NDUFS1

---
id: P28331
gene_symbol: NDUFS1
product_type: PROTEIN
status: IN_PROGRESS
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: >-
  NDUFS1 encodes the 75 kDa subunit of mitochondrial Complex I (NADH:ubiquinone oxidoreductase,
  EC 7.1.1.2), the largest subunit of the complex and a core component of the N-module
  in the
  peripheral (matrix-facing) arm. NDUFS1 contains one [2Fe-2S] cluster and two [4Fe-4S]
  clusters
  that form part of the electron relay chain transferring electrons from FMN (bound
  to NDUFV1)
  toward the ubiquinone-binding Q-module. NDUFS1 is essential for the assembly and
  stability
  of both Complex I and the respiratory supercomplexes (respirasomes). Pathogenic
  mutations in
  NDUFS1 cause mitochondrial Complex I deficiency, nuclear type 5 (MC1DN5), presenting
  with
  Leigh syndrome and related encephalopathies. During apoptosis, NDUFS1 is a caspase
  substrate
  whose cleavage disrupts mitochondrial electron transport. MDM2 can bind and sequester
  NDUFS1
  to modulate respiration and apoptotic signaling.
alternative_products:
  - name: '1'
    id: P28331-1
  - name: '2'
    id: P28331-2
    sequence_note: VSP_042682
  - name: '3'
    id: P28331-3
    sequence_note: VSP_043728, VSP_043729
  - name: '4'
    id: P28331-4
    sequence_note: VSP_043727
  - name: '5'
    id: P28331-5
    sequence_note: VSP_045864
existing_annotations:
# ============================================================
# IBA ANNOTATIONS (phylogenetic inference from GO_Central)
# ============================================================
  - term:
      id: GO:0008137
      label: NADH dehydrogenase (ubiquinone) activity
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    qualifier: contributes_to
    review:
      summary: >-
        IBA annotation with 'contributes_to' qualifier for the complex-level NADH
        dehydrogenase
        (ubiquinone) activity. GO:0008137 represents the overall reaction of Complex
        I
        (NADH + ubiquinone + 5H+_in -> NAD+ + ubiquinol + 4H+_out). NDUFS1 is a core
        subunit
        of the N-module that harbors Fe-S clusters critical for electron relay, but
        the full
        catalytic cycle of Complex I requires all 45 subunits. The 'contributes_to'
        qualifier
        is appropriate and phylogenetically sound (PMID:31557978, PMID:30879903).
      action: ACCEPT
      reason: >-
        NDUFS1 contributes to the NADH dehydrogenase ubiquinone activity of Complex
        I by
        providing key Fe-S clusters in the electron relay chain. The 'contributes_to'
        qualifier
        is correct because the full catalytic reaction requires multiple subunits.
        The
        IBA
        annotation is phylogenetically well-supported. This represents a core function
        of the
        gene product.
      supported_by:
        - reference_id: PMID:31557978
          supporting_text: >-
            NDUFS1, encodes the NADH-ubiquinone oxidoreductase 75 kDa subunit, the
            largest
            subunit of CI that accommodates three iron-sulfur clusters in the N-module,
            which
            binds and oxidizes NADH
        - reference_id: PMID:30879903
          supporting_text: >-
            MDM2 negatively regulates NADH:ubiquinone oxidoreductase 75 kDa Fe-S protein
            1
            (NDUFS1), leading to decreased mitochondrial respiration
        - reference_id: file:human/NDUFS1/NDUFS1-deep-research-falcon.md
          supporting_text: >-
            NDUFS1 encodes the NADH:ubiquinone oxidoreductase 75 kDa core subunit
            of
            mitochondrial complex I in Homo sapiens. It is a core subunit of the hydrophilic
            N-module of complex I, positioned where NADH oxidation and iron-sulfur
            Fe-S
            chain
            electron transfer occur.
  - term:
      id: GO:0032981
      label: mitochondrial respiratory chain complex I assembly
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: >-
        IBA annotation for Complex I assembly. NDUFS1 plays a key role in the assembly
        and
        stability of Complex I as demonstrated by multiple studies. Mutations in NDUFS1
        lead
        to decreased stability of the entire N-module and prevent proper Complex I
        assembly
        and supercomplex formation (PMID:31557978, PMID:30879903, PMID:16478720).
        This
        IBA
        is phylogenetically sound and well-supported experimentally.
      action: ACCEPT
      reason: >-
        Core biological process for NDUFS1. Multiple experimental studies demonstrate
        that
        NDUFS1 mutations destabilize the N-module and impair Complex I assembly. The
        IBA
        annotation captures this conserved role accurately.
      supported_by:
        - reference_id: PMID:31557978
          supporting_text: >-
            the biallelic mutations in NDUFS1 led to a decreased stability of the
            entire
            N-module of CI and disrupted the electron transfer between two iron-sulfur
            clusters
        - reference_id: PMID:16478720
          supporting_text: >-
            The mutation (Q522K replacement) in NDUFS1 gene, coding for the 75-kDa
            Fe-S
            subunit
            of the complex, was associated with (a) reduced level of the mature complex

# ============================================================
# 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,
        so
        proton transmembrane transport is a logical consequence of the NADH dehydrogenase
        activity. However, the proton-pumping machinery is located in the membrane
        arm
        (P-module) of Complex I, not in the peripheral arm N-module where NDUFS1 resides.
        NDUFS1 does not directly participate in proton translocation. As an IEA it
        is
        acceptable
        as a broader process annotation for a complex subunit, even though the proton
        pumping
        is mechanistically distant from NDUFS1's specific role.
      action: ACCEPT
      reason: >-
        While proton translocation is mechanistically performed by the membrane arm
        subunits
        (not by NDUFS1), this is a legitimate broader process annotation for a Complex
        I
        subunit via logical inference from the complex-level activity. The annotation
        is
        acceptable as an IEA, albeit not the most informative for NDUFS1 specifically.
  - term:
      id: GO:0005743
      label: mitochondrial inner membrane
    evidence_type: IEA
    original_reference_id: GO_REF:0000120
    review:
      summary: >-
        IEA annotation for mitochondrial inner membrane localization. NDUFS1 is a
        peripheral
        membrane protein on the matrix side of the inner membrane, as part of Complex
        I. This
        is confirmed by cryo-EM structures (PMID:28844695) and UniProt subcellular
        location.
      action: ACCEPT
      reason: >-
        Correct localization. NDUFS1 is part of Complex I which is embedded in the
        inner
        mitochondrial membrane. NDUFS1 specifically is on the matrix-facing peripheral
        arm
        but is associated with the membrane complex.
      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
  - term:
      id: GO:0008137
      label: NADH dehydrogenase (ubiquinone) activity
    evidence_type: IEA
    original_reference_id: GO_REF:0000120
    review:
      summary: >-
        IEA annotation for NADH dehydrogenase (ubiquinone) activity from combined
        automated
        methods. This uses the 'enables' qualifier (inferred from InterPro, EC number,
        etc.).
        The IBA annotation above uses the more appropriate 'contributes_to' qualifier.
        While
        the IEA is not wrong at the broad level, the 'enables' qualifier is less precise
        for
        a subunit of a multi-protein enzyme complex.
      action: ACCEPT
      reason: >-
        Correct in terms of the function but the 'enables' qualifier from automated
        annotation
        is less precise than 'contributes_to' from the IBA. Acceptable as an IEA annotation
        since automated pipelines typically default to 'enables'.
  - term:
      id: GO:0016020
      label: membrane
    evidence_type: IEA
    original_reference_id: GO_REF:0000002
    review:
      summary: >-
        IEA annotation for generic 'membrane' localization from InterPro. This is
        very
        broad.
        The more specific GO:0005743 (mitochondrial inner membrane) is also annotated.
        This
        IEA is not wrong but is uninformative given the availability of more specific
        terms.
      action: ACCEPT
      reason: >-
        Correct but very generic. Acceptable for an IEA annotation as a broader parent
        of the
        more specific mitochondrial inner membrane annotation.
  - term:
      id: GO:0016491
      label: oxidoreductase activity
    evidence_type: IEA
    original_reference_id: GO_REF:0000120
    review:
      summary: >-
        IEA annotation for general oxidoreductase activity from InterPro domain mappings.
        NDUFS1 is part of Complex I which catalyzes an oxidoreductase reaction (NADH
        oxidation
        coupled to ubiquinone reduction). This is a correct but very broad parent
        term.
        The more
        specific GO:0008137 (NADH dehydrogenase ubiquinone activity) is also annotated.
      action: ACCEPT
      reason: >-
        Correct but general. Acceptable for IEA annotations to be broader than experimental
        annotations. The more specific GO:0008137 is also present.
  - term:
      id: GO:0016651
      label: oxidoreductase activity, acting on NAD(P)H
    evidence_type: IEA
    original_reference_id: GO_REF:0000002
    review:
      summary: >-
        IEA annotation from InterPro for oxidoreductase activity acting on NAD(P)H.
        This is
        an intermediate-specificity term. Complex I oxidizes NADH (not NADPH), so
        GO:0016651 is accurate as a parent term of GO:0008137.
      action: ACCEPT
      reason: >-
        Correct classification at an intermediate level. Complex I oxidizes NADH,
        which
        falls
        under the NAD(P)H-acting oxidoreductase class. Acceptable IEA annotation.
  - 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 UniProtKB keyword
        mapping.
        NDUFS1 is a core subunit of Complex I, the entry point of the mitochondrial
        respiratory
        electron transport chain. This is a correct and appropriate biological process
        annotation.
      action: ACCEPT
      reason: >-
        Correct. NDUFS1 is part of Complex I which is the first enzyme of the respiratory
        electron transport chain. This is a core biological process annotation.
      supported_by:
        - reference_id: PMID:31557978
          supporting_text: >-
            Complex I (CI, NADH:ubiquinone oxidoreductase) is the first and largest
            enzyme
            of
            the mitochondrial respiratory chain in humans
  - term:
      id: GO:0042773
      label: ATP synthesis coupled electron transport
    evidence_type: IEA
    original_reference_id: GO_REF:0000002
    review:
      summary: >-
        IEA annotation from InterPro for ATP synthesis coupled electron transport.
        Complex
        I
        couples electron transfer from NADH to ubiquinone with proton translocation
        that drives
        ATP synthesis. This is a broader process annotation that accurately describes
        the
        physiological context of Complex I function.
      action: ACCEPT
      reason: >-
        Correct. Complex I function is coupled to ATP synthesis via the proton motive
        force.
        This is an appropriate biological process annotation for a Complex I subunit.
  - term:
      id: GO:0046872
      label: metal ion binding
    evidence_type: IEA
    original_reference_id: GO_REF:0000043
    review:
      summary: >-
        IEA annotation from UniProtKB keyword mapping for metal ion binding. NDUFS1
        binds
        iron ions as part of its [2Fe-2S] and [4Fe-4S] clusters. This is correct but
        very
        broad. More specific iron-sulfur cluster binding terms are also annotated.
      action: ACCEPT
      reason: >-
        Correct but generic. NDUFS1 binds iron ions via its three Fe-S clusters. The
        more
        specific GO:0051536, GO:0051537, and GO:0051539 are also annotated and are
        more
        informative.
  - term:
      id: GO:0051536
      label: iron-sulfur cluster binding
    evidence_type: IEA
    original_reference_id: GO_REF:0000120
    review:
      summary: >-
        IEA annotation for iron-sulfur cluster binding from combined automated methods.
        NDUFS1 binds one [2Fe-2S] cluster and two [4Fe-4S] clusters. This is a well-supported
        core molecular function of NDUFS1. UniProt documents the specific Fe-S cluster
        binding
        sites with PROSITE and sequence similarity evidence.
      action: ACCEPT
      reason: >-
        Core molecular function. NDUFS1 contains three Fe-S clusters essential for
        electron
        relay in Complex I. Well supported by structural and biochemical evidence.
      supported_by:
        - reference_id: PMID:31557978
          supporting_text: >-
            Val228 is located between the two iron-sulfur clusters N4 and N5 in subunit
            NDUFS1
  - term:
      id: GO:0051537
      label: 2 iron, 2 sulfur cluster binding
    evidence_type: IEA
    original_reference_id: GO_REF:0000043
    review:
      summary: >-
        IEA annotation for [2Fe-2S] cluster binding from UniProtKB keyword mapping.
        NDUFS1
        binds one [2Fe-2S] cluster (designated N1b in EPR nomenclature) via its 2Fe-2S
        ferredoxin-type domain at residues 30-108. The binding residues are Cys64,
        Cys75,
        Cys78, and Cys92 according to UniProt.
      action: ACCEPT
      reason: >-
        Correct. NDUFS1 binds one [2Fe-2S] cluster in its N-terminal ferredoxin domain.
        Supported by sequence analysis, domain architecture, and structural studies.
  - term:
      id: GO:0051539
      label: 4 iron, 4 sulfur cluster binding
    evidence_type: IEA
    original_reference_id: GO_REF:0000043
    review:
      summary: >-
        IEA annotation for [4Fe-4S] cluster binding from UniProtKB keyword mapping.
        NDUFS1
        binds two [4Fe-4S] clusters (designated N4 and N5 in EPR nomenclature). The
        binding
        residues are documented in UniProt: cluster 1 via Cys124/Cys128/Cys131/His137
        and
        cluster 2 via Cys176/Cys179/Cys182/Cys226. These clusters are critical for
        electron
        tunneling between the N- and Q-modules (PMID:31557978).
      action: ACCEPT
      reason: >-
        Correct. NDUFS1 binds two [4Fe-4S] clusters that are essential for electron
        transfer.
        The Val228Ala mutation between clusters N4 and N5 reduces electron tunneling
        rate
        by 35-fold (PMID:31557978), demonstrating the functional importance of these
        clusters.
      supported_by:
        - reference_id: PMID:31557978
          supporting_text: >-
            the residue Val228 was critical for bridging the electron transfer between
            the
            N4 and N5 clusters, as electrons tunnelled primarily through this relatively
            bulky residue

# ============================================================
# IPI ANNOTATIONS (protein-protein interaction / protein binding)
# ============================================================
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:24344204
    review:
      summary: >-
        IPI annotation for protein binding with NDUFA9 (Q16795) from Guarani et al.
        (2014).
        This study used interaction proteomics to map Complex I assembly factor associations.
        NDUFS1 interaction with NDUFA9 is expected as both are Complex I subunits.
        NDUFA9
        is
        in the Q-module and NDUFS1 is at the N/Q-module interface. However, 'protein
        binding'
        is uninformative; the interaction reflects Complex I subunit assembly.
      action: KEEP_AS_NON_CORE
      reason: >-
        The NDUFS1-NDUFA9 interaction reflects inter-subunit contacts within Complex
        I, which
        is already captured by the CC annotation for Complex I membership (GO:0045271).
        'Protein binding' is uninformative as a GO term.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:29128334
    review:
      summary: >-
        IPI annotation for protein binding with SOAT1 (P35610) from Malty et al. (2017).
        This was a large-scale mitochondrial protein interaction map. The biological
        significance of an NDUFS1-SOAT1 interaction is unclear. SOAT1 is an ER-localized
        acyl-CoA:cholesterol acyltransferase, and an interaction with a mitochondrial
        matrix
        protein is unlikely to be functionally meaningful.
      action: KEEP_AS_NON_CORE
      reason: >-
        High-throughput protein-protein interaction data. The NDUFS1-SOAT1 interaction
        has
        no known biological relevance and may be an artifact. 'Protein binding' is
        uninformative.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:32807793
    review:
      summary: >-
        IPI annotation for protein binding with OSMR (Q99650) from Sharanek et al.
        (2020).
        This study demonstrated that OSMR is targeted to the mitochondrial matrix
        and
        interacts with NDUFS1/NDUFS2 of Complex I to promote mitochondrial respiration.
        The interaction was validated by co-immunoprecipitation. This is a biologically
        meaningful regulatory interaction, though 'protein binding' is uninformative.
      action: KEEP_AS_NON_CORE
      reason: >-
        The OSMR-NDUFS1 interaction is biologically interesting (OSMR promotes Complex
        I
        respiration in glioma stem cells), but this is a regulatory/pathological context
        interaction, not a core function of NDUFS1. 'Protein binding' is uninformative.
      supported_by:
        - reference_id: PMID:32807793
          supporting_text: >-
            OSMR interacts with NADH ubiquinone oxidoreductase 1/2 (NDUFS1/2) of complex
            I
            and promotes mitochondrial respiration
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:33961781
    review:
      summary: >-
        IPI annotation for protein binding with NDUFA9 (Q16795) from Huttlin et al.
        (2021)
        dual proteome-scale network study. Confirms the NDUFS1-NDUFA9 Complex I subunit
        interaction. Already captured by Complex I membership annotation.
      action: KEEP_AS_NON_CORE
      reason: >-
        Redundant confirmation of a known Complex I subunit interaction. 'Protein
        binding'
        is uninformative; the interaction is already captured by GO:0045271 (part_of
        respiratory chain complex I).
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:40205054
    review:
      summary: >-
        IPI annotation for protein binding with NDUFA9 (Q16795) from Schaffer et al.
        (2025)
        multimodal cell maps study. Third detection of NDUFS1-NDUFA9 interaction.
        These
        are
        fellow Complex I subunits.
      action: KEEP_AS_NON_CORE
      reason: >-
        Yet another confirmation of the NDUFS1-NDUFA9 Complex I subunit interaction.
        'Protein binding' is uninformative.

# ============================================================
# LOCALIZATION ANNOTATIONS
# ============================================================
  - term:
      id: GO:0005739
      label: mitochondrion
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: >-
        IEA annotation for mitochondrial localization via Ensembl Compara ortholog
        transfer.
        NDUFS1 has a mitochondrial transit peptide (residues 1-23, cleaved after Thr-23)
        and
        is well-established as a mitochondrial protein. Multiple IDA annotations also
        confirm
        this localization.
      action: ACCEPT
      reason: >-
        Correct localization, well-supported by transit peptide, IDA evidence, and
        proteomics
        data.
  - term:
      id: GO:0009055
      label: electron transfer activity
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: >-
        IEA annotation for electron transfer activity via Ensembl Compara ortholog
        transfer
        from mouse (Q91VD9). NDUFS1 contains three Fe-S clusters that form part of
        the
        electron relay chain in Complex I, transferring electrons from FMN toward
        ubiquinone.
        This is the subunit-specific molecular function of NDUFS1 -- it enables electron
        transfer activity independently via its Fe-S clusters
        (file:human/NDUFS1/NDUFS1-deep-research-falcon.md).
      action: ACCEPT
      reason: >-
        This is the core subunit-specific molecular function of NDUFS1. The three
        Fe-S
        clusters
        in NDUFS1 directly participate in electron transfer within Complex I. Unlike
        the
        complex-level NADH dehydrogenase activity (which NDUFS1 'contributes_to'),
        electron
        transfer activity is an intrinsic property of the NDUFS1 subunit.
      supported_by:
        - reference_id: PMID:1935949
          supporting_text: >-
            Determination of the cDNA sequence for the human mitochondrial 75-kDa
            Fe-S
            protein
            of NADH-coenzyme Q reductase
        - reference_id: PMID:31557978
          supporting_text: >-
            the residue Val228 was critical for bridging the electron transfer between
            the N4
            and N5 clusters
  - term:
      id: GO:0032981
      label: mitochondrial respiratory chain complex I assembly
    evidence_type: IEA
    original_reference_id: GO_REF:0000120
    review:
      summary: >-
        IEA annotation for Complex I assembly from combined automated methods. Redundant
        with
        the IBA and IMP annotations for the same term. Consistent with experimental
        data.
      action: ACCEPT
      reason: >-
        Correct and consistent with IBA and IMP annotations for the same term. Duplicates
        are
        expected when multiple evidence sources converge.
  - term:
      id: GO:0045271
      label: respiratory chain complex I
    evidence_type: IEA
    original_reference_id: GO_REF:0000120
    review:
      summary: >-
        IEA annotation for Complex I membership from combined automated methods. NDUFS1
        is
        a core subunit of Complex I, confirmed by immunopurification and mass spectrometry
        (PMID:12611891) and cryo-EM structures (PMID:28844695).
      action: ACCEPT
      reason: >-
        Correct. NDUFS1 is a core subunit of respiratory chain Complex I. Well established
        by
        multiple experimental approaches.
  - term:
      id: GO:0005739
      label: mitochondrion
    evidence_type: IDA
    original_reference_id: GO_REF:0000052
    review:
      summary: >-
        IDA annotation for mitochondrial localization from HPA immunofluorescence
        curation.
        Direct experimental evidence supporting NDUFS1 mitochondrial localization.
      action: ACCEPT
      reason: >-
        Direct experimental evidence from immunofluorescence. Consistent with all
        other
        localization data.
  - term:
      id: GO:0005743
      label: mitochondrial inner membrane
    evidence_type: IDA
    original_reference_id: PMID:28844695
    review:
      summary: >-
        IDA annotation from ComplexPortal based on cryo-EM structure of the human
        respiratory
        megacomplex I2III2IV2 (Guo et al. 2017). This study resolved the architecture
        of
        Complex I in the inner membrane context, directly demonstrating NDUFS1 as
        part
        of
        the membrane-associated complex.
      action: ACCEPT
      reason: >-
        Direct structural evidence from cryo-EM. The megacomplex structure shows Complex
        I
        (including NDUFS1) embedded in the inner mitochondrial membrane.
      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 the review by Signes and Fernandez-Vizarra
        (2018) on OXPHOS complex assembly. Complex I is the entry point for NADH-derived
        electrons into the respiratory chain, a core component of aerobic respiration.
        This
        is a broad but correct biological process annotation.
      action: ACCEPT
      reason: >-
        Correct. Complex I is essential for aerobic respiration. NDUFS1, as a core
        subunit,
        participates in this process. Acceptable as a broader process annotation.
      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
    review:
      summary: >-
        NAS annotation from ComplexPortal for proton motive force-driven mitochondrial
        ATP
        synthesis. Complex I couples electron transfer to proton pumping, generating
        part of
        the proton motive force that drives ATP synthase. However, NDUFS1 is in the
        N-module
        peripheral arm and does not directly participate in proton translocation (which
        occurs
        in the membrane arm P-module). Nevertheless, Complex I as a whole does contribute
        to
        the proton motive force, and NDUFS1's electron transfer activity is mechanistically
        coupled to this proton pumping. This is acceptable as a broader process annotation
        for a Complex I subunit, though it is less directly applicable to NDUFS1 than
        to
        membrane arm subunits.
      action: KEEP_AS_NON_CORE
      reason: >-
        Complex I does contribute to the proton motive force driving ATP synthesis,
        but NDUFS1
        is in the N-module and does not directly participate in proton translocation.
        The
        annotation is not wrong at the complex level but is peripherally related to
        NDUFS1's
        specific role. Keep as non-core rather than removing (unlike for Complex II
        subunits
        which truly do not pump protons, Complex I does pump protons as part of its
        catalytic
        cycle).
  - term:
      id: GO:0005739
      label: mitochondrion
    evidence_type: HTP
    original_reference_id: PMID:34800366
    review:
      summary: >-
        HTP annotation for mitochondrial localization from quantitative high-confidence
        human
        mitochondrial proteome study (Morgenstern et al. 2021). NDUFS1 was identified
        in the
        mitochondrial proteome.
      action: ACCEPT
      reason: >-
        Correct. NDUFS1 is a well-established mitochondrial protein confirmed by proteomics.

# ============================================================
# KEY EXPERIMENTAL ANNOTATIONS - Complex I assembly (IMP)
# ============================================================
  - term:
      id: GO:0032981
      label: mitochondrial respiratory chain complex I assembly
    evidence_type: IMP
    original_reference_id: PMID:16478720
    review:
      summary: >-
        IMP annotation from Iuso et al. (2006). This study investigated the pathogenic
        mechanism
        of a C1564A mutation in the NDUFS1 gene (Q522K replacement) and found it was
        associated
        with reduced level of the mature complex, demonstrating NDUFS1's role in Complex
        I
        assembly.
      action: ACCEPT
      reason: >-
        Direct experimental evidence showing NDUFS1 mutations impair Complex I assembly.
        The Q522K mutation caused reduced levels of mature Complex I in patient fibroblasts.
      supported_by:
        - reference_id: PMID:16478720
          supporting_text: >-
            The mutation (Q522K replacement) in NDUFS1 gene, coding for the 75-kDa
            Fe-S
            subunit
            of the complex, was associated with (a) reduced level of the mature complex

# ============================================================
# KEY EXPERIMENTAL ANNOTATIONS - Complex I membership (IDA, IMP, NAS)
# ============================================================
  - 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). This study used immunocapture followed
        by
        mass spectrometry to identify all subunits of human Complex I, directly demonstrating
        NDUFS1 as a component of the purified complex.
      action: ACCEPT
      reason: >-
        Direct experimental identification of NDUFS1 as a subunit of immunopurified
        human
        Complex I by mass spectrometry. Core structural 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:16478720
    review:
      summary: >-
        IMP annotation from Iuso et al. (2006). NDUFS1 mutation (Q522K) leads to reduced
        level of the mature Complex I, demonstrating NDUFS1's role as a subunit of
        the
        complex.
      action: ACCEPT
      reason: >-
        IMP evidence from mutant analysis demonstrating NDUFS1 is required for mature
        Complex I.
        Consistent with IDA evidence.
      supported_by:
        - reference_id: PMID:16478720
          supporting_text: >-
            The mutation (Q522K replacement) in NDUFS1 gene, coding for the 75-kDa
            Fe-S
            subunit
            of the complex, was associated with (a) reduced level of the mature complex
  - term:
      id: GO:0045271
      label: respiratory chain complex I
    evidence_type: NAS
    original_reference_id: PMID:9878551
    review:
      summary: >-
        NAS annotation from Loeffen et al. (1998). This study completed the characterization
        of all human Complex I cDNAs, discussing NDUFS1 as a known subunit of the
        complex.
      action: ACCEPT
      reason: >-
        Correct. NDUFS1 is well-established as a Complex I subunit. This early characterization
        study placed it in the complex context.
      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

# ============================================================
# KEY EXPERIMENTAL ANNOTATIONS - NADH dehydrogenase activity (IMP, enables)
# ============================================================
  - term:
      id: GO:0008137
      label: NADH dehydrogenase (ubiquinone) activity
    evidence_type: IMP
    original_reference_id: PMID:30879903
    review:
      summary: >-
        IMP annotation with 'enables' qualifier from Elkholi et al. (2019). This study
        showed
        that MDM2 binds NDUFS1, preventing its mitochondrial localization and causing
        Complex I
        destabilization and loss of oxidative phosphorylation efficiency. The IMP
        evidence
        demonstrates that NDUFS1 is required for NADH dehydrogenase activity. Note
        the
        GOA
        TSV uses 'enables' qualifier here, while the IBA and older IMP annotations
        use
        'contributes_to'. For GO:0008137 representing the full complex reaction,
        'contributes_to' is more precise, but 'enables' is defensible for the core
        catalytic
        subunit.
      action: ACCEPT
      reason: >-
        Valid IMP evidence. MDM2 sequestration of NDUFS1 leads to decreased Complex
        I activity,
        demonstrating NDUFS1 is essential for the NADH dehydrogenase activity. The
        'enables'
        vs 'contributes_to' qualifier difference from the IBA is acceptable.
      supported_by:
        - reference_id: PMID:30879903
          supporting_text: >-
            MDM2 directly binds and sequesters NDUFS1, preventing its mitochondrial
            localization
            and ultimately causing complex I and supercomplex destabilization and
            inefficiency
            of oxidative phosphorylation
  - term:
      id: GO:0008137
      label: NADH dehydrogenase (ubiquinone) activity
    evidence_type: IMP
    original_reference_id: PMID:31557978
    review:
      summary: >-
        IMP annotation with 'enables' qualifier from Ni et al. (2019). This study
        characterized
        NDUFS1 mutations (V228A and D252G) and showed they caused loss of Complex
        I
        catalytic
        activity and disrupted electron transfer between iron-sulfur clusters N4 and
        N5.
        In-gel activity assays revealed almost no enzymatic activity in the NDUFS1
        mutant.
      action: ACCEPT
      reason: >-
        Strong IMP evidence. NDUFS1 mutations directly abolish Complex I enzymatic
        activity,
        with almost no in-gel activity and dramatic reduction in electron tunneling
        rate
        (35-fold decrease for V228A). Demonstrates NDUFS1 is essential for the NADH
        dehydrogenase
        activity.
      supported_by:
        - reference_id: PMID:31557978
          supporting_text: >-
            the biallelic mutations in NDUFS1 led to a decreased stability of the
            entire
            N-module of CI and disrupted the electron transfer between two iron-sulfur
            clusters

# ============================================================
# KEY EXPERIMENTAL ANNOTATIONS - Electron transport (IMP)
# ============================================================
  - term:
      id: GO:0006120
      label: mitochondrial electron transport, NADH to ubiquinone
    evidence_type: IMP
    original_reference_id: PMID:31557978
    review:
      summary: >-
        IMP annotation from Ni et al. (2019). NDUFS1 mutations disrupt electron transfer
        within Complex I, specifically between iron-sulfur clusters N4 and N5. Seahorse
        respiration assays showed basal respiration, ATP-linked respiration, maximal
        respiration, and spare respiratory capacity were all less than 50% of controls.
      action: ACCEPT
      reason: >-
        Core biological process annotation. Direct experimental evidence that NDUFS1
        mutations
        impair mitochondrial electron transport from NADH to ubiquinone. The electron
        tunneling
        calculations provide mechanistic insight into how NDUFS1 mediates this process.
      supported_by:
        - reference_id: PMID:31557978
          supporting_text: >-
            the basal respiration, ATP-linked respiration, maximal respiration, and
            the
            spare
            respiration capacity were less than 50% compared with controls

# ============================================================
# Protein binding from key functional studies
# ============================================================
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:30879903
    review:
      summary: >-
        IPI annotation for NDUFS1 interaction with MDM2 (Q00987) from Elkholi et al.
        (2019).
        MDM2 directly binds and sequesters NDUFS1, preventing its mitochondrial localization.
        This is a biologically significant regulatory interaction -- MDM2's amino-terminal
        region is sufficient to bind NDUFS1, alter supercomplex assembly, and induce
        apoptosis.
        The interaction is independent of p53. However, 'protein binding' is uninformative.
      action: KEEP_AS_NON_CORE
      reason: >-
        The MDM2-NDUFS1 interaction is biologically significant (MDM2 regulates Complex
        I
        through NDUFS1), but it represents a regulatory interaction, not a core molecular
        function of NDUFS1. 'Protein binding' is uninformative as a GO term.
      supported_by:
        - reference_id: PMID:30879903
          supporting_text: >-
            MDM2 directly binds and sequesters NDUFS1, preventing its mitochondrial
            localization
            and ultimately causing complex I and supercomplex destabilization
  - term:
      id: GO:0005739
      label: mitochondrion
    evidence_type: IDA
    original_reference_id: PMID:30879903
    review:
      summary: >-
        IDA annotation for mitochondrial localization from Elkholi et al. (2019).
        This
        study
        used subcellular fractionation and immunoblotting to demonstrate NDUFS1 mitochondrial
        localization, as well as showing that MDM2 prevents NDUFS1 from reaching mitochondria.
      action: ACCEPT
      reason: >-
        Direct experimental evidence for mitochondrial localization, consistent with
        all other
        data.
      supported_by:
        - reference_id: PMID:30879903
          supporting_text: >-
            MDM2 directly binds and sequesters NDUFS1, preventing its mitochondrial
            localization
  - term:
      id: GO:0032981
      label: mitochondrial respiratory chain complex I assembly
    evidence_type: IMP
    original_reference_id: PMID:30879903
    review:
      summary: >-
        IMP annotation from Elkholi et al. (2019). MDM2-mediated sequestration of
        NDUFS1
        caused complex I and supercomplex destabilization, demonstrating NDUFS1's
        role
        in
        assembly and stability of Complex I.
      action: ACCEPT
      reason: >-
        IMP evidence showing that preventing NDUFS1 mitochondrial localization (via
        MDM2
        sequestration) destabilizes Complex I assembly and supercomplexes.
      supported_by:
        - reference_id: PMID:30879903
          supporting_text: >-
            MDM2 directly binds and sequesters NDUFS1, preventing its mitochondrial
            localization
            and ultimately causing complex I and supercomplex destabilization
  - term:
      id: GO:0032981
      label: mitochondrial respiratory chain complex I assembly
    evidence_type: IMP
    original_reference_id: PMID:31557978
    review:
      summary: >-
        IMP annotation from Ni et al. (2019). NDUFS1 mutations led to decreased stability
        of the entire N-module and impaired supercomplex formation. BN-PAGE showed
        only
        a
        small fraction of supercomplexes were formed compared to controls.
      action: ACCEPT
      reason: >-
        Strong IMP evidence. Mutations in NDUFS1 specifically destabilize the N-module
        of
        Complex I and prevent proper supercomplex formation.
      supported_by:
        - reference_id: PMID:31557978
          supporting_text: >-
            Only a small fraction of supercomplexes were formed compared to controls

# ============================================================
# Reactome TAS annotations - mitochondrial matrix
# ============================================================
  - term:
      id: GO:0005759
      label: mitochondrial matrix
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-163217
    review:
      summary: >-
        TAS annotation from Reactome for mitochondrial matrix localization, based
        on
        the
        Complex I NADH oxidation reaction. NDUFS1 is a peripheral membrane protein
        on
        the
        matrix side of Complex I. UniProt states NDUFS1 is on the matrix side of the
        inner
        membrane.
      action: ACCEPT
      reason: >-
        Correct. NDUFS1 is in the peripheral arm of Complex I facing the mitochondrial
        matrix.
        This is the most specific correct localization for NDUFS1.
  - term:
      id: GO:0005759
      label: mitochondrial matrix
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-6788523
    review:
      summary: >-
        TAS annotation from Reactome for mitochondrial matrix localization, associated
        with
        NUBPL-mediated 4Fe-4S cluster transfer to Complex I subunits. NDUFS1 receives
        its
        Fe-S clusters in the mitochondrial matrix.
      action: ACCEPT
      reason: >-
        Correct. Fe-S cluster insertion into NDUFS1 occurs in the mitochondrial matrix.
  - term:
      id: GO:0005759
      label: mitochondrial matrix
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-6799179
    review:
      summary: >-
        TAS from Reactome for matrix localization, associated with peripheral arm
        subunits
        binding to the 815 kDa complex to form a 980 kDa complex during Complex I
        assembly.
      action: ACCEPT
      reason: >-
        Correct. Assembly intermediates involving NDUFS1 form in the mitochondrial
        matrix.
  - term:
      id: GO:0005759
      label: mitochondrial matrix
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-6799196
    review:
      summary: >-
        TAS from Reactome for matrix localization, associated with the MCIA complex
        and
        NDUFAF2-7 dissociation from the 980 kDa complex to yield mature Complex I.
      action: ACCEPT
      reason: >-
        Correct. Final assembly steps involving NDUFS1 occur in the mitochondrial
        matrix.
  - term:
      id: GO:0005759
      label: mitochondrial matrix
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-6800870
    review:
      summary: >-
        TAS from Reactome for matrix localization, associated with NDUF subunits binding
        to
        form the FP subcomplex.
      action: ACCEPT
      reason: >-
        Correct. The FP (flavoprotein) subcomplex of the N-module forms in the mitochondrial
        matrix.
  - term:
      id: GO:0005759
      label: mitochondrial matrix
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-9838035
    review:
      summary: >-
        TAS from Reactome for matrix localization, associated with CLPXP binding mitochondrial
        matrix proteins. This reflects the general mitochondrial matrix localization
        of NDUFS1
        in the context of mitochondrial quality control/protein degradation.
      action: ACCEPT
      reason: >-
        Correct. NDUFS1 is a matrix protein subject to mitochondrial quality control.
  - term:
      id: GO:0005759
      label: mitochondrial matrix
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-9838081
    review:
      summary: >-
        TAS from Reactome for matrix localization, associated with LONP1 degradation
        of
        mitochondrial matrix proteins. Reflects NDUFS1 as a LONP1 substrate in the
        matrix.
      action: ACCEPT
      reason: >-
        Correct. NDUFS1 is a mitochondrial matrix protein and potential substrate
        for
        LONP1
        protease.
  - term:
      id: GO:0005759
      label: mitochondrial matrix
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-9838093
    review:
      summary: >-
        TAS from Reactome for matrix localization, associated with LONP1 binding mitochondrial
        matrix proteins.
      action: ACCEPT
      reason: >-
        Correct and consistent with other matrix localization annotations.
  - term:
      id: GO:0005759
      label: mitochondrial matrix
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-9838289
    review:
      summary: >-
        TAS from Reactome for matrix localization, associated with CLPXP degradation
        of
        mitochondrial matrix proteins.
      action: ACCEPT
      reason: >-
        Correct and consistent with other matrix localization annotations.

# ============================================================
# NADH dehydrogenase activity with contributes_to qualifier (IMP)
# ============================================================
  - term:
      id: GO:0008137
      label: NADH dehydrogenase (ubiquinone) activity
    evidence_type: IMP
    original_reference_id: PMID:15824269
    qualifier: contributes_to
    review:
      summary: >-
        IMP annotation with 'contributes_to' qualifier from Martin et al. (2005).
        This
        study
        identified a novel homozygous L231V mutation in NDUFS1 in a patient with Leigh
        syndrome
        and Complex I deficiency. Muscle biochemistry showed a Complex I defect. The
        'contributes_to' qualifier is appropriate for a subunit contribution to the
        complex-level
        activity.
      action: ACCEPT
      reason: >-
        Valid IMP evidence. NDUFS1 mutation causes Complex I deficiency, demonstrating
        that
        NDUFS1 contributes to the NADH dehydrogenase activity. The 'contributes_to'
        qualifier
        is the correct usage for a subunit of a multi-protein enzyme complex.
      supported_by:
        - reference_id: PMID:15824269
          supporting_text: >-
            RESULTS: Muscle biochemistry results showed a complex I defect of the
            mitochondrial respiratory chain.
  - term:
      id: GO:0008137
      label: NADH dehydrogenase (ubiquinone) activity
    evidence_type: IMP
    original_reference_id: PMID:16870178
    qualifier: contributes_to
    review:
      summary: >-
        IMP annotation with 'contributes_to' qualifier from Piccoli et al. (2006).
        This
        study
        showed that a genetic defect in the 75 kDa Fe-S protein subunit (NDUFS1) of
        Complex I
        resulted in inhibition of complex activity and enhanced ROS production, which
        were
        reversed by cAMP.
      action: ACCEPT
      reason: >-
        Valid IMP evidence. NDUFS1 defect causes Complex I activity inhibition and
        ROS
        production. The 'contributes_to' qualifier is appropriate.
      supported_by:
        - reference_id: PMID:16870178
          supporting_text: >-
            In fibroblasts from a patient a genetic defect in the 75 kDa FeS-protein
            subunit
            of complex I resulted in inhibition of the activity of the complex and
            enhanced
            ROS production, which were reversed by cAMP
  - term:
      id: GO:0008137
      label: NADH dehydrogenase (ubiquinone) activity
    evidence_type: IMP
    original_reference_id: PMID:16478720
    qualifier: contributes_to
    review:
      summary: >-
        IMP annotation with 'contributes_to' qualifier from Iuso et al. (2006). The
        Q522K
        mutation in NDUFS1 caused marked but not complete inhibition of Complex I
        activity.
      action: ACCEPT
      reason: >-
        Valid IMP evidence showing that NDUFS1 mutation impairs Complex I activity.
        The
        'contributes_to' qualifier is appropriate.
      supported_by:
        - reference_id: PMID:16478720
          supporting_text: >-
            The mutation (Q522K replacement) in NDUFS1 gene, coding for the 75-kDa
            Fe-S
            subunit
            of the complex, was associated with (a) reduced level of the mature complex,
            (b)
            marked, albeit not complete, inhibition of the activity

# ============================================================
# Protein binding and localization from Ricci et al. 2004 (caspase cleavage)
# ============================================================
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:15186778
    review:
      summary: >-
        IPI annotation for NDUFS1 interaction with NDUFS3 (O75251) from Ricci et al.
        (2004).
        This study identified NDUFS1 as a critical caspase substrate in the mitochondria
        during
        apoptosis. The interaction with NDUFS3 reflects that both are Complex I subunits
        (NDUFS3 is in the Q-module adjacent to the N-module). 'Protein binding' is
        uninformative.
      action: KEEP_AS_NON_CORE
      reason: >-
        The NDUFS1-NDUFS3 interaction reflects inter-subunit contacts within Complex
        I.
        'Protein binding' is uninformative. The interaction is already captured by
        GO:0045271.
  - term:
      id: GO:0005758
      label: mitochondrial intermembrane space
    evidence_type: IDA
    original_reference_id: PMID:15186778
    review:
      summary: >-
        IDA annotation for mitochondrial intermembrane space localization from Ricci
        et al.
        (2004). This study showed that cleaved NDUFS1 fragments are released into
        the
        intermembrane space during apoptosis after caspase cleavage. The uncleaved,
        functional
        NDUFS1 is located on the matrix side of the inner membrane. This annotation
        likely
        refers to the detection of NDUFS1 (or its fragments) in the IMS context during
        apoptosis, which is not the normal steady-state localization. The normal localization
        is the matrix face of Complex I.
      action: KEEP_AS_NON_CORE
      reason: >-
        NDUFS1 detection in the intermembrane space likely reflects the apoptotic
        context
        (caspase cleavage releasing fragments). The steady-state localization of functional
        NDUFS1 is the mitochondrial matrix face. This annotation is not wrong but
        reflects
        a non-standard, apoptosis-specific context.
      supported_by:
        - reference_id: PMID:15186778
          supporting_text: >-
            we identify NDUFS1, the 75 kDa subunit of respiratory complex I, as a
            critical
            caspase substrate in the mitochondria
  - term:
      id: GO:0045333
      label: cellular respiration
    evidence_type: IMP
    original_reference_id: PMID:15186778
    review:
      summary: >-
        IMP annotation from Ricci et al. (2004). This study showed that cells expressing
        a
        noncleavable mutant of p75/NDUFS1 sustain mitochondrial membrane potential
        and
        ATP
        levels during apoptosis, demonstrating NDUFS1's role in maintaining cellular
        respiration. This is a correct broader process annotation for NDUFS1.
      action: ACCEPT
      reason: >-
        Valid IMP evidence. Noncleavable NDUFS1 sustains respiration during apoptosis,
        directly demonstrating NDUFS1's role in cellular respiration.
      supported_by:
        - reference_id: PMID:15186778
          supporting_text: >-
            Cells expressing a noncleavable mutant of p75 sustain DeltaPsim and ATP
            levels
            during apoptosis, and ROS production in response to apoptotic stimuli
            is dampened

# ============================================================
# NAS annotations from early characterization
# ============================================================
  - 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). This study completed the characterization
        of human Complex I cDNAs and discussed the complex's function in electron
        transport
        from NADH to ubiquinone.
      action: ACCEPT
      reason: >-
        Correct core biological process. Consistent with the IMP annotation from PMID:31557978
        for the same term.
      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) for NADH dehydrogenase activity.
        This
        study
        discusses Complex I's overall enzymatic function.
      action: ACCEPT
      reason: >-
        Correct. Consistent with multiple IMP and IBA annotations for this term.
      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:0009055
      label: electron transfer activity
    evidence_type: NAS
    original_reference_id: PMID:1935949
    review:
      summary: >-
        NAS annotation from Chow et al. (1991), the original study determining the
        cDNA
        sequence for the human 75 kDa Fe-S protein. The title itself identifies NDUFS1
        as
        a "Fe-S protein of NADH-coenzyme Q reductase," establishing its electron transfer
        function via Fe-S clusters. This is the core subunit-specific molecular function.
      action: ACCEPT
      reason: >-
        Core molecular function annotation. The original characterization of NDUFS1
        identified
        it as an iron-sulfur protein, establishing its role in electron transfer.
        This
        is the
        most appropriate subunit-specific MF for NDUFS1.
      supported_by:
        - reference_id: PMID:1935949
          supporting_text: >-
            Determination of the cDNA sequence for the human mitochondrial 75-kDa
            Fe-S
            protein
            of NADH-coenzyme Q reductase
# ============================================================
# NOTE: GO:0005747 (mitochondrial respiratory chain complex I) is OBSOLETE.
# GO:0045271 (respiratory chain complex I) is the correct active term and is
# already well-annotated above with IDA, IMP, NAS, and IEA evidence.
# No NEW annotations needed.
# ============================================================
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:0000052
    title: Gene Ontology annotation based on curation of immunofluorescence data
    findings: []
  - id: GO_REF:0000107
    title: Automatic transfer of experimentally verified manual GO annotation data
      to orthologs using Ensembl Compara
    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:1935949
    title: Determination of the cDNA sequence for the human mitochondrial 75-kDa Fe-S
      protein of NADH-coenzyme Q reductase.
    findings:
      - statement: >-
          Original characterization of NDUFS1 cDNA, establishing it as the 75 kDa
          Fe-S
          protein
          of the NADH-coenzyme Q reductase complex with homology to bacterial enzymes.
        supporting_text: >-
          It proved to be highly similar to the cDNA sequence for the bovine 75-kDa
          Fe--S
          protein.
  - id: PMID:9878551
    title: 'cDNA of eight nuclear encoded subunits of NADH:ubiquinone oxidoreductase:
      human complex I cDNA characterization completed.'
    findings:
      - statement: >-
          Completion of the characterization of all nuclear-encoded Complex I subunit
          cDNAs,
          establishing the full subunit composition of human Complex I (41 subunits
          at
          the time).
        supporting_text: >-
          Now all currently known 41 proteins of human NADH:ubiquinone oxidoreductase
          have been
          characterized and reported in literature, which enables more complete mutational
          analysis studies of isolated complex I-deficient patients.
  - id: PMID:12611891
    title: The subunit composition of the human NADH dehydrogenase obtained by rapid
      one-step immunopurification.
    findings:
      - statement: >-
          Direct identification of NDUFS1 as a subunit of immunopurified human Complex
          I by
          mass spectrometry, confirming 42 subunits in the complex.
        supporting_text: >-
          Using small amounts of immunoisolated protein, one-dimensional and two-dimensional
          gel electrophoresis, matrix-assisted laser desorption ionization time-of-flight
          (MALDI-TOF) peptide mass finger printing (PMF), and nanoflow liquid chromatography
          mass spectrometry/mass spectrometry (LC-MS/MS), we can resolve and identify
          the
          human homologues of 42 polypeptides detected so far in the more extensively
          studied
          beef heart complex I.
  - id: PMID:15186778
    title: Disruption of mitochondrial function during apoptosis is mediated by caspase
      cleavage of the p75 subunit of complex I of the electron transport chain.
    findings:
      - statement: >-
          NDUFS1 (p75) is a critical caspase substrate in mitochondria. Caspase cleavage
          of
          NDUFS1 during apoptosis disrupts electron transport, causes loss of membrane
          potential,
          and promotes ROS production. Cells expressing noncleavable NDUFS1 sustain
          respiration
          during apoptosis.
        supporting_text: >-
          Here, we identify NDUFS1, the 75 kDa subunit of respiratory complex I, as
          a
          critical
          caspase substrate in the mitochondria.
  - id: PMID:15824269
    title: Leigh syndrome associated with mitochondrial complex I deficiency due to
      a novel mutation in the NDUFS1 gene.
    findings:
      - statement: >-
          A novel homozygous L231V mutation in NDUFS1 causes Leigh syndrome with isolated
          Complex I deficiency in muscle.
        supporting_text: >-
          RESULTS: Muscle biochemistry results showed a complex I defect of the mitochondrial
          respiratory chain.
  - id: PMID:16478720
    title: Dysfunctions of cellular oxidative metabolism in patients with mutations
      in the NDUFS1 and NDUFS4 genes of complex I.
    findings:
      - statement: >-
          NDUFS1 Q522K mutation causes reduced Complex I assembly, marked activity
          inhibition,
          mitochondrial ROS accumulation, decreased glutathione, and enhanced susceptibility
          to oxidative damage. cAMP treatment partially restored activity and eliminated
          ROS.
        supporting_text: >-
          The mutation (Q522K replacement) in NDUFS1 gene, coding for the 75-kDa Fe-S
          subunit
          of the complex, was associated with (a) reduced level of the mature complex,
          (b)
          marked, albeit not complete, inhibition of the activity, (c) accumulation
          of
          H(2)O(2) and O(2)(.-) in mitochondria, (d) decreased cellular content of
          glutathione, (e) enhanced expression and activity of glutathione peroxidase,
          and
          (f) decrease of the mitochondrial potential and enhanced mitochondrial susceptibility
          to reactive oxygen species (ROS) damage
  - id: PMID:16870178
    title: cAMP controls oxygen metabolism in mammalian cells.
    findings:
      - statement: >-
          A genetic defect in the NDUFS1 75 kDa Fe-S protein subunit inhibits Complex
          I
          activity and enhances ROS production, both reversible by cAMP.
        supporting_text: >-
          In fibroblasts from a patient a genetic defect in the 75 kDa FeS-protein
          subunit
          of
          complex I resulted in inhibition of the activity of the complex and enhanced
          ROS
          production, which were reversed by cAMP.
  - 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 study mapping Complex I subunit and assembly factor
          associations.
          NDUFS1 interacts with NDUFA9 and other Complex I subunits.
        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 (edges).
  - 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,
          revealing the precise assignment of all CI subunits including NDUFS1 in
          the
          peripheral
          arm.
        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.
  - id: PMID:29128334
    title: A Map of Human Mitochondrial Protein Interactions Linked to Neurodegeneration
      Reveals New Mechanisms of Redox Homeostasis and NF-κB Signaling.
    findings:
      - statement: >-
          Large-scale mitochondrial protein interaction map. Detected NDUFS1-SOAT1
          interaction.
        supporting_text: >-
          we report a high-confidence MP network including 1,964 interactions among
          772
          proteins
  - id: PMID:30030361
    title: Assembly of mammalian oxidative phosphorylation complexes I-V and supercomplexes.
    findings:
      - statement: >-
          Comprehensive review of OXPHOS complex assembly. Complex I assembly is a
          stepwise
          process involving multiple assembly factors. The N-module containing NDUFS1
          is added
          late in the assembly pathway.
        supporting_text: >-
          The assembly of the five oxidative phosphorylation system (OXPHOS) complexes
          in the
          inner mitochondrial membrane is an intricate process.
  - id: PMID:30879903
    title: MDM2 Integrates Cellular Respiration and Apoptotic Signaling through NDUFS1
      and the Mitochondrial Network.
    findings:
      - statement: >-
          MDM2 directly binds and sequesters NDUFS1, preventing its mitochondrial
          localization,
          causing Complex I and supercomplex destabilization, decreased respiration,
          oxidative
          stress, and apoptosis. This is independent of p53.
        supporting_text: >-
          MDM2 negatively regulates NADH:ubiquinone oxidoreductase 75 kDa Fe-S protein
          1
          (NDUFS1), leading to decreased mitochondrial respiration, marked oxidative
          stress,
          and commitment to the mitochondrial pathway of apoptosis.
  - id: PMID:31557978
    title: Mutations in NDUFS1 Cause Metabolic Reprogramming and Disruption of the
      Electron Transfer.
    findings:
      - statement: >-
          NDUFS1 biallelic mutations (V228A and D252G) lead to decreased N-module
          stability,
          disrupted electron transfer between Fe-S clusters N4 and N5, impaired Complex
          I
          assembly, loss of enzymatic activity, and metabolic reprogramming with altered
          glutathione levels indicative of ROS stress. Val228 is critical for electron
          tunneling
          between N4 and N5 clusters (35-fold reduction in tunneling rate upon V228A
          mutation).
        supporting_text: >-
          the biallelic mutations in NDUFS1 led to a decreased stability of the entire
          N-module
          of CI and disrupted the electron transfer between two iron-sulfur clusters.
  - id: PMID:32807793
    title: OSMR controls glioma stem cell respiration and confers resistance of glioblastoma
      to ionizing radiation.
    findings:
      - statement: >-
          OSMR interacts with NDUFS1/NDUFS2 in the mitochondrial matrix and promotes
          Complex
          I
          respiration. Loss of OSMR impairs spare respiratory capacity and increases
          ROS.
        supporting_text: >-
          OSMR interacts with NADH ubiquinone oxidoreductase 1/2 (NDUFS1/2) of complex
          I and
          promotes mitochondrial respiration.
  - id: PMID:33961781
    title: Dual proteome-scale networks reveal cell-specific remodeling of the human
      interactome.
    findings:
      - statement: >-
          Large-scale proteomics study detecting NDUFS1-NDUFA9 interaction as part
          of
          Complex I subunit interactions.
        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: >-
          NDUFS1 identified as a high-confidence mitochondrial protein in quantitative
          proteomics study.
        supporting_text: >-
          We classified >8,000 proteins in mitochondrial preparations of human cells
          and
          defined a mitochondrial high-confidence proteome of >1,100 proteins (MitoCoP).
  - id: PMID:40205054
    title: Multimodal cell maps as a foundation for structural and functional genomics.
    findings:
      - statement: >-
          Large-scale multimodal cell mapping study detecting NDUFS1-NDUFA9 interaction.
        supporting_text: >-
          Here we construct a global map of human subcellular architecture through
          joint
          measurement of biophysical interactions and immunofluorescence images for
          over
          5,100 proteins in U2OS osteosarcoma cells.
  - id: Reactome:R-HSA-163217
    title: Complex I oxidises NADH to NAD+, reduces CoQ to CoQH2
    findings: []
  - id: Reactome:R-HSA-6788523
    title: NUBPL transfers 4Fe-4S to Complex I subunits
    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-9838035
    title: CLPXP binds mitochondrial matrix proteins
    findings: []
  - id: Reactome:R-HSA-9838081
    title: LONP1 degrades mitochondrial matrix proteins
    findings: []
  - id: Reactome:R-HSA-9838093
    title: LONP1 binds mitochondrial matrix proteins
    findings: []
  - id: Reactome:R-HSA-9838289
    title: CLPXP degrades mitochondrial matrix proteins
    findings: []
  - id: file:human/NDUFS1/NDUFS1-deep-research-falcon.md
    title: Deep research review of NDUFS1 gene function (Falcon provider)
    findings:
      - statement: >-
          NDUFS1 is a core subunit of the N-module of Complex I containing Fe-S clusters
          essential for electron transfer. Structural studies place NDUFS1 at the
          N/Q-module
          interface. Mutations cause Complex I deficiency and Leigh syndrome spectrum
          disorders.
        supporting_text: >-
          NDUFS1 encodes the NADH:ubiquinone oxidoreductase 75 kDa core subunit of
          mitochondrial complex I in Homo sapiens. It is a core subunit of the hydrophilic
          N-module of complex I, positioned where NADH oxidation and iron-sulfur Fe-S
          chain
          electron transfer occur.
core_functions:
  - 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
      - id: GO:0032981
        label: mitochondrial respiratory chain complex I assembly
    locations:
      - id: GO:0005759
        label: mitochondrial matrix
    description: >-
      NDUFS1 is the largest core subunit (75 kDa) of mitochondrial Complex I (NADH:ubiquinone
      oxidoreductase, EC 7.1.1.2), located in the N-module of the peripheral (matrix-facing)
      arm. It contains one [2Fe-2S] cluster and two [4Fe-4S] clusters that form part
      of the
      electron relay chain from FMN (bound to NDUFV1) toward the ubiquinone-binding
      Q-module.
      NDUFS1 enables electron transfer activity (GO:0009055) via its Fe-S clusters
      and
      contributes to the overall NADH dehydrogenase (ubiquinone) activity (GO:0008137)
      of the
      45-subunit Complex I holoenzyme. NDUFS1 is essential for N-module stability,
      Complex
      I
      assembly, and supercomplex formation. Mutations in NDUFS1 disrupt electron tunneling
      between Fe-S clusters N4 and N5, destabilize the N-module, and cause mitochondrial
      Complex I deficiency (MC1DN5) with Leigh syndrome spectrum phenotypes.
    supported_by:
      - reference_id: PMID:31557978
        supporting_text: >-
          NDUFS1, encodes the NADH-ubiquinone oxidoreductase 75 kDa subunit, the largest
          subunit of CI that accommodates three iron-sulfur clusters in the N-module,
          which
          binds and oxidizes NADH
      - reference_id: PMID:30879903
        supporting_text: >-
          MDM2 directly binds and sequesters NDUFS1, preventing its mitochondrial
          localization
          and ultimately causing complex I and supercomplex destabilization and inefficiency
          of
          oxidative phosphorylation
      - reference_id: PMID:1935949
        supporting_text: >-
          Determination of the cDNA sequence for the human mitochondrial 75-kDa Fe-S
          protein
          of
          NADH-coenzyme Q reductase
    in_complex:
      id: GO:0045271
      label: respiratory chain complex I