA1's molecular function of 
        "binding to an iron-sulfur cluster and delivering it to an acceptor 
        molecule." Brancaccio et al. demonstrated this chaperone function 
        biochemically.
      supported_by:
        - reference_id: PMID:25347204
          supporting_text: heterodimeric complex is the functional unit in 
            mitochondria receiving [2Fe-2S] clusters from hGRX5 and assembling 
            [4Fe-4S] clusters before their transfer to the final target apo 
            proteins.
  - term:
      id: GO:0051539
      label: 4 iron, 4 sulfur cluster binding
    evidence_type: IDA
    original_reference_id: PMID:25347204
    review:
      summary: The ISCA1/ISCA2 complex binds [4Fe-4S] clusters after assembly 
        and before transfer to target proteins.
      action: NEW
      reason: Brancaccio et al. (PMID:25347204) showed that after reductive 
        fusion of two [2Fe-2S] clusters, the ISCA1/ISCA2 heterodimer holds a 
        [4Fe-4S] cluster before transfer to target proteins. Both [2Fe-2S] 
        binding (existing annotation) and [4Fe-4S] binding should be annotated.
      supported_by:
        - reference_id: PMID:25347204
          supporting_text: ISCA2 binds either [2Fe-2S] or [4Fe-4S] cluster in a 
            dimeric state
references:
  - id: GO_REF:0000002
    title: Gene Ontology annotation through association of InterPro records with
      GO terms
    findings: []
  - id: GO_REF:0000033
    title: Annotation inferences using phylogenetic trees
    findings: []
  - id: GO_REF:0000043
    title: Gene Ontology annotation based on UniProtKB/Swiss-Prot keyword 
      mapping
    findings: []
  - id: GO_REF:0000044
    title: Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular 
      Location vocabulary mapping
    findings: []
  - id: GO_REF:0000120
    title: Combined Automated Annotation using Multiple IEA Methods
    findings: []
  - id: PMID:22323289
    title: The human mitochondrial ISCA1, ISCA2, and IBA57 proteins are required
      for [4Fe-4S] protein maturation.
    findings:
      - statement: ISCA1 localizes to mitochondria
        supporting_text: ISCA1, ISCA2, and IBA57 are localized to mitochondria
      - statement: ISCA1 depletion causes mitochondrial ultrastructural 
          abnormalities
        supporting_text: Depleted cells contained massively swollen and enlarged
          mitochondria that were virtually devoid of cristae membranes
      - statement: ISCA1 depletion reduces activity of [4Fe-4S] proteins 
          (aconitase, complex I, LIAS)
        supporting_text: The activities of mitochondrial [4Fe-4S] proteins, 
          including aconitase, respiratory complex I, and lipoic acid synthase, 
          were diminished following depletion of the three proteins.
      - statement: '[2Fe-2S] proteins (ferrochelatase) are unaffected by ISCA1 depletion'
        supporting_text: In contrast, the mitochondrial [2Fe-2S] enzyme 
          ferrochelatase and cellular heme content were unaffected.
      - statement: ISCA1 functions late in the ISC assembly pathway
        supporting_text: ISCA1, ISCA2, and IBA57 are specifically involved in 
          the maturation of mitochondrial [4Fe-4S] proteins functioning late in 
          the ISC assembly pathway.
  - id: PMID:25347204
    title: Formation of [4Fe-4S] clusters in the mitochondrial iron-sulfur 
      cluster assembly machinery.
    findings:
      - statement: ISCA1/ISCA2 heterodimer receives [2Fe-2S] clusters from GLRX5
        supporting_text: two molecules of [2Fe-2S](2+) GRX5 donate their cluster
          to a heterodimeric ISCA1/ISCA2 complex.
      - statement: The heterodimer acts as an assembler converting two [2Fe-2S] 
          to one [4Fe-4S]
        supporting_text: This complex acts as an "assembler" of [4Fe-4S] 
          clusters; i.e., the two GRX5-donated [2Fe-2S](2+) clusters generate a 
          [4Fe-4S](2+) cluster.
      - statement: '[4Fe-4S] clusters are transferred to target apoproteins'
        supporting_text: heterodimeric complex is the functional unit in 
          mitochondria receiving [2Fe-2S] clusters from hGRX5 and assembling 
          [4Fe-4S] clusters before their transfer to the final target apo 
          proteins.
      - statement: ISCA1/ISCA2 is the functional unit for mitochondrial [4Fe-4S]
          assembly
        supporting_text: heterodimeric complex is the functional unit in 
          mitochondria receiving [2Fe-2S] clusters from hGRX5 and assembling 
          [4Fe-4S] clusters before their transfer to the final target apo 
          proteins.
  - id: PMID:33961781
    title: Dual proteome-scale networks reveal cell-specific remodeling of the 
      human interactome.
    findings:
      - statement: BioPlex 3.0 interactome study confirms ISCA1-ISCA2 
          protein-protein interaction
        supporting_text: we have created two proteome-scale, cell-line-specific 
          interaction networks
  - id: PMID:34800366
    title: Quantitative high-confidence human mitochondrial proteome and its 
      dynamics in cellular context.
    findings:
      - statement: ISCA1 identified as mitochondrial protein in high-confidence 
          mitochondrial proteome (MitoCoP)
        supporting_text: We classified >8,000 proteins in mitochondrial 
          preparations of human cells and defined a mitochondrial 
          high-confidence proteome of >1,100 proteins (MitoCoP).
  - id: PMID:40205054
    title: Multimodal cell maps as a foundation for structural and functional 
      genomics.
    findings:
      - statement: Confirms ISCA1-ISCA2 interaction
        supporting_text: Multimodal cell maps as a foundation for structural and
          functional genomics
  - id: Reactome:R-HSA-8878815
    title: Formation of 4Fe-4S cluster on ISCA1:ISCA2
    findings:
      - statement: ISCA1:ISCA2 complex forms [4Fe-4S] clusters in mitochondrial 
          matrix
  - id: Reactome:R-HSA-9854984
    title: Transfer of Fe-S clusters to SDHB
    findings:
      - statement: ISCA1 involved in Fe-S cluster transfer to target proteins 
          including SDHB
  - id: file:human/ISCA1/ISCA1-deep-research-falcon.md
    title: Deep research report on ISCA1
    findings: []
core_functions:
  - description: ISCA1 is a core component of the late-acting mitochondrial 
      [4Fe-4S] cluster assembly machinery. The ISCA1/ISCA2 heterodimer receives 
      [2Fe-2S] clusters from GLRX5 and catalyzes their reductive fusion into 
      [4Fe-4S] clusters, requiring electrons from FDX2/FDXR and the additional 
      factor IBA57. This function is essential for maturation of mitochondrial 
      [4Fe-4S] proteins including aconitase, respiratory complex I subunits, and
      lipoic acid synthase.
    molecular_function:
      id: GO:0140132
      label: iron-sulfur cluster chaperone activity
    directly_involved_in:
      - id: GO:0044572
        label: '[4Fe-4S] cluster assembly'
    locations:
      - id: GO:0005759
        label: mitochondrial matrix
    in_complex:
      id: GO:0120510
      label: mitochondrial [4Fe-4S] assembly complex
    supported_by:
      - reference_id: PMID:22323289
        supporting_text: ISCA1, ISCA2, and IBA57 are specifically involved in 
          the maturation of mitochondrial [4Fe-4S] proteins functioning late in 
          the ISC assembly pathway.
      - reference_id: PMID:25347204
        supporting_text: This complex acts as an "assembler" of [4Fe-4S] 
          clusters; i.e., the two GRX5-donated [2Fe-2S](2+) clusters generate a 
          [4Fe-4S](2+) cluster.
suggested_experiments:
  - description: Structural characterization of the human ISCA1/ISCA2/IBA57 
      complex with bound Fe-S clusters to understand the molecular mechanism of 
      [2Fe-2S] to [4Fe-4S] conversion.
  - description: Identification of the complete set of [4Fe-4S] target proteins 
      that depend on ISCA1/ISCA2 for cluster acquisition versus those using 
      alternative delivery pathways.
tags:
  - iron-sulfur-cluster-biogenesis