NUBPL

UniProt ID: Q8TB37
Organism: Homo sapiens
Review Status: INITIALIZED
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Gene Description

NUBPL (nucleotide-binding protein-like; also called IND1 homolog / huInd1) is a mitochondrial iron-sulfur cluster transfer protein of the Mrp/NBP35 family of P-loop NTPase Fe-S carrier proteins. Synthesized with an N-terminal mitochondrial transit peptide and imported into the mitochondrial matrix, it binds a single [4Fe-4S] cluster in a labile fashion via a conserved CXXC motif and acts as a dedicated assembly factor that delivers Fe-S cofactor(s) to subunits of respiratory chain Complex I (NADH:ubiquinone oxidoreductase). NUBPL is not a structural subunit of the Complex I holoenzyme; rather it is required for maturation of the peripheral (matrix) arm, and its loss leads to failure to accumulate Fe-S-containing subunits such as NDUFS1 and NDUFV1, reduced Complex I activity, remodeling of respiratory supercomplexes, and altered mitochondrial morphology. The protein also carries a Walker-A/P-loop ATP-binding motif characteristic of the family. In humans, biallelic loss-of-function variants in NUBPL cause mitochondrial complex I deficiency, nuclear type 21 (MC1DN21), a leukoencephalopathy with a distinctive MRI pattern.

Existing Annotations Review

GO Term Evidence Action Reason
GO:0005739 mitochondrion
IBA
GO_REF:0000033
MARK AS OVER ANNOTATED
Summary: Phylogenetic (IBA) localization to mitochondrion. Correct but generic relative to the experimentally supported and more specific mitochondrial matrix localization.
Reason: NUBPL is experimentally localized to mitochondrion (IDA, PMID:19752196) and more specifically to the mitochondrial matrix (Reactome TAS, ARBA IEA), consistent with a matrix-soluble assembly factor. The broad IBA "mitochondrion" call is superseded by the specific matrix annotation and is not treated as a distinct core localization.
Propagation Review
Root cause: NO FAILURE NON CORE
Failure modes: GRANULARITY MISMATCH
Supporting Evidence:
file:human/NUBPL/NUBPL-uniprot.txt
SUBCELLULAR LOCATION: Mitochondrion
GO:0032981 mitochondrial respiratory chain complex I assembly
IBA
GO_REF:0000033
ACCEPT
Summary: Phylogenetic (IBA) assignment of the core biological process. This matches the experimentally established role of NUBPL/IND1 as an assembly factor critically required for respiratory Complex I.
Reason: Independently supported by experimental IMP evidence (PMID:19752196), where huInd1 knockdown strongly decreased Complex I protein and activity. This is a core function.
Supporting Evidence:
PMID:19752196
huInd1, that is critically required for the assembly of complex I
GO:0016226 iron-sulfur cluster assembly
IBA
GO_REF:0000033
ACCEPT
Summary: Phylogenetic (IBA) assignment of iron-sulfur cluster assembly. NUBPL binds a [4Fe-4S] cluster and delivers Fe-S cofactor(s) to Complex I subunits, so it participates in the Fe-S maturation of the Complex I assembly pathway.
Reason: Consistent with the family (Mrp/NBP35 Fe-S carrier proteins) and with the experimentally demonstrated Fe-S delivery role toward Complex I (PMID:19752196). This is a core function, complementary to Complex I assembly.
Supporting Evidence:
PMID:19752196
a possible role in the delivery of one or more Fe/S clusters to complex I subunits
GO:0051539 4 iron, 4 sulfur cluster binding
IBA
GO_REF:0000033
ACCEPT
Summary: Phylogenetic (IBA) assignment of [4Fe-4S] cluster binding, the core molecular function. NUBPL binds one [4Fe-4S] cluster via a conserved CXXC motif.
Reason: Directly and independently supported by experimental IDA (PMID:19752196) and by the UniProt COFACTOR annotation ("Binds 1 [4Fe-4S] cluster"). This is a genuine, core MF.
Supporting Evidence:
file:human/NUBPL/NUBPL-uniprot.txt
Note=Binds 1 [4Fe-4S] cluster.
GO:0005524 ATP binding
IEA
GO_REF:0000002
KEEP AS NON CORE
Summary: InterPro/keyword-based ATP binding. NUBPL is a Mrp/NBP35 P-loop NTPase with a Walker-A/P-loop motif and an annotated ATP-binding site (residues 75-82).
Reason: The ATP-binding P-loop is a real, conserved feature of the family, but nucleotide binding is ancillary to NUBPL's defining function (Fe-S cluster binding and delivery to Complex I). No experimental characterization of ATP hydrolysis by human NUBPL is available, so it is retained as a non-core feature-based annotation.
Propagation Review
Root cause: NO FAILURE NON CORE
Failure modes: GRANULARITY MISMATCH
Supporting Evidence:
file:human/NUBPL/NUBPL-uniprot.txt
/ligand="ATP"
GO:0005739 mitochondrion
IEA
GO_REF:0000044
MARK AS OVER ANNOTATED
Summary: UniProt Subcellular Location keyword mapping to mitochondrion. Correct but generic relative to the specific mitochondrial matrix localization.
Reason: Duplicates the experimentally supported mitochondrion localization at a broad granularity; the matrix-specific annotation is preferred as the core localization.
Propagation Review
Root cause: NO FAILURE NON CORE
Failure modes: GRANULARITY MISMATCH
Supporting Evidence:
file:human/NUBPL/NUBPL-uniprot.txt
SUBCELLULAR LOCATION: Mitochondrion
GO:0005759 mitochondrial matrix
IEA
GO_REF:0000117
ACCEPT
Summary: ARBA machine-learning assignment to mitochondrial matrix. Consistent with a matrix-soluble assembly factor that acts on the peripheral (matrix) arm of Complex I and with the Reactome TAS matrix annotations.
Reason: NUBPL is a soluble mitochondrial protein imported via a cleavable transit peptide, and its Complex I substrate subunits (NDUFS1, NDUFV1) mature in the matrix. The matrix is the most specific well-supported localization.
Propagation Review
Root cause: NO FAILURE CORE
Supporting Evidence:
file:human/NUBPL/NUBPL-uniprot.txt
TRANSIT 1..38
GO:0016226 iron-sulfur cluster assembly
IEA
GO_REF:0000002
ACCEPT
Summary: InterPro-based iron-sulfur cluster assembly, redundant with the IBA assignment of the same term. Core biological process for this Fe-S carrier protein.
Reason: Same conclusion as the IBA annotation of GO:0016226; supported by the [4Fe-4S] binding and delivery role toward Complex I.
Propagation Review
Root cause: NO FAILURE CORE
Supporting Evidence:
PMID:19752196
a possible role in the delivery of one or more Fe/S clusters to complex I subunits
GO:0032981 mitochondrial respiratory chain complex I assembly
IEA
GO_REF:0000117
ACCEPT
Summary: ARBA machine-learning assignment of Complex I assembly, redundant with the IBA and IMP annotations of the same term. Core biological process.
Reason: Same core conclusion as the experimental IMP (PMID:19752196) and IBA annotations.
Propagation Review
Root cause: NO FAILURE CORE
Supporting Evidence:
PMID:19752196
huInd1, that is critically required for the assembly of complex I
GO:0051536 iron-sulfur cluster binding
IEA
GO_REF:0000002
MARK AS OVER ANNOTATED
Summary: InterPro-based generic iron-sulfur cluster binding. This is the parent of the specific [4Fe-4S] cluster binding (GO:0051539) that is experimentally supported.
Reason: NUBPL binds specifically a [4Fe-4S] cluster (UniProt COFACTOR; IDA PMID:19752196), which is captured by the more precise GO:0051539. The broad parent term is uninformative and redundant relative to the specific child.
Propagation Review
Root cause: NO FAILURE NON CORE
Failure modes: GRANULARITY MISMATCH
Supporting Evidence:
file:human/NUBPL/NUBPL-uniprot.txt
Note=Binds 1 [4Fe-4S] cluster.
GO:0140663 ATP-dependent FeS chaperone activity
IEA
GO_REF:0000002
ACCEPT
Summary: InterPro-based ATP-dependent FeS chaperone activity, defined as "binding to and delivering metal ions to a target protein, driven by ATP hydrolysis." This is the most specific molecular-function term for NUBPL's role as an Fe-S carrier that delivers its [4Fe-4S] cluster to Complex I subunits.
Reason: Matches the experimentally supported function: NUBPL binds a [4Fe-4S] cluster and delivers Fe-S cofactor(s) to Complex I subunits (PMID:19752196), and belongs to the ATP-binding Mrp/NBP35 carrier family. This captures the carrier/delivery molecular activity better than bare Fe-S binding and is retained as core.
Propagation Review
Root cause: NO FAILURE CORE
Supporting Evidence:
PMID:19752196
a possible role in the delivery of one or more Fe/S clusters to complex I subunits
GO:0005515 protein binding
IPI
PMID:32296183
A reference map of the human binary protein interactome.
MARK AS OVER ANNOTATED
Summary: Bare "protein binding" from the HuRI binary (Y2H) interactome, capturing NUBPL interactions with NUBP2 (Q9Y5Y2) and a KDM8/JMJD5 isoform (Q8N371-3). Uninformative as a molecular function.
Reason: GO:0005515 conveys no specific function. The high-throughput binary interactions do not establish a defined mitochondrial molecular activity for NUBPL; per policy an experimental IPI is retained but flagged as over-annotated rather than removed.
Supporting Evidence:
file:human/NUBPL/NUBPL-uniprot.txt
Q8TB37; Q9Y5Y2: NUBP2; NbExp=6
GO:0005739 mitochondrion
IDA
GO_REF:0000052
ACCEPT
Summary: Immunofluorescence-based (HPA, IDA) localization to mitochondrion. Directly supports mitochondrial localization of NUBPL.
Reason: Experimental (IDA) mitochondrial localization consistent with the UniProt subcellular location and the more specific matrix annotations. Retained; the matrix term is the finer-grained core localization.
Supporting Evidence:
file:human/NUBPL/NUBPL-uniprot.txt
SUBCELLULAR LOCATION: Mitochondrion
GO:0005739 mitochondrion
HTP
PMID:34800366
Quantitative high-confidence human mitochondrial proteome an...
KEEP AS NON CORE
Summary: High-throughput (HTP) mitochondrial-proteome localization to mitochondrion from a quantitative high-confidence human mitochondrial proteome study.
Reason: Corroborating high-throughput evidence for mitochondrial localization; consistent with the IDA annotations but non-core relative to the specific matrix localization.
Supporting Evidence:
file:human/NUBPL/NUBPL-uniprot.txt
SUBCELLULAR LOCATION: Mitochondrion
GO:0005759 mitochondrial matrix
TAS
Reactome:R-HSA-5690023
ACCEPT
Summary: Reactome TAS placing NUBPL in the mitochondrial matrix, in the reaction where NUBPL binds the [4Fe-4S] cluster. Consistent with a matrix-soluble assembly factor.
Reason: Mitochondrial matrix is the specific, well-supported localization for this soluble assembly factor whose Complex I substrate subunits mature in the matrix.
Supporting Evidence:
file:human/NUBPL/NUBPL-uniprot.txt
TRANSIT 1..38
GO:0005759 mitochondrial matrix
TAS
Reactome:R-HSA-6788523
ACCEPT
Summary: Reactome TAS matrix localization from the reaction "NUBPL transfers 4Fe-4S to Complex I subunits." Duplicate of the same matrix localization.
Reason: Same well-supported matrix localization; consistent with NUBPL's Fe-S delivery role.
Supporting Evidence:
file:human/NUBPL/NUBPL-uniprot.txt
TRANSIT 1..38
GO:0005759 mitochondrial matrix
TAS
Reactome:R-HSA-6788556
ACCEPT
Summary: Reactome TAS matrix localization from the reaction "NUBPL transfers 4Fe-4S to NDUFV1, V2." Duplicate of the same matrix localization.
Reason: Same well-supported matrix localization; consistent with NUBPL's Fe-S delivery role.
Supporting Evidence:
file:human/NUBPL/NUBPL-uniprot.txt
TRANSIT 1..38
GO:0005739 mitochondrion
IDA
PMID:19752196
Human ind1, an iron-sulfur cluster assembly factor for respi...
ACCEPT
Summary: Experimental (IDA) mitochondrial localization from the primary characterization of huInd1 (Sheftel et al. 2009), which established the subcellular location of NUBPL.
Reason: This is the source experimental IDA underlying the UniProt "Mitochondrion" subcellular location (ECO:0000269|PubMed:19752196). Core mitochondrial localization.
Supporting Evidence:
file:human/NUBPL/NUBPL-uniprot.txt
SUBCELLULAR LOCATION: Mitochondrion {ECO:0000269|PubMed:19752196}
GO:0007005 mitochondrion organization
IMP
PMID:19752196
Human ind1, an iron-sulfur cluster assembly factor for respi...
KEEP AS NON CORE
Summary: IMP annotation based on the altered mitochondrial morphology observed upon huInd1 knockdown. This is a downstream, pleiotropic consequence of loss of Complex I rather than a direct core function of NUBPL.
Reason: NUBPL's direct role is Fe-S cluster binding and delivery for Complex I assembly; the "alteration of mitochondrial morphology" reported on knockdown is a secondary effect of respiratory-chain dysfunction, so this BP is retained as non-core rather than a defining function.
Supporting Evidence:
PMID:19752196
remodeling of respiratory supercomplexes, and alteration of mitochondrial morphology
GO:0032981 mitochondrial respiratory chain complex I assembly
IMP
PMID:19752196
Human ind1, an iron-sulfur cluster assembly factor for respi...
ACCEPT
Summary: Experimental (IMP) evidence that NUBPL/huInd1 is required for Complex I assembly: RNAi knockdown caused strong decreases in Complex I protein and activity. This is a core biological process.
Reason: This IMP is the primary experimental basis for NUBPL's function as a Complex I assembly factor and underlies the disease association (MC1DN21).
Supporting Evidence:
PMID:19752196
Knockdown of huInd1 in HeLa cells by RNA interference technology led to strong decreases in complex I protein and activity levels
GO:0051539 4 iron, 4 sulfur cluster binding
IDA
PMID:19752196
Human ind1, an iron-sulfur cluster assembly factor for respi...
ACCEPT
Summary: Experimental (IDA) evidence that NUBPL/huInd1 binds an Fe-S cluster via a conserved CXXC motif. This is the core molecular function, matching the UniProt COFACTOR annotation of one [4Fe-4S] cluster.
Reason: Directly demonstrated cofactor binding; the CXXC-motif cysteines (Cys-244/Cys-247) are required for Complex I assembly, tying the [4Fe-4S] binding to function.
Supporting Evidence:
PMID:19752196
huInd1 can bind an Fe/S cluster via a conserved CXXC motif in a labile fashion

Core Functions

Binds a single [4Fe-4S] cluster via a conserved CXXC motif and acts as an ATP-binding Mrp/NBP35-family Fe-S carrier that delivers Fe-S cofactor(s) to respiratory Complex I subunits during their maturation in the mitochondrial matrix.

Supporting Evidence:
  • PMID:19752196
    a possible role in the delivery of one or more Fe/S clusters to complex I subunits
  • file:human/NUBPL/NUBPL-uniprot.txt
    Note=Binds 1 [4Fe-4S] cluster.

Binds a [4Fe-4S] iron-sulfur cluster, the cofactor that NUBPL carries and transfers; the cluster is coordinated by a conserved CXXC motif (Cys-244/Cys-247) required for Complex I assembly.

Supporting Evidence:
  • PMID:19752196
    huInd1 can bind an Fe/S cluster via a conserved CXXC motif in a labile fashion
  • file:human/NUBPL/NUBPL-uniprot.txt
    Note=Binds 1 [4Fe-4S] cluster.

References

Gene Ontology annotation through association of InterPro records with GO terms
Annotation inferences using phylogenetic trees
Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location vocabulary mapping, accompanied by conservative changes to GO terms applied by UniProt
Gene Ontology annotation based on curation of immunofluorescence data
Electronic Gene Ontology annotations created by ARBA machine learning models
Human ind1, an iron-sulfur cluster assembly factor for respiratory complex I.
  • huInd1 (NUBPL) is a mitochondrial P-loop NTPase critically required for the assembly of respiratory Complex I; knockdown decreases Complex I protein and activity and loss of peripheral-arm subunits.
    "huInd1, that is critically required for the assembly of complex I. huInd1 can bind an Fe/S cluster via a conserved CXXC motif in a labile fashion."
A reference map of the human binary protein interactome.
  • Large-scale binary (Y2H) interactome map (HuRI); the source of the NUBPL protein binding (IPI) annotations to NUBP2 and a KDM8 isoform.
    "we present a human 'all-by-all' reference interactome map of human binary protein interactions, or 'HuRI'."
Quantitative high-confidence human mitochondrial proteome and its dynamics in cellular context.
  • High-confidence human mitochondrial proteome; corroborates mitochondrial localization of NUBPL (HTP).
    "Quantitative high-confidence human mitochondrial proteome and its dynamics in cellular context."
Reactome:R-HSA-5690023
NUBPL binds 4Fe-4S
Reactome:R-HSA-6788523
NUBPL transfers 4Fe-4S to Complex I subunits
Reactome:R-HSA-6788556
NUBPL transfers 4Fe-4S to NDUFV1, V2

📚 Additional Documentation

Notes

(NUBPL-notes.md)

NUBPL (IND1 homolog) — review notes

UniProt: Q8TB37 (NUBPL_HUMAN). HGNC:20278. Gene synonym C14orf127. 319 aa precursor
with an N-terminal mitochondrial transit peptide (residues 1-38); mature chain 39-319
(PRO_0000184950) [file:human/NUBPL/NUBPL-uniprot.txt "TRANSIT 1..38 /note=\"Mitochondrion\""].

Identity / family

  • RecName "Iron-sulfur cluster transfer protein NUBPL"; AltNames "IND1 homolog",
    "Nucleotide-binding protein-like", "huInd1" [file:human/NUBPL/NUBPL-uniprot.txt
    "RecName: Full=Iron-sulfur cluster transfer protein NUBPL"].
  • Member of the Mrp/NBP35 ATP-binding proteins family — a P-loop NTPase family of
    Fe-S cluster carrier/assembly factors [file:human/NUBPL/NUBPL-uniprot.txt
    "Belongs to the Mrp/NBP35 ATP-binding proteins family"].
  • InterPro/Pfam signatures: Mrp/NBP35 ATP-bd (IPR019591), NUBPL-like (IPR044304),
    P-loop NTPase (IPR027417), Mrp-like_CS (IPR000808); PANTHER PTHR42961
    "IRON-SULFUR PROTEIN NUBPL"; CDD cd02037 Mrp_NBP35 [file:human/NUBPL/NUBPL-uniprot.txt].

Molecular function

  • COFACTOR: binds 1 [4Fe-4S] cluster (ChEBI:49883) [file:human/NUBPL/NUBPL-uniprot.txt
    "Name=[4Fe-4S] cluster; Xref=ChEBI:CHEBI:49883" / "Note=Binds 1 [4Fe-4S] cluster."].
  • The Fe-S cluster is bound via a conserved CXXC motif; mutagenesis of Cys-244 and
    Cys-247 (C->A double mutant) causes a defect in complex I assembly
    [file:human/NUBPL/NUBPL-uniprot.txt "MUTAGEN 244 ... Defect in complex I assembly;
    when associated with A-247."]. The primary paper: "huInd1 can bind an Fe/S cluster
    via a conserved CXXC motif in a labile fashion" [PMID:19752196 abstract].
  • ATP-binding P-loop: BINDING 75..82 ligand ATP (CHEBI:30616), ECO:0000255
    [file:human/NUBPL/NUBPL-uniprot.txt "BINDING 75..82 /ligand=\"ATP\""]. Sequence has
    the classic Walker-A/P-loop "GKGGVGKS" at ~res 74-81 (SQ line). Keywords include
    ATP-binding and Nucleotide-binding [file:human/NUBPL/NUBPL-uniprot.txt "KW ...
    ATP-binding ... Nucleotide-binding"].
  • GO:0140663 "ATP-dependent FeS chaperone activity" is defined as "Binding to and
    delivering metal ions to a target protein, driven by ATP hydrolysis" (OLS/GO). This
    is the most specific MF term matching NUBPL's role as an Fe-S cluster carrier that
    delivers the cluster to Complex I subunits. It is currently only IEA (InterPro).

Biological process

  • Function (UniProt): "Iron-sulfur cluster transfer protein involved in the assembly of
    the mitochondrial membrane respiratory chain NADH dehydrogenase (Complex I) ... May
    deliver one or more Fe-S clusters to complex I subunits" (ECO:0000269|PubMed:19752196)
    [file:human/NUBPL/NUBPL-uniprot.txt "Iron-sulfur cluster transfer protein involved in
    the assembly of the mitochondrial membrane respiratory chain NADH dehydrogenase"].
  • Primary evidence (PMID:19752196, Sheftel et al., MCB 2009): huInd1 is "critically
    required for the assembly of complex I". RNAi knockdown → "strong decreases in complex
    I protein and activity levels, remodeling of respiratory supercomplexes, and alteration
    of mitochondrial morphology"; loss of specific peripheral-arm subunits (NDUFS1, NDUFV1,
    NDUFS3, NDUFA13) with a 450-kDa membrane-arm subcomplex; iron associated with complex I
    reflects dependence on huInd1 [PMID:19752196 abstract, full text not cached].
  • Core BP: GO:0032981 mitochondrial respiratory chain complex I assembly; the Fe-S
    delivery step also justifies GO:0016226 iron-sulfur cluster assembly.
  • GO:0007005 mitochondrion organization (IMP, PMID:19752196): supported by the observed
    "alteration of mitochondrial morphology" on knockdown, but this is a downstream/
    pleiotropic consequence of loss of Complex I rather than a direct core function — keep
    as non-core.

Localization

  • Mitochondrion (SUBCELLULAR LOCATION), ECO:0000269|PubMed:19752196
    [file:human/NUBPL/NUBPL-uniprot.txt "SUBCELLULAR LOCATION: Mitochondrion"]. IDA in GOA
    from PMID:19752196 and HPA (GO_REF:0000052). Multiple Reactome TAS + ARBA IEA place it
    in the mitochondrial matrix (GO:0005759), consistent with a matrix-soluble assembly
    factor acting on the peripheral (matrix) arm of Complex I.
  • HTP mitochondrion annotation from PMID:34800366 (high-confidence human mitochondrial
    proteome) — corroborating high-throughput localization.

Interactions

  • IntAct: NUBPL interacts with NUBP2 (Q9Y5Y2; NbExp=6) and KDM8/JMJD5 isoform
    (Q8N371-3; NbExp=3) [file:human/NUBPL/NUBPL-uniprot.txt "Q8TB37; Q9Y5Y2: NUBP2" /
    "Q8TB37; Q8N371-3: KDM8"]. GOA carries these as two bare GO:0005515 "protein binding"
    IPI rows from PMID:32296183 (HuRI binary interactome). NUBP2 is a cytosolic
    Fe-S-cluster (CIA) NBP35-family paralog; a Y2H interaction with NUBPL does not
    establish a specific mitochondrial molecular function, so bare "protein binding" is an
    over-annotation.
  • Reactome (R-HSA-6788523, R-HSA-6788556): NUBPL transfers the [4Fe-4S] cluster to
    Complex I subunits (NDUFS1/S2/S7/S8 and NDUFV1/V2); process requires the HSPA9:HSCB
    co-chaperone (Maio et al. 2017) [reactome/R-HSA-6788523.md].

Disease

  • Mitochondrial complex I deficiency, nuclear type 21 (MC1DN21; MIM:618242), autosomal
    recessive; variants incl. G56R, D105Y, L193F [file:human/NUBPL/NUBPL-uniprot.txt
    "Mitochondrial complex I deficiency, nuclear type 21 (MC1DN21)"]. Confirms the
    physiological requirement of NUBPL for Complex I in humans (PMID:20818383, PMID:23553477).

Reactome pathway

  • DR Reactome R-HSA-6799198 "Complex I biogenesis" [file:human/NUBPL/NUBPL-uniprot.txt
    "Reactome; R-HSA-6799198; Complex I biogenesis."].

Curation decisions (summary)

  • MF core: GO:0051539 (4Fe-4S binding, IDA PMID:19752196) ACCEPT — genuine, experimentally
    supported cofactor binding. GO:0140663 (ATP-dependent FeS chaperone activity) captures
    the carrier/delivery activity; IEA accepted as the specific MF. GO:0051536 (parent
    Fe-S binding, IEA) MARK_AS_OVER_ANNOTATED (redundant parent of 0051539). GO:0005524
    ATP binding (IEA-KW): KEEP_AS_NON_CORE (P-loop present; ancillary to the chaperone
    cycle). Bare GO:0005515 protein binding IPI: MARK_AS_OVER_ANNOTATED (per policy, never
    REMOVE an IPI).
  • BP core: GO:0032981 complex I assembly (IMP + IBA + IEA) ACCEPT. GO:0016226 Fe-S
    cluster assembly (IBA + IEA) ACCEPT (the Fe-S delivery step). GO:0007005 mitochondrion
    organization (IMP) KEEP_AS_NON_CORE (secondary morphology effect).
  • CC: mitochondrion / mitochondrial matrix — ACCEPT the experimental IDA
    (GO:0005739, PMID:19752196) and matrix TAS/IEA; keep the broad IBA/IEA mitochondrion as
    non-core relative to the specific matrix localization.
  • NUBPL is NOT a structural subunit of Complex I; do not assign NADH dehydrogenase
    (GO:0008137) activity.

📄 View Raw YAML

id: Q8TB37
gene_symbol: NUBPL
product_type: PROTEIN
status: INITIALIZED
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: >-
  NUBPL (nucleotide-binding protein-like; also called IND1 homolog / huInd1) is a
  mitochondrial iron-sulfur cluster transfer protein of the Mrp/NBP35 family of P-loop
  NTPase Fe-S carrier proteins. Synthesized with an N-terminal mitochondrial transit
  peptide and imported into the mitochondrial matrix, it binds a single [4Fe-4S] cluster
  in a labile fashion via a conserved CXXC motif and acts as a dedicated assembly factor
  that delivers Fe-S cofactor(s) to subunits of respiratory chain Complex I
  (NADH:ubiquinone oxidoreductase). NUBPL is not a structural subunit of the Complex I
  holoenzyme; rather it is required for maturation of the peripheral (matrix) arm, and its
  loss leads to failure to accumulate Fe-S-containing subunits such as NDUFS1 and NDUFV1,
  reduced Complex I activity, remodeling of respiratory supercomplexes, and altered
  mitochondrial morphology. The protein also carries a Walker-A/P-loop ATP-binding motif
  characteristic of the family. In humans, biallelic loss-of-function variants in NUBPL
  cause mitochondrial complex I deficiency, nuclear type 21 (MC1DN21), a
  leukoencephalopathy with a distinctive MRI pattern.
alternative_products:
- name: '1'
  id: Q8TB37-1
- name: '2'
  id: Q8TB37-2
  sequence_note: VSP_020985, VSP_008797
existing_annotations:
- term:
    id: GO:0005739
    label: mitochondrion
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: is_active_in
  review:
    summary: >-
      Phylogenetic (IBA) localization to mitochondrion. Correct but generic relative to
      the experimentally supported and more specific mitochondrial matrix localization.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      NUBPL is experimentally localized to mitochondrion (IDA, PMID:19752196) and more
      specifically to the mitochondrial matrix (Reactome TAS, ARBA IEA), consistent with
      a matrix-soluble assembly factor. The broad IBA "mitochondrion" call is superseded
      by the specific matrix annotation and is not treated as a distinct core localization.
    propagation_review:
      root_cause: NO_FAILURE_NON_CORE
      failure_modes:
      - GRANULARITY_MISMATCH
    supported_by:
    - reference_id: file:human/NUBPL/NUBPL-uniprot.txt
      supporting_text: "SUBCELLULAR LOCATION: Mitochondrion"
- term:
    id: GO:0032981
    label: mitochondrial respiratory chain complex I assembly
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: >-
      Phylogenetic (IBA) assignment of the core biological process. This matches the
      experimentally established role of NUBPL/IND1 as an assembly factor critically
      required for respiratory Complex I.
    action: ACCEPT
    reason: >-
      Independently supported by experimental IMP evidence (PMID:19752196), where huInd1
      knockdown strongly decreased Complex I protein and activity. This is a core function.
    supported_by:
    - reference_id: PMID:19752196
      supporting_text: >-
        huInd1, that is critically required for the assembly of complex I
- term:
    id: GO:0016226
    label: iron-sulfur cluster assembly
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: >-
      Phylogenetic (IBA) assignment of iron-sulfur cluster assembly. NUBPL binds a
      [4Fe-4S] cluster and delivers Fe-S cofactor(s) to Complex I subunits, so it
      participates in the Fe-S maturation of the Complex I assembly pathway.
    action: ACCEPT
    reason: >-
      Consistent with the family (Mrp/NBP35 Fe-S carrier proteins) and with the
      experimentally demonstrated Fe-S delivery role toward Complex I (PMID:19752196).
      This is a core function, complementary to Complex I assembly.
    supported_by:
    - reference_id: PMID:19752196
      supporting_text: >-
        a possible role in the delivery of one or more Fe/S clusters to complex I subunits
- term:
    id: GO:0051539
    label: 4 iron, 4 sulfur cluster binding
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: enables
  review:
    summary: >-
      Phylogenetic (IBA) assignment of [4Fe-4S] cluster binding, the core molecular
      function. NUBPL binds one [4Fe-4S] cluster via a conserved CXXC motif.
    action: ACCEPT
    reason: >-
      Directly and independently supported by experimental IDA (PMID:19752196) and by the
      UniProt COFACTOR annotation ("Binds 1 [4Fe-4S] cluster"). This is a genuine, core MF.
    supported_by:
    - reference_id: file:human/NUBPL/NUBPL-uniprot.txt
      supporting_text: "Note=Binds 1 [4Fe-4S] cluster."
- term:
    id: GO:0005524
    label: ATP binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: enables
  review:
    summary: >-
      InterPro/keyword-based ATP binding. NUBPL is a Mrp/NBP35 P-loop NTPase with a
      Walker-A/P-loop motif and an annotated ATP-binding site (residues 75-82).
    action: KEEP_AS_NON_CORE
    reason: >-
      The ATP-binding P-loop is a real, conserved feature of the family, but nucleotide
      binding is ancillary to NUBPL's defining function (Fe-S cluster binding and delivery
      to Complex I). No experimental characterization of ATP hydrolysis by human NUBPL is
      available, so it is retained as a non-core feature-based annotation.
    propagation_review:
      root_cause: NO_FAILURE_NON_CORE
      failure_modes:
      - GRANULARITY_MISMATCH
    supported_by:
    - reference_id: file:human/NUBPL/NUBPL-uniprot.txt
      supporting_text: /ligand="ATP"
- term:
    id: GO:0005739
    label: mitochondrion
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: >-
      UniProt Subcellular Location keyword mapping to mitochondrion. Correct but generic
      relative to the specific mitochondrial matrix localization.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Duplicates the experimentally supported mitochondrion localization at a broad
      granularity; the matrix-specific annotation is preferred as the core localization.
    propagation_review:
      root_cause: NO_FAILURE_NON_CORE
      failure_modes:
      - GRANULARITY_MISMATCH
    supported_by:
    - reference_id: file:human/NUBPL/NUBPL-uniprot.txt
      supporting_text: "SUBCELLULAR LOCATION: Mitochondrion"
- term:
    id: GO:0005759
    label: mitochondrial matrix
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  qualifier: located_in
  review:
    summary: >-
      ARBA machine-learning assignment to mitochondrial matrix. Consistent with a
      matrix-soluble assembly factor that acts on the peripheral (matrix) arm of Complex I
      and with the Reactome TAS matrix annotations.
    action: ACCEPT
    reason: >-
      NUBPL is a soluble mitochondrial protein imported via a cleavable transit peptide,
      and its Complex I substrate subunits (NDUFS1, NDUFV1) mature in the matrix. The
      matrix is the most specific well-supported localization.
    propagation_review:
      root_cause: NO_FAILURE_CORE
    supported_by:
    - reference_id: file:human/NUBPL/NUBPL-uniprot.txt
      supporting_text: "TRANSIT         1..38"
- term:
    id: GO:0016226
    label: iron-sulfur cluster assembly
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: involved_in
  review:
    summary: >-
      InterPro-based iron-sulfur cluster assembly, redundant with the IBA assignment of
      the same term. Core biological process for this Fe-S carrier protein.
    action: ACCEPT
    reason: >-
      Same conclusion as the IBA annotation of GO:0016226; supported by the [4Fe-4S]
      binding and delivery role toward Complex I.
    propagation_review:
      root_cause: NO_FAILURE_CORE
    supported_by:
    - reference_id: PMID:19752196
      supporting_text: >-
        a possible role in the delivery of one or more Fe/S clusters to complex I subunits
- term:
    id: GO:0032981
    label: mitochondrial respiratory chain complex I assembly
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  qualifier: involved_in
  review:
    summary: >-
      ARBA machine-learning assignment of Complex I assembly, redundant with the IBA and
      IMP annotations of the same term. Core biological process.
    action: ACCEPT
    reason: >-
      Same core conclusion as the experimental IMP (PMID:19752196) and IBA annotations.
    propagation_review:
      root_cause: NO_FAILURE_CORE
    supported_by:
    - reference_id: PMID:19752196
      supporting_text: >-
        huInd1, that is critically required for the assembly of complex I
- term:
    id: GO:0051536
    label: iron-sulfur cluster binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: enables
  review:
    summary: >-
      InterPro-based generic iron-sulfur cluster binding. This is the parent of the
      specific [4Fe-4S] cluster binding (GO:0051539) that is experimentally supported.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      NUBPL binds specifically a [4Fe-4S] cluster (UniProt COFACTOR; IDA PMID:19752196),
      which is captured by the more precise GO:0051539. The broad parent term is
      uninformative and redundant relative to the specific child.
    propagation_review:
      root_cause: NO_FAILURE_NON_CORE
      failure_modes:
      - GRANULARITY_MISMATCH
    supported_by:
    - reference_id: file:human/NUBPL/NUBPL-uniprot.txt
      supporting_text: "Note=Binds 1 [4Fe-4S] cluster."
- term:
    id: GO:0140663
    label: ATP-dependent FeS chaperone activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: enables
  review:
    summary: >-
      InterPro-based ATP-dependent FeS chaperone activity, defined as "binding to and
      delivering metal ions to a target protein, driven by ATP hydrolysis." This is the
      most specific molecular-function term for NUBPL's role as an Fe-S carrier that
      delivers its [4Fe-4S] cluster to Complex I subunits.
    action: ACCEPT
    reason: >-
      Matches the experimentally supported function: NUBPL binds a [4Fe-4S] cluster and
      delivers Fe-S cofactor(s) to Complex I subunits (PMID:19752196), and belongs to the
      ATP-binding Mrp/NBP35 carrier family. This captures the carrier/delivery molecular
      activity better than bare Fe-S binding and is retained as core.
    propagation_review:
      root_cause: NO_FAILURE_CORE
    supported_by:
    - reference_id: PMID:19752196
      supporting_text: >-
        a possible role in the delivery of one or more Fe/S clusters to complex I subunits
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:32296183
  qualifier: enables
  review:
    summary: >-
      Bare "protein binding" from the HuRI binary (Y2H) interactome, capturing NUBPL
      interactions with NUBP2 (Q9Y5Y2) and a KDM8/JMJD5 isoform (Q8N371-3). Uninformative
      as a molecular function.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      GO:0005515 conveys no specific function. The high-throughput binary interactions do
      not establish a defined mitochondrial molecular activity for NUBPL; per policy an
      experimental IPI is retained but flagged as over-annotated rather than removed.
    supported_by:
    - reference_id: file:human/NUBPL/NUBPL-uniprot.txt
      supporting_text: "Q8TB37; Q9Y5Y2: NUBP2; NbExp=6"
- term:
    id: GO:0005739
    label: mitochondrion
  evidence_type: IDA
  original_reference_id: GO_REF:0000052
  qualifier: located_in
  review:
    summary: >-
      Immunofluorescence-based (HPA, IDA) localization to mitochondrion. Directly
      supports mitochondrial localization of NUBPL.
    action: ACCEPT
    reason: >-
      Experimental (IDA) mitochondrial localization consistent with the UniProt
      subcellular location and the more specific matrix annotations. Retained; the matrix
      term is the finer-grained core localization.
    supported_by:
    - reference_id: file:human/NUBPL/NUBPL-uniprot.txt
      supporting_text: "SUBCELLULAR LOCATION: Mitochondrion"
- term:
    id: GO:0005739
    label: mitochondrion
  evidence_type: HTP
  original_reference_id: PMID:34800366
  qualifier: located_in
  review:
    summary: >-
      High-throughput (HTP) mitochondrial-proteome localization to mitochondrion from a
      quantitative high-confidence human mitochondrial proteome study.
    action: KEEP_AS_NON_CORE
    reason: >-
      Corroborating high-throughput evidence for mitochondrial localization; consistent
      with the IDA annotations but non-core relative to the specific matrix localization.
    supported_by:
    - reference_id: file:human/NUBPL/NUBPL-uniprot.txt
      supporting_text: "SUBCELLULAR LOCATION: Mitochondrion"
- term:
    id: GO:0005759
    label: mitochondrial matrix
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-5690023
  qualifier: located_in
  review:
    summary: >-
      Reactome TAS placing NUBPL in the mitochondrial matrix, in the reaction where NUBPL
      binds the [4Fe-4S] cluster. Consistent with a matrix-soluble assembly factor.
    action: ACCEPT
    reason: >-
      Mitochondrial matrix is the specific, well-supported localization for this soluble
      assembly factor whose Complex I substrate subunits mature in the matrix.
    supported_by:
    - reference_id: file:human/NUBPL/NUBPL-uniprot.txt
      supporting_text: "TRANSIT         1..38"
- term:
    id: GO:0005759
    label: mitochondrial matrix
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-6788523
  qualifier: located_in
  review:
    summary: >-
      Reactome TAS matrix localization from the reaction "NUBPL transfers 4Fe-4S to
      Complex I subunits." Duplicate of the same matrix localization.
    action: ACCEPT
    reason: >-
      Same well-supported matrix localization; consistent with NUBPL's Fe-S delivery role.
    supported_by:
    - reference_id: file:human/NUBPL/NUBPL-uniprot.txt
      supporting_text: "TRANSIT         1..38"
- term:
    id: GO:0005759
    label: mitochondrial matrix
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-6788556
  qualifier: located_in
  review:
    summary: >-
      Reactome TAS matrix localization from the reaction "NUBPL transfers 4Fe-4S to
      NDUFV1, V2." Duplicate of the same matrix localization.
    action: ACCEPT
    reason: >-
      Same well-supported matrix localization; consistent with NUBPL's Fe-S delivery role.
    supported_by:
    - reference_id: file:human/NUBPL/NUBPL-uniprot.txt
      supporting_text: "TRANSIT         1..38"
- term:
    id: GO:0005739
    label: mitochondrion
  evidence_type: IDA
  original_reference_id: PMID:19752196
  qualifier: located_in
  review:
    summary: >-
      Experimental (IDA) mitochondrial localization from the primary characterization of
      huInd1 (Sheftel et al. 2009), which established the subcellular location of NUBPL.
    action: ACCEPT
    reason: >-
      This is the source experimental IDA underlying the UniProt "Mitochondrion"
      subcellular location (ECO:0000269|PubMed:19752196). Core mitochondrial localization.
    supported_by:
    - reference_id: file:human/NUBPL/NUBPL-uniprot.txt
      supporting_text: >-
        SUBCELLULAR LOCATION: Mitochondrion {ECO:0000269|PubMed:19752196}
- term:
    id: GO:0007005
    label: mitochondrion organization
  evidence_type: IMP
  original_reference_id: PMID:19752196
  qualifier: involved_in
  review:
    summary: >-
      IMP annotation based on the altered mitochondrial morphology observed upon huInd1
      knockdown. This is a downstream, pleiotropic consequence of loss of Complex I rather
      than a direct core function of NUBPL.
    action: KEEP_AS_NON_CORE
    reason: >-
      NUBPL's direct role is Fe-S cluster binding and delivery for Complex I assembly; the
      "alteration of mitochondrial morphology" reported on knockdown is a secondary effect
      of respiratory-chain dysfunction, so this BP is retained as non-core rather than a
      defining function.
    supported_by:
    - reference_id: PMID:19752196
      supporting_text: >-
        remodeling of respiratory supercomplexes, and alteration of mitochondrial
        morphology
- term:
    id: GO:0032981
    label: mitochondrial respiratory chain complex I assembly
  evidence_type: IMP
  original_reference_id: PMID:19752196
  qualifier: involved_in
  review:
    summary: >-
      Experimental (IMP) evidence that NUBPL/huInd1 is required for Complex I assembly:
      RNAi knockdown caused strong decreases in Complex I protein and activity. This is a
      core biological process.
    action: ACCEPT
    reason: >-
      This IMP is the primary experimental basis for NUBPL's function as a Complex I
      assembly factor and underlies the disease association (MC1DN21).
    supported_by:
    - reference_id: PMID:19752196
      supporting_text: >-
        Knockdown of huInd1 in HeLa cells by RNA interference technology led to strong
        decreases in complex I protein and activity levels
- term:
    id: GO:0051539
    label: 4 iron, 4 sulfur cluster binding
  evidence_type: IDA
  original_reference_id: PMID:19752196
  qualifier: enables
  review:
    summary: >-
      Experimental (IDA) evidence that NUBPL/huInd1 binds an Fe-S cluster via a conserved
      CXXC motif. This is the core molecular function, matching the UniProt COFACTOR
      annotation of one [4Fe-4S] cluster.
    action: ACCEPT
    reason: >-
      Directly demonstrated cofactor binding; the CXXC-motif cysteines (Cys-244/Cys-247)
      are required for Complex I assembly, tying the [4Fe-4S] binding to function.
    supported_by:
    - reference_id: PMID:19752196
      supporting_text: >-
        huInd1 can bind an Fe/S cluster via a conserved CXXC motif in a labile fashion
core_functions:
- description: >-
    Binds a single [4Fe-4S] cluster via a conserved CXXC motif and acts as an
    ATP-binding Mrp/NBP35-family Fe-S carrier that delivers Fe-S cofactor(s) to
    respiratory Complex I subunits during their maturation in the mitochondrial matrix.
  molecular_function:
    id: GO:0140663
    label: ATP-dependent FeS chaperone activity
  directly_involved_in:
  - id: GO:0032981
    label: mitochondrial respiratory chain complex I assembly
  - id: GO:0016226
    label: iron-sulfur cluster assembly
  locations:
  - id: GO:0005759
    label: mitochondrial matrix
  supported_by:
  - reference_id: PMID:19752196
    supporting_text: >-
      a possible role in the delivery of one or more Fe/S clusters to complex I subunits
  - reference_id: file:human/NUBPL/NUBPL-uniprot.txt
    supporting_text: "Note=Binds 1 [4Fe-4S] cluster."
- description: >-
    Binds a [4Fe-4S] iron-sulfur cluster, the cofactor that NUBPL carries and transfers;
    the cluster is coordinated by a conserved CXXC motif (Cys-244/Cys-247) required for
    Complex I assembly.
  molecular_function:
    id: GO:0051539
    label: 4 iron, 4 sulfur cluster binding
  directly_involved_in:
  - id: GO:0032981
    label: mitochondrial respiratory chain complex I assembly
  locations:
  - id: GO:0005759
    label: mitochondrial matrix
  supported_by:
  - reference_id: PMID:19752196
    supporting_text: >-
      huInd1 can bind an Fe/S cluster via a conserved CXXC motif in a labile fashion
  - reference_id: file:human/NUBPL/NUBPL-uniprot.txt
    supporting_text: "Note=Binds 1 [4Fe-4S] cluster."
references:
- id: GO_REF:0000002
  title: Gene Ontology annotation through association of InterPro records with GO
    terms
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: >-
      InterPro2GO pipeline. Correctly recovers family-level MF/BP terms (ATP binding,
      Fe-S binding, ATP-dependent FeS chaperone activity, Fe-S cluster assembly). The
      generic parent GO:0051536 is redundant with the specific GO:0051539.
- id: GO_REF:0000033
  title: Annotation inferences using phylogenetic trees
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      PAN-GO/IBA pipeline; correctly recovers the core functions (4Fe-4S binding,
      Complex I assembly, Fe-S cluster assembly, mitochondrial localization).
- id: GO_REF:0000044
  title: Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location
    vocabulary mapping, accompanied by conservative changes to GO terms applied by
    UniProt
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: >-
      SubCell keyword mapping to mitochondrion; correct but generic relative to the
      matrix-specific localization.
- id: GO_REF:0000052
  title: Gene Ontology annotation based on curation of immunofluorescence data
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: >-
      HPA immunofluorescence supporting mitochondrial localization (IDA).
- id: GO_REF:0000117
  title: Electronic Gene Ontology annotations created by ARBA machine learning models
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: >-
      ARBA machine-learning annotations for mitochondrial matrix localization and
      Complex I assembly; consistent with experimental and Reactome evidence.
- id: PMID:19752196
  title: Human ind1, an iron-sulfur cluster assembly factor for respiratory complex
    I.
  findings:
  - statement: >-
      huInd1 (NUBPL) is a mitochondrial P-loop NTPase critically required for the
      assembly of respiratory Complex I; knockdown decreases Complex I protein and
      activity and loss of peripheral-arm subunits.
    reference_section_type: ABSTRACT
    supporting_text: >-
      huInd1, that is critically required for the assembly of complex I. huInd1 can
      bind an Fe/S cluster via a conserved CXXC motif in a labile fashion.
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Primary characterization of human NUBPL/IND1. Only the abstract is cached
      (full_text_available: false); all supporting_text quotes are verbatim from the
      cached abstract. Establishes Fe-S binding, Complex I assembly requirement, and
      mitochondrial localization (source of the UniProt ECO:0000269 annotations).
- id: PMID:32296183
  title: A reference map of the human binary protein interactome.
  findings:
  - statement: >-
      Large-scale binary (Y2H) interactome map (HuRI); the source of the NUBPL protein
      binding (IPI) annotations to NUBP2 and a KDM8 isoform.
    reference_section_type: ABSTRACT
    supporting_text: >-
      we present a human 'all-by-all' reference interactome map of human binary protein
      interactions, or 'HuRI'.
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: >-
      High-throughput binary interactome; supports the existence of interactions but not
      a specific molecular function for NUBPL. Underlies the over-annotated bare
      "protein binding" (GO:0005515) IPI rows.
- id: PMID:34800366
  title: Quantitative high-confidence human mitochondrial proteome and its dynamics
    in cellular context.
  findings:
  - statement: >-
      High-confidence human mitochondrial proteome; corroborates mitochondrial
      localization of NUBPL (HTP).
    reference_section_type: ABSTRACT
    supporting_text: >-
      Quantitative high-confidence human mitochondrial proteome and its dynamics in
      cellular context.
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: >-
      High-throughput mitochondrial proteome; supports mitochondrial localization but is
      non-core relative to the specific matrix annotation.
- id: Reactome:R-HSA-5690023
  title: NUBPL binds 4Fe-4S
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Reactome reaction describing NUBPL binding the [4Fe-4S] cofactor in the
      mitochondrial matrix; consistent with UniProt COFACTOR and the primary literature.
- id: Reactome:R-HSA-6788523
  title: NUBPL transfers 4Fe-4S to Complex I subunits
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Reactome reaction describing NUBPL transferring the [4Fe-4S] cluster to Complex I
      subunits (NDUFS1/S2/S7/S8); supports the Fe-S delivery / Complex I assembly role.
- id: Reactome:R-HSA-6788556
  title: NUBPL transfers 4Fe-4S to NDUFV1, V2
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Reactome reaction describing NUBPL transferring the [4Fe-4S] cluster to NDUFV1/V2;
      supports the Fe-S delivery / Complex I assembly role.