NDUFV2

id: P19404
gene_symbol: NDUFV2
product_type: PROTEIN
status: INITIALIZED
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: NDUFV2 (NADH dehydrogenase [ubiquinone] flavoprotein 2; also called the
  24 kDa subunit) is a nuclear-encoded core catalytic subunit of the N-module (NADH-oxidising
  module) of mitochondrial respiratory Complex I (NADH:ubiquinone oxidoreductase). Together
  with NDUFV1 (51 kDa, which carries the FMN and NADH-binding site) and NDUFS1 it forms
  the flavoprotein (FP) subcomplex at the tip of the peripheral (matrix) arm. NDUFV2
  coordinates the N1a [2Fe-2S] iron-sulfur cluster located near the FMN/NADH site,
  and this cluster is part of the electron-entry pathway by which electrons from NADH
  are relayed into the chain of iron-sulfur clusters that ultimately reduce ubiquinone.
  The protein is imported into mitochondria via a cleaved N-terminal transit peptide
  and is a peripheral protein of the mitochondrial inner membrane on the matrix side.
  Loss-of-function or destabilising variants in NDUFV2 cause mitochondrial complex I
  deficiency (nuclear type 7), presenting as an encephalocardiomyopathy with early-onset
  hypertrophic cardiomyopathy, encephalopathy, and Leigh syndrome; a targeting-sequence
  polymorphism has also been reported as a Parkinson disease susceptibility factor.
existing_annotations:
- term:
    id: GO:0003954
    label: NADH dehydrogenase activity
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: contributes_to
  review:
    summary: Phylogenetic (IBA) annotation with the contributes_to qualifier capturing
      that NDUFV2 is a subunit of the NADH dehydrogenase enzyme (Complex I). This is
      the general NADH dehydrogenase activity term; the ubiquinone-specific child term
      GO:0008137 is also annotated and is the more precise molecular function for this
      enzyme.
    action: ACCEPT
    reason: NDUFV2 is a bona fide core subunit of the flavoprotein module of Complex
      I and contributes to its NADH-oxidising activity; contributes_to is the correct
      qualifier for a multi-subunit enzyme subunit.
    supported_by:
    - reference_id: file:human/NDUFV2/NDUFV2-uniprot.txt
      supporting_text: Core subunit of the mitochondrial membrane respiratory chain
        NADH dehydrogenase (Complex I) which catalyzes electron transfer from NADH through
        the respiratory chain, using ubiquinone as an electron acceptor
- term:
    id: GO:0006120
    label: mitochondrial electron transport, NADH to ubiquinone
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: Phylogenetic (IBA) annotation to the core biological process of Complex
      I. This is the central, defining biological role of NDUFV2 as part of the electron-transfer
      chain from NADH to ubiquinone.
    action: ACCEPT
    reason: This is the core BP of NDUFV2; strongly supported by the IBA plus experimental
      (IDA/IMP) and UniProt evidence that NDUFV2 is a core subunit of the NADH-oxidising
      module of Complex I.
    supported_by:
    - reference_id: file:human/NDUFV2/NDUFV2-uniprot.txt
      supporting_text: catalyzes electron transfer from NADH through the respiratory
        chain, using ubiquinone as an electron acceptor
- term:
    id: GO:0045271
    label: respiratory chain complex I
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: part_of
  review:
    summary: Phylogenetic (IBA) annotation placing NDUFV2 as part of respiratory chain
      complex I. This is the correct complex/location for this core subunit and is corroborated
      by multiple experimental (IDA/IMP/IPI) annotations.
    action: ACCEPT
    reason: NDUFV2 is an established structural component of Complex I (flavoprotein/FP
      subcomplex of the peripheral arm); the complex membership is well supported.
    supported_by:
    - reference_id: file:human/NDUFV2/NDUFV2-uniprot.txt
      supporting_text: Core subunit of respiratory chain NADH dehydrogenase (Complex
        I) which is composed of 45 different subunits. This is a component of the flavoprotein-sulfur
        (FP) fragment of the enzyme.
- term:
    id: GO:0005743
    label: mitochondrial inner membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: located_in
  review:
    summary: Electronic (IEA) subcellular-location annotation to the mitochondrial inner
      membrane, the correct anatomical location for Complex I. NDUFV2 is a peripheral
      inner-membrane protein on the matrix side. Corroborated by IDA (PMID:28844695),
      ISS and TAS annotations to the same term.
    action: ACCEPT
    reason: Consistent with UniProt subcellular location and the well-established topology
      of Complex I; NDUFV2 sits in the matrix-side peripheral arm anchored at the inner
      membrane.
    supported_by:
    - reference_id: file:human/NDUFV2/NDUFV2-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Mitochondrion inner membrane'
- term:
    id: GO:0008137
    label: NADH dehydrogenase (ubiquinone) activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: enables
  review:
    summary: Electronic (IEA) annotation to the enzyme's specific catalytic molecular
      function, NADH:ubiquinone oxidoreductase activity (EC 7.1.1.2, RHEA:29091). This
      is the defining catalytic activity of Complex I; NDUFV2 is a core subunit contributing
      to it.
    action: MODIFY
    reason: The NADH:ubiquinone oxidoreductase reaction is a property of the assembled
      holoenzyme, not of NDUFV2 in isolation. A single subunit does not independently
      enable the full reaction, so the enables qualifier over-states NDUFV2's role;
      contributes_to is the appropriate qualifier (as for the curated IBA/IMP annotations
      to the same term). Retain the term but with contributes_to.
    proposed_replacement_terms:
    - id: GO:0008137
      label: NADH dehydrogenase (ubiquinone) activity
    supported_by:
    - reference_id: file:human/NDUFV2/NDUFV2-uniprot.txt
      supporting_text: Reaction=a ubiquinone + NADH + 5 H(+)(in) = a ubiquinol + NAD(+)
        + 4 H(+)(out)
- term:
    id: GO:0016491
    label: oxidoreductase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: enables
  review:
    summary: InterPro-based (IEA) annotation to the very general parent term oxidoreductase
      activity. NDUFV2's redox function is captured far more precisely by the child
      terms NADH dehydrogenase (ubiquinone) activity (GO:0008137) and electron transfer
      activity (GO:0009055), which are also annotated.
    action: MARK_AS_OVER_ANNOTATED
    reason: The term is not wrong (Complex I is an oxidoreductase) but is uninformatively
      general given that more specific and better-supported MF terms are already present.
- term:
    id: GO:1902600
    label: proton transmembrane transport
  evidence_type: IEA
  original_reference_id: GO_REF:0000108
  qualifier: involved_in
  review:
    summary: Automatic inference (from the GO:0008137 catalytic activity mapping) that
      the gene product is involved in proton transmembrane transport. This is a complex-level
      property arising from the proton-pumping membrane (ND) arm of Complex I, not from
      NDUFV2, which sits in the soluble N-module of the peripheral arm and coordinates
      the N1a [2Fe-2S] cluster of the electron-input pathway.
    action: MARK_AS_OVER_ANNOTATED
    reason: Proton translocation is performed by the antiporter-like subunits of the
      membrane arm; attributing it to the N-module electron-input subunit NDUFV2 over-annotates
      a whole-complex activity onto an individual peripheral-arm subunit.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:28380382
  qualifier: enables
  review:
    summary: IPI evidence (with HSCB/HSC20 co-chaperone, UniProtKB:Q8IWL3) that NDUFV2
      binds the HSC20-based Fe-S transfer complex. This is a real and biologically meaningful
      interaction (Fe-S cluster delivery to Complex I), but the GO term itself is the
      uninformative bare 'protein binding'.
    action: MARK_AS_OVER_ANNOTATED
    reason: Bare protein binding conveys no specific molecular function. The underlying
      biology (NDUFV2 acquires its [2Fe-2S] cluster via the HSC20 co-chaperone system)
      is better represented by the Fe-S cluster binding MF (proposed as a NEW annotation)
      rather than by generic protein binding.
    supported_by:
    - reference_id: PMID:28380382
      supporting_text: The five Fe-S cluster subunits of Complex I also interact with
        HSC20 to acquire their clusters, highlighting the crucial role of HSC20 in the
        assembly of the mitochondrial respiratory chain.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:32296183
  qualifier: enables
  review:
    summary: IPI from a genome-scale binary interactome (yeast two-hybrid reference
      map). Contributes a bare 'protein binding' annotation with no functional specificity.
    action: MARK_AS_OVER_ANNOTATED
    reason: Bare protein binding from a high-throughput interactome screen is uninformative
      as a molecular function and does not reflect NDUFV2's characterized role in Complex
      I.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:32814053
  qualifier: enables
  review:
    summary: IPI from a large-scale neurodegenerative-disease interactome mapping study;
      the many partner proteins captured under this single 'protein binding' term are
      mostly high-throughput screen hits without a defined functional relationship to
      NDUFV2.
    action: MARK_AS_OVER_ANNOTATED
    reason: Bare protein binding from a high-throughput screen is uninformative and
      does not add specific molecular-function knowledge beyond NDUFV2's role in Complex
      I.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:33961781
  qualifier: enables
  review:
    summary: IPI from a proteome-scale affinity-purification interactome (BioPlex).
      Bare 'protein binding' with no functional specificity.
    action: MARK_AS_OVER_ANNOTATED
    reason: Bare protein binding from a high-throughput interactome dataset is uninformative
      as a molecular function.
- term:
    id: GO:0006120
    label: mitochondrial electron transport, NADH to ubiquinone
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: involved_in
  review:
    summary: Electronic (IEA) annotation to the core biological process. Duplicates
      the IBA and experimental annotations to the same term and is fully consistent
      with NDUFV2's characterized role.
    action: ACCEPT
    reason: Core BP of NDUFV2; independently supported by IBA and experimental (IDA/IMP)
      evidence to the same term.
    supported_by:
    - reference_id: file:human/NDUFV2/NDUFV2-uniprot.txt
      supporting_text: catalyzes electron transfer from NADH through the respiratory
        chain, using ubiquinone as an electron acceptor
- term:
    id: GO:0045271
    label: respiratory chain complex I
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: part_of
  review:
    summary: Electronic (IEA) annotation placing NDUFV2 as part of respiratory chain
      complex I. Duplicates the IBA and multiple experimental (IDA/IMP/IPI) annotations
      to the same term.
    action: ACCEPT
    reason: Well-established complex membership; corroborated by phylogenetic and experimental
      evidence.
    supported_by:
    - reference_id: file:human/NDUFV2/NDUFV2-uniprot.txt
      supporting_text: This is a component of the flavoprotein-sulfur (FP) fragment
        of the enzyme.
- term:
    id: GO:0005743
    label: mitochondrial inner membrane
  evidence_type: IDA
  original_reference_id: PMID:28844695
  qualifier: located_in
  review:
    summary: Direct assay (IDA, ComplexPortal) localising NDUFV2 to the mitochondrial
      inner membrane, based on the cryo-EM structure of the human respiratory megacomplex
      in which the position of each Complex I subunit including NDUFV2 was assigned.
    action: ACCEPT
    reason: Correct anatomical location for this Complex I subunit; supported by the
      structural study and consistent with UniProt subcellular location.
    supported_by:
    - reference_id: PMID:28844695
      supporting_text: The structure not only reveals the precise assignment of individual
        subunits of human CI and CIII
- term:
    id: GO:0009060
    label: aerobic respiration
  evidence_type: NAS
  original_reference_id: PMID:30030361
  qualifier: involved_in
  review:
    summary: Author-statement (NAS, ComplexPortal) annotation of the Complex I holoenzyme
      to aerobic respiration. As a core Complex I subunit, NDUFV2 participates in the
      OXPHOS system that underpins aerobic respiration, though this is a broad complex-level
      process rather than NDUFV2's specific molecular role.
    action: KEEP_AS_NON_CORE
    reason: Valid at the pathway level (Complex I is central to aerobic respiration/OXPHOS)
      but broader than the core electron-transport function; retained as non-core context.
    supported_by:
    - reference_id: PMID:30030361
      supporting_text: The assembly of the five oxidative phosphorylation system (OXPHOS)
        complexes in the inner mitochondrial membrane is an intricate process.
- term:
    id: GO:0042776
    label: proton motive force-driven mitochondrial ATP synthesis
  evidence_type: NAS
  original_reference_id: PMID:30030361
  qualifier: involved_in
  review:
    summary: Author-statement (NAS, ComplexPortal) annotation to proton motive force-driven
      ATP synthesis. ATP synthesis is the function of Complex V (ATP synthase); Complex
      I contributes only indirectly by helping establish the proton-motive force via
      its membrane arm, and NDUFV2 (an N-module electron-input subunit) is doubly removed
      from ATP synthesis.
    action: MARK_AS_OVER_ANNOTATED
    reason: ATP synthesis is performed by Complex V, not Complex I; attributing it to
      the peripheral-arm subunit NDUFV2 over-annotates a downstream, whole-OXPHOS-system
      outcome onto an individual electron-transport subunit.
- term:
    id: GO:0045271
    label: respiratory chain complex I
  evidence_type: IPI
  original_reference_id: PMID:28844695
  qualifier: part_of
  review:
    summary: IPI evidence (ComplexPortal) that NDUFV2 is a component of respiratory
      chain complex I, based on the cryo-EM megacomplex structure with defined subunit
      composition.
    action: ACCEPT
    reason: Direct structural/physical evidence for Complex I membership; a core, well-supported
      annotation.
    supported_by:
    - reference_id: PMID:28844695
      supporting_text: The structure not only reveals the precise assignment of individual
        subunits of human CI and CIII
- term:
    id: GO:0005743
    label: mitochondrial inner membrane
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: located_in
  review:
    summary: Sequence-similarity (ISS) annotation to the mitochondrial inner membrane,
      transferred from the bovine ortholog (UniProtKB:P04394). Consistent with the IDA
      and IEA annotations to the same location.
    action: ACCEPT
    reason: Correct location; the bovine ortholog basis is sound and matches UniProt
      subcellular location and the topology of Complex I.
    supported_by:
    - reference_id: file:human/NDUFV2/NDUFV2-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Mitochondrion inner membrane'
- term:
    id: GO:0005739
    label: mitochondrion
  evidence_type: HTP
  original_reference_id: PMID:34800366
  qualifier: located_in
  review:
    summary: High-throughput (HTP) proteomics annotation to mitochondrion from a quantitative
      high-confidence human mitochondrial proteome. Correct but less specific than the
      mitochondrial inner membrane annotations.
    action: ACCEPT
    reason: Correct localisation; a broader parent of the inner-membrane location and
      consistent with the well-established mitochondrial residence of NDUFV2.
    supported_by:
    - reference_id: PMID:34800366
      supporting_text: Quantitative high-confidence human mitochondrial proteome and
        its dynamics in cellular context.
- term:
    id: GO:0045271
    label: respiratory chain complex I
  evidence_type: IDA
  original_reference_id: PMID:12611891
  qualifier: part_of
  review:
    summary: Direct assay (IDA) demonstrating NDUFV2 as a component of human NADH dehydrogenase
      (Complex I) by one-step immunopurification followed by mass-spectrometric identification
      of the subunit composition.
    action: ACCEPT
    reason: Direct biochemical evidence for Complex I membership from purified human
      enzyme; a core, well-supported annotation.
    supported_by:
    - reference_id: PMID:12611891
      supporting_text: we can resolve and identify the human homologues of 42 polypeptides
        detected so far in the more extensively studied beef heart complex I
- term:
    id: GO:0045271
    label: respiratory chain complex I
  evidence_type: IMP
  original_reference_id: PMID:12754703
  qualifier: part_of
  review:
    summary: Mutant-phenotype (IMP) evidence for Complex I membership. A homozygous
      splice-site mutation reducing NDUFV2 protein by 70% causes isolated Complex I
      deficiency, demonstrating that NDUFV2 is required for a functional Complex I.
    action: ACCEPT
    reason: Human loss-of-function evidence directly links NDUFV2 to Complex I integrity/function;
      strongly supports complex membership.
    supported_by:
    - reference_id: PMID:12754703
      supporting_text: resulted in 70% decreased NDUFV2 protein and complex I deficiency
- term:
    id: GO:0045271
    label: respiratory chain complex I
  evidence_type: IDA
  original_reference_id: PMID:28844695
  qualifier: part_of
  review:
    summary: Direct assay (IDA) for Complex I membership from the cryo-EM structure
      of the human respiratory megacomplex, which assigns NDUFV2 to a defined position
      within Complex I.
    action: ACCEPT
    reason: Structural evidence directly places NDUFV2 within Complex I; core, well-supported
      annotation.
    supported_by:
    - reference_id: PMID:28844695
      supporting_text: The structure not only reveals the precise assignment of individual
        subunits of human CI and CIII
- term:
    id: GO:0045271
    label: respiratory chain complex I
  evidence_type: NAS
  original_reference_id: PMID:9878551
  qualifier: part_of
  review:
    summary: Author-statement (NAS) annotation of NDUFV2 as one of the nuclear-encoded
      subunits of human NADH:ubiquinone oxidoreductase (Complex I).
    action: ACCEPT
    reason: Consistent with the many stronger (IDA/IMP/IPI) annotations to the same
      term; NDUFV2 is an established Complex I subunit.
    supported_by:
    - reference_id: PMID:9878551
      supporting_text: 'NADH:ubiquinone oxidoreductase (complex I) is an extremely complicated
        multiprotein complex located in the inner mitochondrial membrane.'
- term:
    id: GO:0006120
    label: mitochondrial electron transport, NADH to ubiquinone
  evidence_type: IDA
  original_reference_id: PMID:28844695
  qualifier: involved_in
  review:
    summary: Direct assay (IDA) supporting NDUFV2's involvement in NADH-to-ubiquinone
      electron transport, from the structural and functional characterisation of the
      human respiratory megacomplex including determination of catalytic activity and
      cofactor content.
    action: ACCEPT
    reason: Core BP of NDUFV2, directly supported by the structural and functional study
      of the human enzyme.
    supported_by:
    - reference_id: file:human/NDUFV2/NDUFV2-uniprot.txt
      supporting_text: the electrons from NADH are accepted by flavin mononucleotide
        (FMN) and then passed along a chain of iron-sulfur clusters by electron tunnelling
        to the final acceptor ubiquinone
- term:
    id: GO:0008137
    label: NADH dehydrogenase (ubiquinone) activity
  evidence_type: IDA
  original_reference_id: PMID:28844695
  qualifier: enables
  review:
    summary: Direct assay (IDA) annotation of the specific NADH:ubiquinone oxidoreductase
      catalytic activity, based on the cryo-EM structure that established the function,
      catalytic activity and cofactor of the human enzyme. As a subunit, NDUFV2 contributes
      to rather than solely enables the holoenzyme activity, but the catalytic molecular
      function is the defining function of the assembly it belongs to.
    action: MODIFY
    reason: The catalytic activity is a property of the assembled complex, not of NDUFV2
      alone; a single subunit does not independently enable the full NADH:ubiquinone
      reaction. The complex-level MF is best expressed with the contributes_to qualifier
      (as in the curated IMP annotation from PMID:12754703), rather than enables. Retain
      the term but with contributes_to.
    proposed_replacement_terms:
    - id: GO:0008137
      label: NADH dehydrogenase (ubiquinone) activity
    supported_by:
    - reference_id: file:human/NDUFV2/NDUFV2-uniprot.txt
      supporting_text: Reaction=a ubiquinone + NADH + 5 H(+)(in) = a ubiquinol + NAD(+)
        + 4 H(+)(out)
- term:
    id: GO:0008137
    label: NADH dehydrogenase (ubiquinone) activity
  evidence_type: IMP
  original_reference_id: PMID:12754703
  qualifier: contributes_to
  review:
    summary: Mutant-phenotype (IMP) evidence with the contributes_to qualifier. Reducing
      NDUFV2 protein by ~70% causes Complex I deficiency, showing NDUFV2 contributes
      to the NADH:ubiquinone oxidoreductase activity of the holoenzyme.
    action: ACCEPT
    reason: Human loss-of-function evidence that NDUFV2 is required for full Complex
      I catalytic activity; contributes_to is the appropriate qualifier for a subunit.
    supported_by:
    - reference_id: PMID:12754703
      supporting_text: resulted in 70% decreased NDUFV2 protein and complex I deficiency
- term:
    id: GO:0005743
    label: mitochondrial inner membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-163217
  qualifier: located_in
  review:
    summary: Reactome-derived (TAS) annotation to the mitochondrial inner membrane,
      from the pathway event in which Complex I oxidises NADH and reduces ubiquinone.
      Correct location for this Complex I subunit.
    action: ACCEPT
    reason: Correct location, redundant with the IDA/ISS/IEA inner-membrane annotations;
      consistent with the topology of Complex I.
- term:
    id: GO:0005743
    label: mitochondrial inner membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-6788556
  qualifier: located_in
  review:
    summary: Reactome-derived (TAS) annotation to the mitochondrial inner membrane,
      from a Complex I biogenesis event (Fe-S transfer to NDUFV1/V2). Correct location.
    action: ACCEPT
    reason: Correct location; redundant with other inner-membrane annotations.
- term:
    id: GO:0005743
    label: mitochondrial inner membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-6799179
  qualifier: located_in
  review:
    summary: Reactome-derived (TAS) annotation to the mitochondrial inner membrane,
      from a Complex I assembly event. Correct location.
    action: ACCEPT
    reason: Correct location; redundant with other inner-membrane annotations.
- term:
    id: GO:0005743
    label: mitochondrial inner membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-6799196
  qualifier: located_in
  review:
    summary: Reactome-derived (TAS) annotation to the mitochondrial inner membrane,
      from a Complex I assembly event. Correct location.
    action: ACCEPT
    reason: Correct location; redundant with other inner-membrane annotations.
- term:
    id: GO:0005743
    label: mitochondrial inner membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-6800870
  qualifier: located_in
  review:
    summary: Reactome-derived (TAS) annotation to the mitochondrial inner membrane,
      from the event in which NDUF subunits bind to form the FP subcomplex. Correct
      location for NDUFV2, which is part of the FP subcomplex.
    action: ACCEPT
    reason: Correct location; consistent with NDUFV2 being a component of the flavoprotein
      (FP) subcomplex of the peripheral arm.
- term:
    id: GO:0005739
    label: mitochondrion
  evidence_type: IDA
  original_reference_id: PMID:12754703
  qualifier: located_in
  review:
    summary: Direct assay (IDA) annotation to mitochondrion. Correct but less specific
      than the mitochondrial inner membrane annotations; consistent with NDUFV2's characterized
      mitochondrial residence.
    action: ACCEPT
    reason: Correct localisation; a broad parent of the inner-membrane location.
    supported_by:
    - reference_id: file:human/NDUFV2/NDUFV2-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Mitochondrion inner membrane'
- term:
    id: GO:0006120
    label: mitochondrial electron transport, NADH to ubiquinone
  evidence_type: IMP
  original_reference_id: PMID:12754703
  qualifier: involved_in
  review:
    summary: Mutant-phenotype (IMP) evidence for involvement in NADH-to-ubiquinone electron
      transport. Reduced NDUFV2 causes Complex I deficiency, i.e. impaired electron
      transport through Complex I.
    action: ACCEPT
    reason: Core BP; human loss-of-function evidence directly links NDUFV2 to Complex
      I electron-transport function.
    supported_by:
    - reference_id: PMID:12754703
      supporting_text: resulted in 70% decreased NDUFV2 protein and complex I deficiency
- term:
    id: GO:0006120
    label: mitochondrial electron transport, NADH to ubiquinone
  evidence_type: NAS
  original_reference_id: PMID:9570948
  qualifier: involved_in
  review:
    summary: Author-statement (NAS) annotation to the core electron-transport BP, from
      a study of NDUFV2 as the 24-kDa subunit of mitochondrial Complex I in the context
      of Parkinson disease susceptibility.
    action: ACCEPT
    reason: Core BP; consistent with the many stronger annotations to the same term.
    supported_by:
    - reference_id: PMID:9570948
      supporting_text: the gene encoding the 24-kDa subunit of mitochondrial complex
        I
- term:
    id: GO:0007399
    label: nervous system development
  evidence_type: IMP
  original_reference_id: PMID:9570948
  qualifier: involved_in
  review:
    summary: IMP annotation to nervous system development, derived from a genetic-association
      study reporting an NDUFV2 targeting-sequence polymorphism (Ala29Val) as a Parkinson
      disease susceptibility factor. This is a disease-susceptibility association in
      a neurodegenerative disorder, not evidence that NDUFV2 has a developmental role
      in building the nervous system.
    action: MARK_AS_OVER_ANNOTATED
    reason: The supporting study is a PD case-control association, not a developmental
      phenotype; annotating NDUFV2 to nervous system development over-interprets a susceptibility
      polymorphism. The gene's role in neural tissue is better understood as bioenergetic
      support via Complex I rather than a developmental function.
    supported_by:
    - reference_id: PMID:9570948
      supporting_text: A novel polymorphism (Ala29Val) in the mitochondrial targeting
        sequence of NDUFV2 was found in patients with PD
- term:
    id: GO:0008137
    label: NADH dehydrogenase (ubiquinone) activity
  evidence_type: NAS
  original_reference_id: PMID:9570948
  qualifier: enables
  review:
    summary: Author-statement (NAS) annotation to the specific NADH:ubiquinone oxidoreductase
      catalytic activity of Complex I, of which NDUFV2 is the 24-kDa subunit.
    action: MODIFY
    reason: The NADH:ubiquinone oxidoreductase reaction is a property of the assembled
      holoenzyme; NDUFV2 as a single subunit contributes to but does not independently
      enable it. The contributes_to qualifier is appropriate (matching the curated IBA/IMP
      annotations to the same term). Retain the term but with contributes_to.
    proposed_replacement_terms:
    - id: GO:0008137
      label: NADH dehydrogenase (ubiquinone) activity
    supported_by:
    - reference_id: PMID:9570948
      supporting_text: the gene encoding the 24-kDa subunit of mitochondrial complex
        I
- term:
    id: GO:0009055
    label: electron transfer activity
  evidence_type: NAS
  original_reference_id: PMID:7488192
  qualifier: enables
  review:
    summary: Author-statement (NAS) annotation to electron transfer activity. NDUFV2
      is the 24-kDa iron-sulfur subunit of Complex I and coordinates the N1a [2Fe-2S]
      cluster in the electron-input pathway, giving it a genuine electron-transfer role
      within the enzyme.
    action: ACCEPT
    reason: Well-founded MF; NDUFV2 carries a [2Fe-2S] redox cofactor and participates
      in the electron-relay chain from NADH toward ubiquinone.
    supported_by:
    - reference_id: PMID:7488192
      supporting_text: the 24-kDa iron-sulfur subunit of mitochondrial NADH-ubiquinone
        oxidoreductase (Complex I)
- term:
    id: GO:0048738
    label: cardiac muscle tissue development
  evidence_type: IMP
  original_reference_id: PMID:12754703
  qualifier: involved_in
  review:
    summary: IMP annotation to cardiac muscle tissue development, from the observation
      that a homozygous NDUFV2 splice mutation causes early-onset hypertrophic cardiomyopathy.
      This reflects a bioenergetic disease phenotype of Complex I deficiency in cardiac
      tissue rather than a direct role of NDUFV2 in the developmental program of the
      heart.
    action: KEEP_AS_NON_CORE
    reason: The cardiomyopathy phenotype is real and clinically important, but it arises
      from loss of Complex I energy production rather than a developmental function
      of NDUFV2; retained as a non-core, tissue-context annotation rather than a core
      molecular role.
    supported_by:
    - reference_id: PMID:12754703
      supporting_text: causes complex I deficiency and early onset hypertrophic cardiomyopathy
        with trunk hypotonia in three affected sibs
- term:
    id: GO:0006120
    label: mitochondrial electron transport, NADH to ubiquinone
  evidence_type: NAS
  original_reference_id: PMID:9878551
  qualifier: involved_in
  review:
    summary: Author-statement (NAS) annotation to the core electron-transport BP, from
      the characterisation of the nuclear-encoded subunits of human NADH:ubiquinone
      oxidoreductase (Complex I).
    action: ACCEPT
    reason: Core BP; consistent with the many stronger annotations to the same term.
    supported_by:
    - reference_id: PMID:9878551
      supporting_text: Its main function is the transport of electrons from NADH to ubiquinone
- term:
    id: GO:0008137
    label: NADH dehydrogenase (ubiquinone) activity
  evidence_type: NAS
  original_reference_id: PMID:9878551
  qualifier: enables
  review:
    summary: Author-statement (NAS) annotation to the specific NADH:ubiquinone oxidoreductase
      catalytic activity, from the characterisation of the human Complex I subunits.
    action: MODIFY
    reason: The NADH:ubiquinone oxidoreductase reaction is a property of the assembled
      holoenzyme; NDUFV2 as a single subunit contributes to but does not independently
      enable it. The contributes_to qualifier is appropriate (matching the curated IBA/IMP
      annotations to the same term). Retain the term but with contributes_to.
    proposed_replacement_terms:
    - id: GO:0008137
      label: NADH dehydrogenase (ubiquinone) activity
    supported_by:
    - reference_id: PMID:9878551
      supporting_text: Its main function is the transport of electrons from NADH to ubiquinone
- term:
    id: GO:0051537
    label: 2 iron, 2 sulfur cluster binding
  evidence_type: IEA
  original_reference_id: file:human/NDUFV2/NDUFV2-uniprot.txt
  qualifier: enables
  review:
    summary: NDUFV2 binds one [2Fe-2S] iron-sulfur cluster (the N1a cluster) via conserved
      cysteine ligands, a cofactor central to its role in the electron-input pathway
      of Complex I. UniProt annotates the [2Fe-2S] cofactor with experimental (PubMed:28844695)
      evidence and four ligand residues from the cryo-EM structures, and the corresponding
      GO term (GO:0051537) is present in the UniProt GO cross-references (UniProtKB-KW).
      This specific metal-cofactor MF is not represented in the current GOA TSV and
      is proposed here as a NEW annotation to capture NDUFV2's redox chemistry more
      precisely than the generic electron transfer activity term.
    action: NEW
    reason: The [2Fe-2S] cluster binding is a well-supported, defining molecular feature
      of NDUFV2 (2Fe-2S keyword, experimental cofactor annotation, and four structural
      ligand-binding residues in UniProt) that is missing from the curated GO annotation
      set and directly underlies its electron-transfer function in the N-module of Complex
      I.
    supported_by:
    - reference_id: file:human/NDUFV2/NDUFV2-uniprot.txt
      supporting_text: 'Name=[2Fe-2S] cluster; Xref=ChEBI:CHEBI:190135'
    - reference_id: file:human/NDUFV2/NDUFV2-uniprot.txt
      supporting_text: Contains one iron-sulfur cluster
references:
- id: file:human/NDUFV2/NDUFV2-uniprot.txt
  title: UniProtKB P19404 (NDUV2_HUMAN) NADH dehydrogenase [ubiquinone] flavoprotein
    2, mitochondrial
  findings: []
- id: GO_REF:0000002
  title: Gene Ontology annotation through association of InterPro records with GO
    terms
  findings: []
- id: GO_REF:0000024
  title: Manual transfer of experimentally-verified manual GO annotation data to orthologs
    by curator judgment of sequence similarity
  findings: []
- id: GO_REF:0000033
  title: Annotation inferences using phylogenetic trees
  findings: []
- id: GO_REF:0000108
  title: Automatic assignment of GO terms using logical inference, based on on inter-ontology
    links
  findings: []
- id: GO_REF:0000120
  title: Combined Automated Annotation using Multiple IEA Methods
  findings: []
- id: PMID:12611891
  title: The subunit composition of the human NADH dehydrogenase obtained by rapid
    one-step immunopurification.
  findings: []
- id: PMID:12754703
  title: Mutant NDUFV2 subunit of mitochondrial complex I causes early onset hypertrophic
    cardiomyopathy and encephalopathy.
  findings: []
- id: PMID:28380382
  title: A Single Adaptable Cochaperone-Scaffold Complex Delivers Nascent Iron-Sulfur
    Clusters to Mammalian Respiratory Chain Complexes I-III.
  findings: []
- id: PMID:28844695
  title: Architecture of Human Mitochondrial Respiratory Megacomplex I(2)III(2)IV(2).
  findings: []
- id: PMID:30030361
  title: Assembly of mammalian oxidative phosphorylation complexes I-V and supercomplexes.
  findings: []
- id: PMID:32296183
  title: A reference map of the human binary protein interactome.
  findings: []
- id: PMID:32814053
  title: Interactome Mapping Provides a Network of Neurodegenerative Disease Proteins
    and Uncovers Widespread Protein Aggregation in Affected Brains.
  findings: []
- id: PMID:33961781
  title: Dual proteome-scale networks reveal cell-specific remodeling of the human
    interactome.
  findings: []
- id: PMID:34800366
  title: Quantitative high-confidence human mitochondrial proteome and its dynamics
    in cellular context.
  findings: []
- id: PMID:7488192
  title: Structural organization and chromosomal localization of the human nuclear
    gene (NDUFV2) for the 24-kDa iron-sulfur subunit of complex I in mitochondrial
    respiratory chain.
  findings: []
- id: PMID:9570948
  title: Genotype in the 24-kDa subunit gene (NDUFV2) of mitochondrial complex I and
    susceptibility to Parkinson disease.
  findings: []
- id: PMID:9878551
  title: 'cDNA of eight nuclear encoded subunits of NADH:ubiquinone oxidoreductase:
    human complex I cDNA characterization completed.'
  findings: []
- id: Reactome:R-HSA-163217
  title: Complex I oxidises NADH to NAD+, reduces CoQ to CoQH2
  findings: []
- id: Reactome:R-HSA-6788556
  title: NUBPL transfers 4Fe-4S to NDUFV1, V2
  findings: []
- id: Reactome:R-HSA-6799179
  title: Peripheral arm subunits bind the 815kDa complex to form a 980kDa complex
  findings: []
- id: Reactome:R-HSA-6799196
  title: The MCIA complex, NDUFAF2-7 all dissociate from the 980kDa complex, resulting
    in Complex I
  findings: []
- id: Reactome:R-HSA-6800870
  title: NDUF subunits bind to form the FP subcomplex
  findings: []
core_functions:
- description: As a core subunit of the flavoprotein (FP) module of mitochondrial Complex
    I, NDUFV2 coordinates a [2Fe-2S] iron-sulfur cluster (N1a) and contributes to the
    NADH:ubiquinone oxidoreductase activity of the holoenzyme, participating in electron
    transfer from NADH toward ubiquinone.
  molecular_function:
    id: GO:0009055
    label: electron transfer activity
  contributes_to_molecular_function:
    id: GO:0008137
    label: NADH dehydrogenase (ubiquinone) activity
  directly_involved_in:
  - id: GO:0006120
    label: mitochondrial electron transport, NADH to ubiquinone
  locations:
  - id: GO:0005743
    label: mitochondrial inner membrane
  in_complex:
    id: GO:0045271
    label: respiratory chain complex I
  supported_by:
  - reference_id: PMID:28844695
    supporting_text: The structure not only reveals the precise assignment of individual
      subunits of human CI and CIII
  - reference_id: PMID:12754703
    supporting_text: resulted in 70% decreased NDUFV2 protein and complex I deficiency
- description: NDUFV2 binds one [2Fe-2S] iron-sulfur cluster (the N1a cluster) near
    the FMN/NADH site, providing a redox center in the electron-input pathway of Complex
    I.
  molecular_function:
    id: GO:0051537
    label: 2 iron, 2 sulfur cluster binding
  directly_involved_in:
  - id: GO:0006120
    label: mitochondrial electron transport, NADH to ubiquinone
  locations:
  - id: GO:0005743
    label: mitochondrial inner membrane
  in_complex:
    id: GO:0045271
    label: respiratory chain complex I
  supported_by:
  - reference_id: file:human/NDUFV2/NDUFV2-uniprot.txt
    supporting_text: 'Name=[2Fe-2S] cluster; Xref=ChEBI:CHEBI:190135'