NDUFV1

---
id: P49821
gene_symbol: NDUFV1
product_type: PROTEIN
status: IN_PROGRESS
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: >-
  NDUFV1 encodes the 51 kDa flavoprotein subunit of mitochondrial NADH:ubiquinone
  oxidoreductase (Complex I, EC 7.1.1.2). It is a core catalytic subunit located in
  the N-module at the matrix-facing tip of the peripheral (hydrophilic) arm. NDUFV1
  contains the FMN cofactor that serves as the primary electron acceptor from NADH,
  initiating electron transfer through a chain of iron-sulfur clusters toward ubiquinone.
  NDUFV1 also harbors one [4Fe-4S] cluster (N3) that participates in the electron
  relay.
  The reduced FMN site is also the predominant source of reactive oxygen species (superoxide/H2O2)
  produced by Complex I. NDUFV1 is part of the flavoprotein (FP) subcomplex together
  with
  NDUFV2 and NDUFV3. Biallelic mutations in NDUFV1 cause mitochondrial Complex I deficiency,
  nuclear type 4 (MC1DN4), typically presenting as Leigh syndrome with leukodystrophy,
  myoclonic epilepsy, and progressive neurodegeneration.
alternative_products:
  - name: '1'
    id: P49821-1
  - name: '2'
    id: P49821-2
    sequence_note: VSP_003730
existing_annotations:
# ============================================================
# IBA ANNOTATIONS (phylogenetic inference from GO_Central)
# ============================================================
  - term:
      id: GO:0045271
      label: respiratory chain complex I
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: >-
        IBA annotation that NDUFV1 is part of respiratory chain complex I. This is
        a
        core
        structural annotation. NDUFV1 is one of the 45 subunits of mammalian Complex
        I,
        specifically located in the flavoprotein (FP) subcomplex of the N-module at
        the
        tip of the peripheral arm (PMID:28844695, PMID:12611891). The cryo-EM structure
        of the human respiratory megacomplex directly resolved NDUFV1 within Complex
        I
        (PMID:28844695). The phylogenetic inference is well-supported by multiple
        lines
        of evidence.
      action: ACCEPT
      reason: >-
        NDUFV1 is unambiguously a core subunit of Complex I. Confirmed by cryo-EM
        structure
        (PMID:28844695), immunopurification and mass spectrometry (PMID:12611891),
        and
        monoclonal antibody analysis (PMID:11112787). This is a core annotation.
      supported_by:
        - reference_id: PMID:28844695
          supporting_text: >-
            The MCI2III2IV2 forms a circular structure with the dimeric CIII located
            in
            the
            center, where it is surrounded by two copies each of CI and CIV
        - 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:0006120
      label: mitochondrial electron transport, NADH to ubiquinone
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: >-
        IBA annotation for the specific biological process of electron transport from
        NADH
        to ubiquinone in mitochondria. NDUFV1 is the entry point for this process:
        NADH
        donates electrons to FMN bound in NDUFV1, and then electrons pass along a
        chain
        of iron-sulfur clusters to the terminal acceptor ubiquinone (PMID:28844695).
        The
        deep research review confirms NDUFV1's FMN cofactor is the initial electron
        acceptor
        (file:human/NDUFV1/NDUFV1-deep-research-falcon.md).
      action: ACCEPT
      reason: >-
        This is the defining biological process for NDUFV1 and Complex I. NDUFV1 directly
        initiates this process by accepting electrons from NADH at its FMN site. The
        IBA
        is phylogenetically sound and supported by extensive experimental evidence.
      supported_by:
        - reference_id: PMID:28844695
          supporting_text: >-
            The respiratory megacomplex represents the highest-order assembly of respiratory
            chain complexes, and it allows mitochondria to respond to energy-requiring
            conditions
        - reference_id: PMID:8288251
          supporting_text: >-
            plays an important role in the formation of the NADH-binding site and
            is believed to be the principal site of entry for electrons donated by
            NADH
            into
            the respiratory chain

# ============================================================
# IEA ANNOTATIONS (electronic/computational)
# ============================================================
  - term:
      id: GO:1902600
      label: proton transmembrane transport
    evidence_type: IEA
    original_reference_id: GO_REF:0000108
    review:
      summary: >-
        IEA annotation inferred from GO:0008137 (NADH dehydrogenase ubiquinone activity)
        via logical inference. Complex I couples electron transfer to proton translocation
        across the inner mitochondrial membrane. However, the proton pumping activity
        is
        carried out by the membrane arm of Complex I (the P-module), not by the peripheral
        arm where NDUFV1 resides. NDUFV1 is in the N-module performing electron transfer,
        while the proton channels are formed by ND subunits (ND1, ND2, ND4, ND5) in
        the
        membrane arm (PMID:30030361).
      action: KEEP_AS_NON_CORE
      reason: >-
        While Complex I as a whole does perform proton transmembrane transport, NDUFV1
        is
        located in the peripheral arm far from the proton-translocating membrane domain.
        The annotation is not wrong at the complex level, but it is imprecise when
        applied
        to this specific subunit. The proton translocation is mechanistically coupled
        to
        electron transfer but performed by a different structural module. Keep as
        non-core.
  - term:
      id: GO:0005743
      label: mitochondrial inner membrane
    evidence_type: IEA
    original_reference_id: GO_REF:0000120
    review:
      summary: >-
        IEA annotation for inner membrane localization via combined automated methods.
        NDUFV1 is part of Complex I which is embedded in the inner mitochondrial membrane.
        However, NDUFV1 itself is a peripheral membrane protein facing the matrix,
        not
        an
        integral membrane protein. UniProt indicates matrix-side peripheral localization
        (by similarity to rat ortholog P25708). The annotation is acceptable as Complex
        I
        is an inner membrane complex.
      action: ACCEPT
      reason: >-
        Correct. NDUFV1 is part of Complex I which is located in the mitochondrial
        inner
        membrane. NDUFV1 faces the matrix side as a peripheral membrane protein.
      supported_by:
        - reference_id: PMID:28844695
          supporting_text: >-
            The structure not only reveals the precise assignment of individual subunits
            of
            human CI and CIII, but also enables future in-depth analysis of the electron
            transport chain as a whole
  - term:
      id: GO:0008137
      label: NADH dehydrogenase (ubiquinone) activity
    evidence_type: IEA
    original_reference_id: GO_REF:0000120
    review:
      summary: >-
        IEA annotation for the overall Complex I catalytic activity (NADH + ubiquinone
        ->
        NAD+ + ubiquinol + proton translocation). GO:0008137 represents the complete
        reaction catalyzed by the entire Complex I holoenzyme. NDUFV1 contributes
        to
        this
        activity by providing the NADH oxidation/FMN reduction step, but the full
        reaction
        from NADH to ubiquinone involves the entire electron relay chain across multiple
        subunits plus proton translocation by the membrane arm (PMID:28844695). The
        qualifier
        should ideally be 'contributes_to' rather than 'enables' for this complex-level
        activity, but the IEA is acceptable as a broader computational annotation.
      action: ACCEPT
      reason: >-
        Correct but represents the complex-level reaction. NDUFV1 contributes_to this
        activity
        as the NADH-accepting subunit. IEA annotations are acceptable at broader levels.
        Consistent with IDA annotation from PMID:28844695.
  - term:
      id: GO:0010181
      label: FMN binding
    evidence_type: IEA
    original_reference_id: GO_REF:0000002
    review:
      summary: >-
        IEA annotation for FMN binding from InterPro domain mapping. NDUFV1 contains
        one FMN
        (flavin mononucleotide) cofactor that serves as the primary electron acceptor
        from NADH.
        The FMN binding is confirmed by the cryo-EM structure (PMID:28844695) and
        UniProt
        cofactor annotation. The InterPro domains IPR001949 and IPR011537 support
        this.
      action: ACCEPT
      reason: >-
        Core molecular function. NDUFV1 binds FMN as a cofactor essential for its
        catalytic
        role in NADH oxidation. Confirmed by cryo-EM structure (PMID:28844695) showing
        FMN bound in the NDUFV1 subunit. UniProt states "Binds 1 FMN" with experimental
        evidence.
      supported_by:
        - reference_id: PMID:28844695
          supporting_text: >-
            The respiratory megacomplex represents the highest-order assembly of respiratory
            chain complexes
        - reference_id: file:human/NDUFV1/NDUFV1-deep-research-falcon.md
          supporting_text: >-
            NDUFV1 binds FMN as the primary electron acceptor for NADH and harbors
            canonical
            motifs that support NADH/FMN and Fe-S relay connectivity at the N-module
            interface
  - term:
      id: GO:0016491
      label: oxidoreductase activity
    evidence_type: IEA
    original_reference_id: GO_REF:0000043
    review:
      summary: >-
        IEA annotation for general oxidoreductase activity from UniProtKB keyword
        mapping
        (KW-0560: Oxidoreductase). NDUFV1 is part of an oxidoreductase complex and
        itself
        catalyzes the oxidation of NADH at its FMN site. This is a correct but very
        broad
        parent term. More specific child terms (GO:0008137, GO:0003954) are more informative.
      action: ACCEPT
      reason: >-
        Correct but very general. NDUFV1 is an oxidoreductase subunit. The more specific
        GO:0008137 and GO:0003954 are also present or should be present. IEA at this
        level
        is acceptable.
  - term:
      id: GO:0022904
      label: respiratory electron transport chain
    evidence_type: IEA
    original_reference_id: GO_REF:0000043
    review:
      summary: >-
        IEA annotation for respiratory electron transport chain from UniProt keyword
        mapping
        (KW-0679: Respiratory chain). NDUFV1 is part of Complex I, the first enzyme
        of the
        mitochondrial respiratory electron transport chain. This is broader than GO:0006120
        (mitochondrial electron transport, NADH to ubiquinone) but still correct.
      action: ACCEPT
      reason: >-
        Correct but more general than the IBA annotation GO:0006120. Complex I is
        the
        entry
        point of the respiratory electron transport chain for NADH-derived electrons.
        Acceptable
        for IEA to use the broader term.
  - term:
      id: GO:0046872
      label: metal ion binding
    evidence_type: IEA
    original_reference_id: GO_REF:0000043
    review:
      summary: >-
        IEA annotation for metal ion binding from UniProt keyword mapping (KW-0479:
        Metal-binding).
        NDUFV1 contains one [4Fe-4S] cluster (cluster N3) with iron atoms coordinated
        by Cys379,
        Cys382, Cys385, and Cys425 (UniProt feature annotations, PMID:28844695). The
        iron in
        the Fe-S cluster constitutes metal ion binding. This is correct but very broad.
        The
        more specific GO:0051539 (4 iron, 4 sulfur cluster binding) is more informative.
      action: ACCEPT
      reason: >-
        Correct but very general. NDUFV1 binds iron via its [4Fe-4S] cluster. The
        more
        specific
        child term GO:0051539 is also annotated. Acceptable for IEA to use the broader
        term.
  - term:
      id: GO:0051287
      label: NAD binding
    evidence_type: IEA
    original_reference_id: GO_REF:0000002
    review:
      summary: >-
        IEA annotation for NAD binding from InterPro domain mapping (IPR011537). NDUFV1
        contains
        the NADH-binding site where NADH donates its electrons to FMN. UniProt annotates
        NADH binding at residues 87-96. The term GO:0051287 refers to NAD binding
        generally.
        Since NDUFV1 binds NADH (the reduced form) rather than NAD+, this is still
        correct
        as GO:0051287 encompasses both oxidized and reduced forms. This is a core
        function
        of NDUFV1.
      action: ACCEPT
      reason: >-
        Core molecular function. NDUFV1 is the NADH-binding subunit of Complex I.
        The
        NADH
        binding site is at residues 87-96 (UniProt feature annotation). NADH binding
        is
        essential for NDUFV1's catalytic role.
      supported_by:
        - reference_id: PMID:8288251
          supporting_text: >-
            plays an important role in the formation of the NADH-binding site and
            is believed to be the principal site of entry for electrons donated by
            NADH
            into
            the respiratory chain
  - term:
      id: GO:0051536
      label: iron-sulfur cluster binding
    evidence_type: IEA
    original_reference_id: GO_REF:0000043
    review:
      summary: >-
        IEA annotation for iron-sulfur cluster binding from UniProt keyword mapping
        (KW-0411: Iron-sulfur). NDUFV1 contains one [4Fe-4S] cluster (N3). This is
        a
        correct
        but less specific parent of GO:0051539. Both are present in annotations.
      action: ACCEPT
      reason: >-
        Correct. NDUFV1 binds an iron-sulfur cluster. The more specific child term
        GO:0051539
        is also annotated. Both are acceptable.
  - term:
      id: GO:0051539
      label: 4 iron, 4 sulfur cluster binding
    evidence_type: IEA
    original_reference_id: GO_REF:0000120
    review:
      summary: >-
        IEA annotation for [4Fe-4S] cluster binding from combined automated methods
        including
        InterPro domains IPR001949, IPR011537, IPR019575 and UniProt keyword KW-0004
        (4Fe-4S).
        NDUFV1 binds one [4Fe-4S] cluster (N3) confirmed by the cryo-EM structure
        at
        3.4A
        resolution (PMID:28844695). The four cysteine ligands are at positions 379,
        382, 385,
        and 425 as shown in PDB structures 5XTB/5XTD/5XTH.
      action: ACCEPT
      reason: >-
        Core cofactor binding annotation. The [4Fe-4S] cluster N3 is essential for
        the
        electron
        relay from FMN toward the downstream Fe-S clusters in NDUFS1. Confirmed by
        cryo-EM
        structure (PMID:28844695) and UniProt binding site annotations.
      supported_by:
        - reference_id: PMID:28844695
          supporting_text: >-
            The structure not only reveals the precise assignment of individual subunits
            of
            human CI and CIII, but also enables future in-depth analysis of the electron
            transport chain as a whole
        - reference_id: file:human/NDUFV1/NDUFV1-deep-research-falcon.md
          supporting_text: >-
            Electrons flow NADH to FMN (bound in NDUFV1) to series of Fe-S clusters
            to
            terminal cluster N2 near the ubiquinone site

# ============================================================
# IPI ANNOTATIONS (protein-protein interaction)
# ============================================================
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:24344204
    review:
      summary: >-
        IPI annotation for interaction with NDUFV3 (P56181) from Guarani et al. (2014),
        who
        used interaction proteomics to interrogate molecular associations of Complex
        I subunits
        and assembly factors. NDUFV3 is a fellow subunit of the FP subcomplex within
        the
        N-module, so the NDUFV1-NDUFV3 interaction is expected and biologically meaningful
        as intra-complex subunit interaction during Complex I assembly.
      action: KEEP_AS_NON_CORE
      reason: >-
        The NDUFV1-NDUFV3 interaction is biologically meaningful as both are subunits
        of the
        FP subcomplex. However, 'protein binding' is uninformative as a GO term and
        the
        subunit interaction is already captured by the CC annotation GO:0045271 (part_of
        respiratory chain complex I).
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:30021884
    review:
      summary: >-
        IPI annotation for interaction with NDUFV3 (P56181) from Fasci et al. (2018),
        a
        crosslinking mass spectrometry study in intact cell nuclei focused on histone
        interactions. This is a large-scale crosslinking study. The detection of NDUFV1-NDUFV3
        crosslinks likely reflects their close physical proximity within the FP subcomplex.
      action: KEEP_AS_NON_CORE
      reason: >-
        The NDUFV1-NDUFV3 interaction reflects intra-complex proximity within the
        FP
        subcomplex.
        The GO term 'protein binding' is uninformative and the interaction is already
        captured
        by Complex I membership. Keep as non-core.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:32296183
    review:
      summary: >-
        IPI annotation for interaction with CYSRT1 (A8MQ03) from Luck et al. (2020),
        a
        reference map of the human binary protein interactome. CYSRT1 is a small cysteine-rich
        protein of unknown function. The biological significance of an NDUFV1-CYSRT1
        interaction is unclear and likely represents a non-specific or indirect detection
        from this high-throughput screen.
      action: KEEP_AS_NON_CORE
      reason: >-
        High-throughput binary interactome data. The NDUFV1-CYSRT1 interaction has
        no
        known
        biological relevance. Furthermore, 'protein binding' is uninformative as a
        GO
        term.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:32814053
    review:
      summary: >-
        IPI annotations for multiple interactors from Haenig et al. (2020), an interactome
        mapping study focused on neurodegenerative disease proteins. The GOA contains
        many
        individual IPI lines from this PMID with various interactors including PRKCA,
        PSMB1,
        PSMA3, MNDA, VDAC2, COPS2, YWHAG, SETDB1, PSMD5, SMU1, FBXO42, RBBP6, FAM9A,
        LMO3, FBXO25, TBC1D22A, USP25, OPTN, SPAG8, RMND5A, RNF146, ARFGAP3, BTRC,
        KAT5,
        and Q9NTX7. This is a large-scale Y2H-based interactome study. Many of these
        interactions are of unclear biological significance for a mitochondrial matrix-facing
        Complex I subunit. Some may represent protein aggregation artifacts, as the
        study
        specifically examined protein aggregation in neurodegeneration.
      action: KEEP_AS_NON_CORE
      reason: >-
        Large-scale interactome mapping study with many interactors of unclear biological
        relevance to NDUFV1 core function. The term 'protein binding' is uninformative.
        Some interactions (e.g., with proteasome subunits PSMB1, PSMA3, PSMD5) may
        reflect
        protein quality control/degradation rather than functional interactions.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:33961781
    review:
      summary: >-
        IPI annotation for interaction with NDUFV3 (P56181) from Huttlin et al. (2021),
        a
        dual proteome-scale network study. This again detects the NDUFV1-NDUFV3 interaction,
        consistent with both being subunits of the FP subcomplex in Complex I.
      action: KEEP_AS_NON_CORE
      reason: >-
        Confirms the NDUFV1-NDUFV3 intra-complex interaction. Biologically meaningful
        but
        'protein binding' is uninformative and already captured by Complex I membership.

# ============================================================
# IEA ANNOTATIONS (additional computational)
# ============================================================
  - term:
      id: GO:0006120
      label: mitochondrial electron transport, NADH to ubiquinone
    evidence_type: IEA
    original_reference_id: GO_REF:0000120
    review:
      summary: >-
        IEA annotation for the same process as the IBA above, from combined automated
        methods
        (mouse ortholog Q91YT0, Ensembl Compara). Redundant with the IBA but consistent.
      action: ACCEPT
      reason: >-
        Consistent with the IBA annotation. Duplicates are expected when multiple
        evidence
        sources converge on the same annotation.
  - term:
      id: GO:0045271
      label: respiratory chain complex I
    evidence_type: IEA
    original_reference_id: GO_REF:0000120
    review:
      summary: >-
        IEA annotation for the same CC term as the IBA above, from combined automated
        methods
        (mouse ortholog Q91YT0, Ensembl Compara). Redundant with the IBA but consistent.
      action: ACCEPT
      reason: >-
        Consistent with the IBA and multiple IDA/IMP annotations for this term.

# ============================================================
# EXPERIMENTAL ANNOTATIONS (IDA, IMP, IC, NAS, TAS, HTP)
# ============================================================
  - term:
      id: GO:0005743
      label: mitochondrial inner membrane
    evidence_type: IDA
    original_reference_id: PMID:28844695
    review:
      summary: >-
        IDA annotation from ComplexPortal based on Guo et al. (2017), who determined
        the
        cryo-EM structure of the human respiratory megacomplex I2III2IV2 at 3.4A resolution.
        The structure directly visualizes NDUFV1 (residues 27-457) within Complex
        I,
        which
        is embedded in the inner mitochondrial membrane.
      action: ACCEPT
      reason: >-
        Direct experimental evidence from cryo-EM structure showing NDUFV1 as part
        of
        Complex I in the inner mitochondrial membrane. NDUFV1 is a peripheral membrane
        protein
        on the matrix side.
      supported_by:
        - reference_id: PMID:28844695
          supporting_text: >-
            The structure not only reveals the precise assignment of individual subunits
            of
            human CI and CIII, but also enables future in-depth analysis of the electron
            transport chain as a whole
  - term:
      id: GO:0009060
      label: aerobic respiration
    evidence_type: NAS
    original_reference_id: PMID:30030361
    review:
      summary: >-
        NAS annotation from ComplexPortal based on Signes and Fernandez-Vizarra (2018),
        a review of OXPHOS complex assembly. Complex I is a central component of aerobic
        respiration, coupling NADH oxidation to the electron transport chain and proton
        pumping that drives ATP synthesis. NDUFV1 participates in aerobic respiration
        as
        the NADH-accepting subunit of Complex I.
      action: KEEP_AS_NON_CORE
      reason: >-
        Correct but broad. Aerobic respiration encompasses the entire oxidative phosphorylation
        system. NDUFV1's specific involvement is better captured by GO:0006120 (mitochondrial
        electron transport, NADH to ubiquinone). Keep as non-core since aerobic respiration
        is a higher-level process.
  - term:
      id: GO:0042776
      label: proton motive force-driven mitochondrial ATP synthesis
    evidence_type: NAS
    original_reference_id: PMID:30030361
    review:
      summary: >-
        NAS annotation from ComplexPortal suggesting NDUFV1 is involved in proton
        motive
        force-driven mitochondrial ATP synthesis. Complex I contributes to ATP synthesis
        by
        generating part of the proton motive force through proton pumping. However,
        NDUFV1
        is in the peripheral arm (N-module) performing electron transfer, not in the
        membrane
        arm that performs proton translocation. Unlike Complex II (which does not
        pump
        protons
        at all), Complex I does pump protons, so NDUFV1 indirectly contributes to
        PMF
        generation. But the annotation is imprecise for this specific subunit. The
        SDHA
        review
        correctly removed the equivalent annotation for SDHA/Complex II because Complex
        II
        does not pump protons. For NDUFV1/Complex I, the situation is different since
        Complex I
        does pump protons, but NDUFV1's electron transfer role is mechanistically
        separated
        from the proton pumping in the membrane arm.
      action: KEEP_AS_NON_CORE
      reason: >-
        Complex I as a whole contributes to the proton motive force and thus ATP synthesis,
        but NDUFV1 specifically performs electron transfer in the N-module peripheral
        arm,
        not proton translocation. The annotation is not wrong at the complex level,
        but it
        is imprecise for this subunit. Keep as non-core since NDUFV1's direct role
        is
        electron transfer, with proton pumping being a mechanistically coupled but
        structurally distinct function of the membrane arm.
  - term:
      id: GO:0005739
      label: mitochondrion
    evidence_type: HTP
    original_reference_id: PMID:34800366
    review:
      summary: >-
        HTP annotation for mitochondrial localization from Morgenstern et al. (2021),
        a
        quantitative high-confidence human mitochondrial proteome study. NDUFV1 was
        identified
        in the mitochondrial proteome by mass spectrometry.
      action: ACCEPT
      reason: >-
        Correct. NDUFV1 is a well-established mitochondrial protein confirmed by proteomics
        and structural biology.
  - term:
      id: GO:0045271
      label: respiratory chain complex I
    evidence_type: IMP
    original_reference_id: PMID:11112787
    review:
      summary: >-
        IMP annotation from Triepels et al. (2001), who used monoclonal antibodies
        and
        sucrose
        gradient studies to resolve Complex I defects into distinct subunit assembly
        patterns.
        The study examined patients with NDUFV1 defects and showed that mutations
        in
        NDUFV1
        affect Complex I assembly. The IMP evidence code is appropriate because the
        mutant
        phenotype (defective Complex I assembly) demonstrates that NDUFV1 is part
        of
        Complex I.
      action: ACCEPT
      reason: >-
        Valid IMP evidence. Mutations in NDUFV1 cause Complex I assembly defects,
        demonstrating
        that NDUFV1 is required for and part of Complex I.
      supported_by:
        - reference_id: PMID:11112787
          supporting_text: >-
            the other patients had defects in NDUFV1, NDUFS2 (two patients), NDUFS4
            (two
            patients), NDUFS7, and NDUFS8
  - term:
      id: GO:0045271
      label: respiratory chain complex I
    evidence_type: IDA
    original_reference_id: PMID:12611891
    review:
      summary: >-
        IDA annotation from Murray et al. (2003), who determined the subunit composition
        of
        human NADH dehydrogenase by rapid one-step immunopurification. NDUFV1 was
        directly
        identified as a Complex I subunit by mass spectrometry (MALDI-TOF and LC-MS/MS)
        of immunoisolated Complex I.
      action: ACCEPT
      reason: >-
        Direct experimental identification of NDUFV1 as a Complex I subunit by
        immunopurification and mass spectrometry.
      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:24746669
    review:
      summary: >-
        IMP annotation from Wang et al. (2014), who showed that cyclin B1/Cdk1 phosphorylates
        Complex I subunits including NDUFV1 to enhance CI activity during G2/M cell
        cycle
        progression. The study demonstrates that deficiency of phosphorylation in
        CI
        subunits
        results in impairment of CI function, supporting NDUFV1 as a functional component
        of Complex I.
      action: ACCEPT
      reason: >-
        Valid IMP evidence. Phosphorylation of NDUFV1 by cyclin B1/Cdk1 enhances Complex
        I
        activity, and deficiency of phosphorylation impairs CI function, confirming
        NDUFV1
        is a functional component of Complex I.
      supported_by:
        - reference_id: PMID:24746669
          supporting_text: >-
            Cyclin B1/Cdk1-mediated CI phosphorylation enhances CI activity, whereas
            deficiency of such phosphorylation in each of the relevant CI subunits
            results
            in impairment of CI function
  - term:
      id: GO:0045271
      label: respiratory chain complex I
    evidence_type: IDA
    original_reference_id: PMID:28844695
    review:
      summary: >-
        IDA annotation from Guo et al. (2017), the cryo-EM structure of the human
        respiratory
        megacomplex. NDUFV1 (residues 27-457) was directly visualized within Complex
        I at
        3.4A resolution (PDB: 5XTB, 5XTD, 5XTH, 5XTI).
      action: ACCEPT
      reason: >-
        Direct structural evidence from cryo-EM showing NDUFV1 as a subunit of Complex
        I.
        The strongest possible evidence for complex membership.
      supported_by:
        - reference_id: PMID:28844695
          supporting_text: >-
            The structure not only reveals the precise assignment of individual subunits
            of
            human CI and CIII, but also enables future in-depth analysis of the electron
            transport chain as a whole
  - term:
      id: GO:0045271
      label: respiratory chain complex I
    evidence_type: IDA
    original_reference_id: PMID:31536960
    review:
      summary: >-
        IDA annotation from Moutaoufik et al. (2019), who generated mitochondrial
        interaction
        maps using mass spectrometry-based co-fractionation. NDUFV1 was identified
        as
        part
        of Complex I by co-fractionation profiling.
      action: ACCEPT
      reason: >-
        Valid experimental evidence from co-fractionation mass spectrometry confirming
        NDUFV1 in Complex I.
      supported_by:
        - reference_id: PMID:31536960
          supporting_text: >-
            using mass spectrometry-based co-fractionation profiles and phosphoproteomics,
            we generated mitochondrial interaction maps
  - term:
      id: GO:0006120
      label: mitochondrial electron transport, NADH to ubiquinone
    evidence_type: IDA
    original_reference_id: PMID:28844695
    review:
      summary: >-
        IDA annotation from Guo et al. (2017). The cryo-EM structure of the megacomplex
        demonstrates the structural basis for electron transport from NADH to ubiquinone,
        with NDUFV1 containing the FMN cofactor at the entry point. UniProt cites
        this
        reference for the catalytic activity (EC 7.1.1.2).
      action: ACCEPT
      reason: >-
        Direct structural evidence supporting NDUFV1's role in electron transport
        from
        NADH
        to ubiquinone. The FMN cofactor in NDUFV1 is the primary electron acceptor
        from
        NADH.
      supported_by:
        - reference_id: PMID:28844695
          supporting_text: >-
            The respiratory megacomplex represents the highest-order assembly of respiratory
            chain complexes, and it allows mitochondria to respond to energy-requiring
            conditions
  - term:
      id: GO:0008137
      label: NADH dehydrogenase (ubiquinone) activity
    evidence_type: IDA
    original_reference_id: PMID:28844695
    review:
      summary: >-
        IDA annotation for the complex-level catalytic activity from Guo et al. (2017).
        The cryo-EM structure reveals NDUFV1 as the FMN-containing subunit where NADH
        oxidation occurs, contributing to the overall NADH dehydrogenase (ubiquinone)
        activity
        of Complex I. GO:0008137 describes the full reaction of the complex (NADH
        +
        ubiquinone
        + protons -> NAD+ + ubiquinol + translocated protons). NDUFV1 contributes
        to
        this
        by catalyzing the NADH oxidation step.
      action: ACCEPT
      reason: >-
        Valid IDA evidence from the structural study. NDUFV1 is the catalytic subunit
        where
        NADH is oxidized at the FMN site. The annotation is acceptable as NDUFV1 is
        the
        primary functional subunit for this activity, even though the full reaction
        requires
        the entire complex.
      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:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:31536960
    review:
      summary: >-
        IPI annotation for interaction with RAB5IF (Q9BUV8) from Moutaoufik et al.
        (2019).
        UniProt confirms this interaction. RAB5IF is an orphan protein identified
        as
        a
        respirasome assembly factor in this study. The biological significance of
        the
        NDUFV1-RAB5IF interaction may relate to Complex I assembly regulation.
      action: KEEP_AS_NON_CORE
      reason: >-
        The NDUFV1-RAB5IF interaction is biologically interesting given that RAB5IF
        was
        identified as a respirasome assembly factor, but 'protein binding' is uninformative
        as a GO term. Keep as non-core.
      supported_by:
        - reference_id: PMID:31536960
          supporting_text: >-
            we show the orphan C20orf24 as a respirasome assembly factor whose disruption
            markedly reduces respiratory chain activity in patients deficient in complex
            IV
  - term:
      id: GO:0042775
      label: mitochondrial ATP synthesis coupled electron transport
    evidence_type: IMP
    original_reference_id: PMID:24746669
    review:
      summary: >-
        IMP annotation from the CAFA annotation challenge, based on Wang et al. (2014).
        The study showed that cyclin B1/Cdk1 phosphorylation of Complex I subunits
        enhances
        CI activity and mitochondrial respiration with enhanced oxygen consumption
        and
        ATP
        generation. Deficiency of phosphorylation impairs CI function and ATP production.
        The term GO:0042775 encompasses the coupling between electron transport and
        ATP
        synthesis in mitochondria.
      action: KEEP_AS_NON_CORE
      reason: >-
        The annotation is defensible since Complex I electron transport is coupled
        to
        ATP
        synthesis via the proton motive force. However, NDUFV1 specifically performs
        electron
        transfer, not ATP synthesis coupling per se. The term is broader than NDUFV1's
        direct
        role. Keep as non-core.
      supported_by:
        - reference_id: PMID:24746669
          supporting_text: >-
            Mitochondria-targeted cyclin B1/Cdk1 increases mitochondrial respiration
            with
            enhanced oxygen consumption and ATP generation

# ============================================================
# TAS/NAS ANNOTATIONS (Reactome and literature)
# ============================================================
  - term:
      id: GO:0005743
      label: mitochondrial inner membrane
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-163217
    review:
      summary: >-
        TAS annotation from Reactome entry R-HSA-163217 (Complex I oxidises NADH to
        NAD+,
        reduces CoQ to CoQH2). NDUFV1 is part of Complex I which is embedded in the
        inner
        mitochondrial membrane.
      action: ACCEPT
      reason: >-
        Correct localization. Complex I is an inner mitochondrial membrane complex
        and
        NDUFV1 is a core subunit.
  - term:
      id: GO:0005743
      label: mitochondrial inner membrane
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-6788556
    review:
      summary: >-
        TAS annotation from Reactome entry R-HSA-6788556 (NUBPL transfers 4Fe-4S to
        NDUFV1, V2).
        This Reactome entry specifically describes the iron-sulfur cluster insertion
        into
        NDUFV1 and NDUFV2, placing NDUFV1 at the inner membrane during assembly.
      action: ACCEPT
      reason: >-
        Correct. NUBPL transfers the [4Fe-4S] cluster to NDUFV1 during Complex I assembly
        at the inner membrane.
  - term:
      id: GO:0005743
      label: mitochondrial inner membrane
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-6799179
    review:
      summary: >-
        TAS annotation from Reactome entry R-HSA-6799179 (Peripheral arm subunits
        bind
        the
        815kDa complex to form a 980kDa complex). This describes Complex I assembly
        where
        peripheral arm subunits including NDUFV1 join the membrane-anchored subcomplex.
      action: ACCEPT
      reason: >-
        Correct. NDUFV1 is assembled into Complex I at the inner membrane.
  - term:
      id: GO:0005743
      label: mitochondrial inner membrane
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-6799196
    review:
      summary: >-
        TAS annotation from Reactome entry R-HSA-6799196 (The MCIA complex, NDUFAF2-7
        all
        dissociate from the 980kDa complex, resulting in Complex I). This describes
        the final
        maturation step of Complex I at the inner membrane.
      action: ACCEPT
      reason: >-
        Correct. The final Complex I maturation step occurs at the inner membrane.
  - term:
      id: GO:0005743
      label: mitochondrial inner membrane
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-6800870
    review:
      summary: >-
        TAS annotation from Reactome entry R-HSA-6800870 (NDUF subunits bind to form
        the FP
        subcomplex). This describes the assembly of the flavoprotein subcomplex (NDUFV1
        +
        NDUFV2 + NDUFV3) that constitutes the N-module of Complex I.
      action: ACCEPT
      reason: >-
        Correct. NDUFV1 assembles into the FP subcomplex at the inner membrane.
  - term:
      id: GO:0005743
      label: mitochondrial inner membrane
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-9837978
    review:
      summary: >-
        TAS annotation from Reactome entry R-HSA-9837978 (LONP1 binds mitochondrial
        inner
        membrane proteins). This describes the mitochondrial protease LONP1 binding
        to inner
        membrane proteins including Complex I subunits for quality control.
      action: ACCEPT
      reason: >-
        Correct localization. NDUFV1 is a target of LONP1 quality control at the inner
        membrane.
  - term:
      id: GO:0005743
      label: mitochondrial inner membrane
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-9838004
    review:
      summary: >-
        TAS annotation from Reactome entry R-HSA-9838004 (LONP1 degrades mitochondrial
        inner
        membrane proteins). This describes LONP1-mediated degradation of inner membrane
        proteins including Complex I subunits.
      action: ACCEPT
      reason: >-
        Correct localization. NDUFV1 can be degraded by LONP1 at the inner membrane
        as part
        of mitochondrial protein quality control.
  - term:
      id: GO:0005743
      label: mitochondrial inner membrane
    evidence_type: NAS
    original_reference_id: PMID:8288251
    review:
      summary: >-
        NAS annotation from Ali et al. (1993), who cloned cDNA fragments of the 51-kDa
        flavoprotein subunit of mitochondrial NADH:ubiquinone oxidoreductase and localized
        the gene NDUFV1 to chromosome 11q13. The paper describes NDUFV1 as "mitochondrial"
        and as part of Complex I which resides in the inner membrane.
      action: ACCEPT
      reason: >-
        Correct localization supported by the description of NDUFV1 as a mitochondrial
        Complex I subunit.
      supported_by:
        - reference_id: PMID:8288251
          supporting_text: >-
            flavoprotein subunit of mitochondrial NADH:ubiquinone oxidoreductase
            (Complex I)
  - term:
      id: GO:0006120
      label: mitochondrial electron transport, NADH to ubiquinone
    evidence_type: IC
    original_reference_id: PMID:11112787
    review:
      summary: >-
        IC (Inferred by Curator) annotation from Triepels et al. (2001), with the
        WITH
        field
        referencing GO:0045271 (respiratory chain complex I). The curator inferred
        that
        since
        NDUFV1 is part of Complex I (shown by IMP), it is involved in the electron
        transport
        process of Complex I (NADH to ubiquinone). This is a valid curator inference.
      action: ACCEPT
      reason: >-
        Valid curator inference. Since NDUFV1 is part of Complex I and Complex I catalyzes
        electron transport from NADH to ubiquinone, NDUFV1 is involved in this process.
        For NDUFV1 specifically, this is a core function as it is the NADH-accepting
        subunit.
      supported_by:
        - reference_id: PMID:11112787
          supporting_text: >-
            the other patients had defects in NDUFV1, NDUFS2 (two patients), NDUFS4
            (two
            patients), NDUFS7, and NDUFS8
  - term:
      id: GO:0008137
      label: NADH dehydrogenase (ubiquinone) activity
    evidence_type: NAS
    original_reference_id: PMID:8288251
    review:
      summary: >-
        NAS annotation from Ali et al. (1993). The paper describes NDUFV1 as "The
        51-kDa
        flavoprotein subunit of mitochondrial NADH:ubiquinone oxidoreductase (Complex
        I)
        [NADH dehydrogenase (ubiquinone), flavoprotein 1 (51 kDa); EC 1.6.5.3]" and
        states
        it "plays an important role in the formation of the NADH-binding site and
        is
        believed
        to be the principal site of entry for electrons donated by NADH into the respiratory
        chain."
      action: ACCEPT
      reason: >-
        Valid NAS annotation. The paper clearly describes NDUFV1 as part of the NADH
        dehydrogenase (ubiquinone) complex and its role in NADH binding.
      supported_by:
        - reference_id: PMID:8288251
          supporting_text: >-
            NADH dehydrogenase (ubiquinone), flavoprotein 1 (51 kDa); EC
            1.6.5.3] plays an important role in the formation of the NADH-binding
            site
            and is believed
            to be the principal site of entry for electrons donated by NADH into the
            respiratory
            chain
  - term:
      id: GO:0006120
      label: mitochondrial electron transport, NADH to ubiquinone
    evidence_type: NAS
    original_reference_id: PMID:9878551
    review:
      summary: >-
        NAS annotation from Loeffen et al. (1998), who completed the cDNA characterization
        of all nuclear-encoded Complex I subunits. The paper describes Complex I's
        main
        function
        as "the transport of electrons from NADH to ubiquinone, which is accompanied
        by
        translocation of protons from the mitochondrial matrix to the intermembrane
        space."
      action: ACCEPT
      reason: >-
        Valid NAS annotation. The paper clearly describes the function of Complex
        I
        in
        electron transport from NADH to ubiquinone.
      supported_by:
        - reference_id: PMID:9878551
          supporting_text: >-
            Its main function is the transport of electrons from NADH to ubiquinone,
            which
            is accompanied by translocation of protons from the mitochondrial matrix
            to
            the
            intermembrane space
  - term:
      id: GO:0008137
      label: NADH dehydrogenase (ubiquinone) activity
    evidence_type: NAS
    original_reference_id: PMID:9878551
    review:
      summary: >-
        NAS annotation from Loeffen et al. (1998). The paper describes Complex I as
        "NADH:ubiquinone oxidoreductase (complex I)" and discusses its function in
        electron
        transport from NADH to ubiquinone.
      action: ACCEPT
      reason: >-
        Valid NAS annotation consistent with other annotations for this activity.
      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. Its main function
            is
            the
            transport of electrons from NADH to ubiquinone

# ============================================================
# NEW ANNOTATIONS (missing from current set)
# ============================================================
  - term:
      id: GO:0003954
      label: NADH dehydrogenase activity
    evidence_type: IDA
    original_reference_id: PMID:28844695
    review:
      summary: >-
        GO:0003954 (NADH dehydrogenase activity) is defined as "Catalysis of the reaction:
        NADH + H+ + acceptor = NAD+ + reduced acceptor." This is the subunit-specific
        molecular function for NDUFV1, as distinct from GO:0008137 which specifies
        ubiquinone
        as the acceptor and represents the full complex reaction. NDUFV1 alone catalyzes
        NADH oxidation at its FMN cofactor (the acceptor is FMN), independent of whether
        the downstream acceptor is ultimately ubiquinone. This is analogous to how
        SDHA
        was annotated with GO:0000104 (succinate dehydrogenase activity, generic acceptor)
        in addition to GO:0008177 (the quinone-specific complex activity). The cryo-EM
        structure (PMID:28844695) confirms the FMN-dependent NADH oxidation site in
        NDUFV1,
        and UniProt annotation states "electrons from NADH are accepted by flavin
        mononucleotide
        (FMN)." Ali et al. (PMID:8288251) describe NDUFV1 as "the principal site of
        entry
        for electrons donated by NADH into the respiratory chain."
      action: NEW
      reason: >-
        GO:0003954 more precisely captures NDUFV1's intrinsic catalytic function (NADH
        oxidation with a generic acceptor) as opposed to GO:0008137 which specifies
        the
        ubiquinone-dependent overall complex reaction. NDUFV1 alone catalyzes the
        NADH
        ->
        FMN electron transfer step. This term fills a gap where current annotations
        only
        capture the complex-level activity. Should use the 'enables' qualifier since
        NDUFV1
        is sufficient to oxidize NADH at its FMN site.
      supported_by:
        - reference_id: PMID:8288251
          supporting_text: >-
            plays an important role in the formation of the NADH-binding site and
            is believed to be the principal site of entry for electrons donated by
            NADH
            into
            the respiratory chain
        - reference_id: PMID:28844695
          supporting_text: >-
            The respiratory megacomplex represents the highest-order assembly of respiratory
            chain complexes
        - reference_id: file:human/NDUFV1/NDUFV1-deep-research-falcon.md
          supporting_text: >-
            NDUFV1 FMN cofactor is the primary NADH-accepting site and sits at the
            top
            of
            the hydrophilic peripheral arm
  - term:
      id: GO:0009055
      label: electron transfer activity
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: >-
        GO:0009055 (electron transfer activity) is not currently annotated for NDUFV1
        in
        GOA but should be. NDUFV1 performs electron transfer as part of the NADH-to-ubiquinone
        chain: it accepts electrons from NADH at its FMN cofactor and transfers them
        to the
        [4Fe-4S] cluster N3, then onward to NDUFS1. This is analogous to the IBA annotation
        for SDHA with GO:0009055. The deep research review confirms this electron
        transfer
        role across the N-module Fe-S relay (file:human/NDUFV1/NDUFV1-deep-research-falcon.md).
        UniProt keywords include "Electron transport" (KW-0249).
      action: NEW
      reason: >-
        Electron transfer activity is a core molecular function of NDUFV1. The FMN
        cofactor
        accepts electrons from NADH and transfers them to the [4Fe-4S] cluster N3,
        continuing
        to the downstream Fe-S chain. This is the subunit-specific MF of NDUFV1 and
        is
        missing from the current annotation set. Analogous to SDHA's IBA annotation
        for
        GO:0009055.
      supported_by:
        - reference_id: PMID:8288251
          supporting_text: >-
            is believed to be the principal site of entry for electrons donated by
            NADH
            into
            the respiratory chain
        - reference_id: file:human/NDUFV1/NDUFV1-deep-research-falcon.md
          supporting_text: >-
            Electrons flow NADH to FMN (bound in NDUFV1) to series of Fe-S clusters
            to
            terminal cluster N2 near the ubiquinone site
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: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:8288251
    title: Chromosomal localization of the human gene encoding the 51-kDa subunit
      of mitochondrial complex I (NDUFV1) to 11q13.
    findings:
      - statement: >-
          NDUFV1 encodes the 51-kDa flavoprotein subunit of Complex I, which forms
          the
          NADH-binding site and is the principal site of electron entry from NADH
          into
          the
          respiratory chain. The gene maps to chromosome 11q13.
        supporting_text: >-
          plays an important role in the formation of the NADH-binding site and
          is believed to be the principal site of entry for electrons donated by NADH
          into
          the respiratory chain
        reference_section_type: ABSTRACT
        full_text_unavailable: true
  - id: PMID:9878551
    title: 'cDNA of eight nuclear encoded subunits of NADH:ubiquinone oxidoreductase:
      human complex I cDNA characterization completed.'
    findings:
      - statement: >-
          Complex I functions in electron transport from NADH to ubiquinone, coupled
          to
          proton translocation from the mitochondrial matrix to the intermembrane
          space.
          Human Complex I consists of 41 subunits (now known to be 45), 34 nuclear-encoded.
        supporting_text: >-
          NADH:ubiquinone oxidoreductase (complex I) is an extremely complicated multiprotein
          complex located in the inner mitochondrial membrane. Its main function is
          the
          transport
          of electrons from NADH to ubiquinone, which is accompanied by translocation
          of protons
          from the mitochondrial matrix to the intermembrane space.
        reference_section_type: ABSTRACT
        full_text_unavailable: true
  - id: PMID:11112787
    title: Human complex I defects can be resolved by monoclonal antibody analysis
      into distinct subunit assembly patterns.
    findings:
      - statement: >-
          Monoclonal antibody and sucrose gradient analysis of Complex I deficient
          patients
          including NDUFV1 mutants reveals distinct subunit assembly patterns. NDUFV1
          defects
          can be distinguished from assembly factor defects using this approach.
        supporting_text: >-
          the other patients had defects in NDUFV1, NDUFS2 (two patients), NDUFS4
          (two
          patients), NDUFS7, and NDUFS8. We show here that Western blotting with these
          antibodies, particularly when used in conjunction with sucrose gradient
          studies
          and enzymatic activity measurements, helps distinguish catalytic versus
          assembly
          defects
        reference_section_type: ABSTRACT
        full_text_unavailable: true
  - id: PMID:12611891
    title: The subunit composition of the human NADH dehydrogenase obtained by rapid
      one-step immunopurification.
    findings:
      - statement: >-
          NDUFV1 was directly identified as a Complex I subunit by immunopurification
          and
          mass spectrometry (MALDI-TOF and LC-MS/MS). The study resolved 42 polypeptides
          from immunoisolated human Complex I.
        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
        reference_section_type: ABSTRACT
        full_text_unavailable: true
  - id: PMID:24344204
    title: TIMMDC1/C3orf1 functions as a membrane-embedded mitochondrial complex I
      assembly factor through association with the MCIA complex.
    findings:
      - statement: >-
          Interaction proteomics of 15 core CI subunits and assembly factors identified
          TIMMDC1 as a new CI assembly factor. NDUFV1 was among the core subunits
          used
          as
          baits, and its interaction with NDUFV3 was detected.
        supporting_text: >-
          We employed interaction proteomics to interrogate the molecular associations
          of 15
          core subunits and assembly factors previously linked to human CI deficiency,
          resulting
          in a network of 101 proteins and 335 interactions
        reference_section_type: ABSTRACT
        full_text_unavailable: true
  - id: PMID:24746669
    title: Cyclin B1/Cdk1 coordinates mitochondrial respiration for cell-cycle G2/M
      progression.
    findings:
      - statement: >-
          Cyclin B1/Cdk1 localizes to the mitochondrial matrix and phosphorylates
          Complex
          I
          subunits including NDUFV1, enhancing CI activity and mitochondrial respiration
          for
          G2/M cell cycle progression. Deficiency of phosphorylation impairs CI function.
        supporting_text: >-
          Cyclin B1/Cdk1-mediated CI phosphorylation enhances CI activity, whereas
          deficiency
          of such phosphorylation in each of the relevant CI subunits results in impairment
          of CI function. Mitochondria-targeted cyclin B1/Cdk1 increases mitochondrial
          respiration with enhanced oxygen consumption and ATP generation
        reference_section_type: ABSTRACT
        full_text_unavailable: true
  - id: PMID:28844695
    title: Architecture of Human Mitochondrial Respiratory Megacomplex I(2)III(2)IV(2).
    findings:
      - statement: >-
          Cryo-EM structure of the human respiratory megacomplex I2III2IV2 at 3.4A
          resolution.
          NDUFV1 (residues 27-457) was directly resolved within Complex I. The structure
          confirms NDUFV1 contains FMN and one [4Fe-4S] cluster. UniProt cites this
          reference
          for NDUFV1's function, catalytic activity (EC 7.1.1.2), cofactors, and subunit
          composition.
        supporting_text: >-
          The structure not only reveals the precise assignment of individual subunits
          of
          human CI and CIII, but also enables future in-depth analysis of the electron
          transport chain as a whole
        reference_section_type: ABSTRACT
        full_text_unavailable: true
  - id: PMID:30021884
    title: Histone Interaction Landscapes Visualized by Crosslinking Mass Spectrometry
      in Intact Cell Nuclei.
    findings:
      - statement: >-
          Crosslinking mass spectrometry in intact nuclei detected NDUFV1-NDUFV3 crosslinks,
          reflecting their close physical proximity within the FP subcomplex of Complex
          I.
        supporting_text: >-
          we use crosslinking mass spectrometry (XL-MS) to chart the protein-protein
          interactions in intact human nuclei
  - id: PMID:30030361
    title: Assembly of mammalian oxidative phosphorylation complexes I-V and supercomplexes.
    findings:
      - statement: >-
          Review of OXPHOS complex assembly. Complex I is built in a stepwise fashion
          through
          the actions of several assembly factors. The N-module (containing NDUFV1,
          NDUFV2,
          NDUFS1) is assembled as the last major module to join the growing complex.
        supporting_text: >-
          The assembly of the five oxidative phosphorylation system (OXPHOS) complexes
          in
          the inner mitochondrial membrane is an intricate process
        reference_section_type: ABSTRACT
        full_text_unavailable: true
  - id: PMID:31536960
    title: Rewiring of the Human Mitochondrial Interactome during Neuronal Reprogramming
      Reveals Regulators of the Respirasome and Neurogenesis.
    findings:
      - statement: >-
          Mitochondrial interaction maps generated by co-fractionation mass spectrometry
          identified NDUFV1 in Complex I. The study also found NDUFV1 interacts with
          RAB5IF
          (C20orf24/Q9BUV8), a newly identified respirasome assembly factor.
        supporting_text: >-
          using mass spectrometry-based co-fractionation profiles and phosphoproteomics,
          we generated mitochondrial interaction maps of human pluripotent embryonal
          carcinoma
          stem cells and differentiated neuronal-like cells
        reference_section_type: ABSTRACT
        full_text_unavailable: false
  - 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:
      - statement: >-
          Large-scale interactome mapping detected multiple NDUFV1 protein-protein
          interactions
          including with proteasome subunits (PSMB1, PSMA3, PSMD5), signaling proteins
          (PRKCA, YWHAG), and many others. Many of these interactions are of unclear
          biological significance for a mitochondrial Complex I subunit.
        supporting_text: >-
          we report on an interactome map that focuses on
          neurodegenerative disease (ND), connects ∼5,000 human proteins via ∼30,000
          candidate interactions and is generated by systematic yeast two-hybrid
          interaction screening
  - id: PMID:33961781
    title: Dual proteome-scale networks reveal cell-specific remodeling of the human
      interactome.
    findings:
      - statement: >-
          Dual proteome-scale network study confirmed NDUFV1-NDUFV3 interaction, consistent
          with both being subunits of the FP subcomplex within Complex I.
        supporting_text: >-
          Through affinity-purification mass spectrometry, 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: >-
          NDUFV1 was identified in the high-confidence human mitochondrial proteome
          by
          quantitative mass spectrometry, confirming its mitochondrial localization.
        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: 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: []
  - id: Reactome:R-HSA-9837978
    title: LONP1 binds mitochondrial inner membrane proteins
    findings: []
  - id: Reactome:R-HSA-9838004
    title: LONP1 degrades mitochondrial inner membrane proteins
    findings: []
  - id: file:human/NDUFV1/NDUFV1-deep-research-falcon.md
    title: Deep research review of NDUFV1 gene function (Falcon provider)
    findings:
      - statement: >-
          NDUFV1 is the 51 kDa FMN-binding core subunit of mitochondrial Complex I
          located
          in the N-module at the matrix-facing tip of the peripheral arm. It catalyzes
          NADH
          oxidation as the initial electron acceptor and passes electrons through
          Fe-S
          clusters
          to ubiquinone. The reduced FMN site is the predominant source of ROS from
          Complex
          I.
          Biallelic mutations cause MC1DN4/Leigh syndrome.
        supporting_text: >-
          NDUFV1 binds FMN as the primary electron acceptor for NADH and harbors canonical
          motifs that support NADH/FMN and Fe-S relay connectivity at the N-module
          interface.
          Electrons flow NADH to FMN (bound in NDUFV1) to series of Fe-S clusters
          to terminal
          cluster N2 near the ubiquinone site.
core_functions:
  - molecular_function:
      id: GO:0003954
      label: NADH dehydrogenase 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
    description: >-
      NDUFV1 is the catalytic flavoprotein subunit of mitochondrial NADH:ubiquinone
      oxidoreductase (Complex I). It contains a covalently bound FMN cofactor and
      one
      [4Fe-4S] cluster (N3). NDUFV1 enables NADH dehydrogenase activity (GO:0003954)
      by oxidizing NADH at the FMN site, and enables electron transfer activity (GO:0009055)
      by passing electrons through its [4Fe-4S] cluster to the downstream Fe-S relay
      in
      NDUFS1. It contributes to the overall NADH dehydrogenase (ubiquinone) activity
      (GO:0008137) of the full Complex I holoenzyme, which couples electron transfer
      to
      proton translocation across the inner mitochondrial membrane. NDUFV1 is located
      in
      the N-module at the matrix-facing tip of the peripheral arm of Complex I
      (GO:0045271), embedded in the inner mitochondrial membrane (GO:0005743). The
      biological process is mitochondrial electron transport, NADH to ubiquinone
      (GO:0006120). FMN binding (GO:0010181), NAD binding (GO:0051287), and [4Fe-4S]
      cluster binding (GO:0051539) are core cofactor-binding functions essential for
      catalysis.
    supported_by:
      - reference_id: PMID:28844695
        supporting_text: >-
          The structure not only reveals the precise assignment of individual subunits
          of
          human CI and CIII, but also enables future in-depth analysis of the electron
          transport chain as a whole
      - reference_id: PMID:8288251
        supporting_text: >-
          plays an important role in the formation of the NADH-binding site and
          is believed to be the principal site of entry for electrons donated by NADH
          into
          the respiratory chain
      - reference_id: file:human/NDUFV1/NDUFV1-deep-research-falcon.md
        supporting_text: >-
          NDUFV1 binds FMN as the primary electron acceptor for NADH and harbors canonical
          motifs that support NADH/FMN and Fe-S relay connectivity at the N-module
          interface
    in_complex:
      id: GO:0045271
      label: respiratory chain complex I