id: O00217
gene_symbol: NDUFS8
product_type: PROTEIN
status: INITIALIZED
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: NDUFS8 (TYKY subunit; Complex I-23kDa) is a nuclear-encoded core catalytic
  subunit of mitochondrial respiratory Complex I (NADH:ubiquinone oxidoreductase, EC
  7.1.1.2). It is a component of the iron-sulfur (IP) peripheral arm of the complex and
  coordinates two [4Fe-4S] clusters (N6a and N6b) through two ferredoxin-type domains;
  these clusters form part of the intramolecular electron-transfer wire that carries
  electrons from NADH toward ubiquinone. NDUFS8 is essential both for Complex I catalytic
  activity and for its assembly/stability. The protein is imported into mitochondria
  (cleavable transit peptide) and resides in the mitochondrial inner membrane as a
  peripheral membrane protein on the matrix side. It is highly conserved from bacteria
  (NuoI) to humans and is ubiquitously expressed, with highest levels in heart and
  skeletal muscle. Recessive loss-of-function mutations cause mitochondrial complex I
  deficiency (MC1DN2) and Leigh syndrome.
existing_annotations:
- term:
    id: GO:0003954
    label: NADH dehydrogenase activity
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: contributes_to
  review:
    summary: Phylogenetic (IBA) annotation that NDUFS8 contributes to NADH dehydrogenase
      activity as part of Complex I. NADH oxidation is a property of the assembled
      complex; the contributes_to qualifier correctly reflects that no single subunit
      catalyzes the reaction alone.
    action: ACCEPT
    reason: Consistent with NDUFS8 being a core subunit of the NADH:ubiquinone
      oxidoreductase; the contributes_to qualifier is appropriate for a whole-complex
      activity.
    supported_by:
    - reference_id: file:human/NDUFS8/NDUFS8-uniprot.txt
      supporting_text: Core subunit of the mitochondrial membrane respiratory chain
        NADH dehydrogenase (Complex I) which catalyzes electron transfer from
        NADH through the respiratory chain, using ubiquinone as an electron
        acceptor
- term:
    id: GO:0006120
    label: mitochondrial electron transport, NADH to ubiquinone
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: Phylogenetic (IBA) annotation to the core Complex I biological process,
      electron transport from NADH to ubiquinone. This is the central function of the
      complex to which NDUFS8 contributes as an Fe-S-carrying core subunit.
    action: ACCEPT
    reason: Directly represents NDUFS8's role in the NADH-to-ubiquinone electron
      transfer chain; strongly supported across orthologs and by literature.
    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:0045271
    label: respiratory chain complex I
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: part_of
  review:
    summary: Phylogenetic (IBA) annotation placing NDUFS8 as part of respiratory chain
      complex I. This is the correct cellular-component/complex assignment.
    action: ACCEPT
    reason: NDUFS8 is a well-established core subunit of Complex I in all organisms
      examined; complex membership is confirmed structurally and biochemically.
    supported_by:
    - reference_id: file:human/NDUFS8/NDUFS8-uniprot.txt
      supporting_text: Core subunit of respiratory chain NADH dehydrogenase (Complex
        I) which is composed of 45 different subunits
- term:
    id: GO:0005743
    label: mitochondrial inner membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: located_in
  review:
    summary: Electronic annotation to mitochondrial inner membrane, the correct
      anatomical location of NDUFS8 as a peripheral inner-membrane subunit of Complex I
      on the matrix side.
    action: ACCEPT
    reason: Matches UniProt subcellular location (inner membrane, peripheral, matrix
      side) and the location of the assembled complex; supported by an independent IDA
      annotation (PMID:28844695).
    supported_by:
    - reference_id: file:human/NDUFS8/NDUFS8-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Mitochondrion inner membrane'
- term:
    id: GO:0008137
    label: NADH dehydrogenase (ubiquinone) activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: enables
  review:
    summary: Electronic annotation (RHEA:29091 / EC:7.1.1.2) to the Complex I catalytic
      activity, matching the UniProt CATALYTIC ACTIVITY and EC assignment. This is the
      core molecular function of the complex to which NDUFS8 belongs.
    action: ACCEPT
    reason: The RHEA/EC-based reaction is exactly the Complex I reaction; NDUFS8 is a
      core subunit carrying Fe-S clusters of the electron-transfer wire. Supported by
      IMP (PMID:22499348) showing NDUFS8 variants impair enzyme activity.
    supported_by:
    - reference_id: file:human/NDUFS8/NDUFS8-uniprot.txt
      supporting_text: a ubiquinone + NADH + 5 H(+)(in) = a ubiquinol + NAD(+) + 4
- term:
    id: GO:0016020
    label: membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: located_in
  review:
    summary: InterPro-based electronic annotation to the generic term membrane. This is
      correct but far less informative than the specific mitochondrial inner membrane
      localization already annotated.
    action: MODIFY
    reason: Too general; NDUFS8 localizes specifically to the mitochondrial inner
      membrane, which is already annotated (GO:0005743). Replace the generic term with
      the specific one.
    proposed_replacement_terms:
    - id: GO:0005743
      label: mitochondrial inner membrane
    supported_by:
    - reference_id: file:human/NDUFS8/NDUFS8-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Mitochondrion inner membrane'
- term:
    id: GO:0016651
    label: oxidoreductase activity, acting on NAD(P)H
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: enables
  review:
    summary: InterPro-based electronic annotation to a parent oxidoreductase term. It is
      not wrong but is a generalization of the specific Complex I activity.
    action: MODIFY
    reason: The specific activity, NADH dehydrogenase (ubiquinone) activity (GO:0008137),
      is already annotated and better represents the function; generalize/replace with
      the specific child term.
    proposed_replacement_terms:
    - id: GO:0008137
      label: NADH dehydrogenase (ubiquinone) activity
    supported_by:
    - reference_id: file:human/NDUFS8/NDUFS8-uniprot.txt
      supporting_text: a ubiquinone + NADH + 5 H(+)(in) = a ubiquinol + NAD(+) + 4
- term:
    id: GO:0051539
    label: 4 iron, 4 sulfur cluster binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: enables
  review:
    summary: InterPro-based electronic annotation to [4Fe-4S] cluster binding. NDUFS8
      contains two 4Fe-4S ferredoxin-type domains and binds two [4Fe-4S] clusters that
      form part of the electron-transfer wire of Complex I. This is a genuine core
      molecular function of the subunit.
    action: ACCEPT
    reason: Strongly supported - UniProt annotates two 4Fe-4S ferredoxin-type domains and
      eight cysteine ligands coordinating two [4Fe-4S] clusters; historically the TYKY
      ferredoxin patterns were thought to bind cluster N-2 (PMID:9837812).
    supported_by:
    - reference_id: file:human/NDUFS8/NDUFS8-uniprot.txt
      supporting_text: Note=Binds 2 [4Fe-4S] cluster.
    - reference_id: PMID:9837812
      supporting_text: contains two 4Fe4S ferredoxin consensus patterns, which have
        long been thought to provide the binding site for the iron-sulfur cluster N-2
- term:
    id: GO:1902600
    label: proton transmembrane transport
  evidence_type: IEA
  original_reference_id: GO_REF:0000108
  qualifier: involved_in
  review:
    summary: Electronic annotation inferred logically from the Complex I catalytic
      activity (GO:0008137). While Complex I as a whole is a proton pump, the proton
      translocation is performed by the membrane-arm ND subunits, not by the
      IP-fragment TYKY subunit that carries the Fe-S clusters.
    action: MARK_AS_OVER_ANNOTATED
    reason: NDUFS8 is a peripheral-arm iron-sulfur subunit; proton pumping is a property
      of the membrane arm (ND2/ND4/ND5, NDUFB/NDUFA modules). Assigning
      proton-transmembrane-transport directly to this subunit over-attributes a
      whole-complex/membrane-arm activity to a non-transporting electron-carrier subunit.
    supported_by:
    - reference_id: file:human/NDUFS8/NDUFS8-uniprot.txt
      supporting_text: This is a component of the iron-sulfur (IP) fragment of the
        enzyme
- term:
    id: GO:0045271
    label: respiratory chain complex I
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: part_of
  review:
    summary: Electronic (ARBA/ortholog-based) annotation of Complex I membership,
      redundant with the well-supported experimental and phylogenetic annotations to the
      same term.
    action: ACCEPT
    reason: Correct complex membership; consistent with experimental IDA/IMP/IPI
      annotations to GO:0045271.
    supported_by:
    - reference_id: file:human/NDUFS8/NDUFS8-uniprot.txt
      supporting_text: Core subunit of respiratory chain NADH dehydrogenase (Complex
        I) which is composed of 45 different subunits
- term:
    id: GO:0005743
    label: mitochondrial inner membrane
  evidence_type: IDA
  original_reference_id: PMID:28844695
  qualifier: located_in
  review:
    summary: ComplexPortal IDA localizing NDUFS8 to the mitochondrial inner membrane,
      based on the cryo-EM structure of the human respiratory megacomplex I2III2IV2 in
      which individual Complex I subunits were assigned.
    action: ACCEPT
    reason: Direct structural assignment of Complex I subunits in the inner membrane;
      matches UniProt subcellular location.
    supported_by:
    - reference_id: PMID:28844695
      supporting_text: The structure not only reveals the precise assignment of
        individual subunits of human CI and CIII
- term:
    id: GO:0009060
    label: aerobic respiration
  evidence_type: NAS
  original_reference_id: PMID:30030361
  qualifier: involved_in
  review:
    summary: ComplexPortal NAS annotation placing Complex I (and thus NDUFS8) in aerobic
      respiration. This is a correct but high-level pathway process describing the role
      of the whole OXPHOS system rather than NDUFS8's direct molecular activity.
    action: KEEP_AS_NON_CORE
    reason: True at the pathway level but broader than the core electron-transport
      function; retain as a non-core process annotation.
    supported_by:
    - reference_id: PMID:30030361
      supporting_text: core proteins, performing the catalytic activities
- term:
    id: GO:0042776
    label: proton motive force-driven mitochondrial ATP synthesis
  evidence_type: NAS
  original_reference_id: PMID:30030361
  qualifier: involved_in
  review:
    summary: ComplexPortal NAS annotation linking Complex I to proton-motive-force-driven
      ATP synthesis. Complex I contributes to the proton-motive force, but ATP synthesis
      is carried out by Complex V; for NDUFS8 this is a downstream pathway-level role.
    action: MARK_AS_OVER_ANNOTATED
    reason: This annotation conflates Complex I's contribution to the proton motive force
      with ATP synthesis, which is carried out by Complex V (ATP synthase). NDUFS8's role
      is upstream (electron transport and proton pumping); it does not itself synthesize
      ATP, so proton motive force-driven ATP synthesis is an over-annotation.
    supported_by:
    - reference_id: PMID:30030361
      supporting_text: assembly of the five oxidative phosphorylation system (OXPHOS)
        complexes
- term:
    id: GO:0045271
    label: respiratory chain complex I
  evidence_type: IPI
  original_reference_id: PMID:28844695
  qualifier: part_of
  review:
    summary: ComplexPortal IPI (physical-interaction-based) annotation of Complex I
      membership from the cryo-EM megacomplex structure.
    action: ACCEPT
    reason: Correct complex membership, supported by the structural study; redundant
      with other GO:0045271 annotations.
    supported_by:
    - reference_id: PMID:28844695
      supporting_text: precise assignment of individual subunits of human CI and CIII
- term:
    id: GO:0005739
    label: mitochondrion
  evidence_type: HTP
  original_reference_id: PMID:34800366
  qualifier: located_in
  review:
    summary: High-throughput proteomic evidence (high-confidence human mitochondrial
      proteome) placing NDUFS8 in the mitochondrion. Correct but coarse relative to the
      inner-membrane localization.
    action: ACCEPT
    reason: Accurate organelle-level localization; consistent with the more specific
      inner-membrane annotations.
    supported_by:
    - reference_id: PMID:34800366
      supporting_text: Quantitative high-confidence human mitochondrial proteome
- term:
    id: GO:0045271
    label: respiratory chain complex I
  evidence_type: IMP
  original_reference_id: PMID:11112787
  qualifier: part_of
  review:
    summary: IMP annotation of Complex I membership from a study resolving human Complex
      I assembly defects by monoclonal antibodies, including an NDUFS8 patient.
    action: ACCEPT
    reason: Experimental support for NDUFS8 being a subunit of Complex I whose defect
      alters the complex; defer to curator who read the full text.
    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
  qualifier: part_of
  review:
    summary: IDA annotation of Complex I membership from one-step immunopurification and
      mass-spectrometric identification of the human NADH dehydrogenase subunit
      composition.
    action: ACCEPT
    reason: Direct biochemical demonstration that NDUFS8 co-purifies as a subunit of
      human Complex I.
    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: IDA
  original_reference_id: PMID:31536960
  qualifier: part_of
  review:
    summary: IDA annotation of Complex I / respirasome membership from a mitochondrial
      co-fractionation and interactome study of human cells.
    action: ACCEPT
    reason: Supports NDUFS8 as part of the respirasome/Complex I; consistent with all
      other complex-membership evidence.
    supported_by:
    - reference_id: PMID:31536960
      supporting_text: Regulators of the Respirasome and Neurogenesis
- term:
    id: GO:0045271
    label: respiratory chain complex I
  evidence_type: NAS
  original_reference_id: PMID:9878551
  qualifier: part_of
  review:
    summary: NAS annotation of Complex I membership from the cDNA characterization of
      human Complex I subunits.
    action: ACCEPT
    reason: Consistent with NDUFS8 being one of the characterized human Complex I
      subunits; redundant with stronger experimental evidence.
    supported_by:
    - reference_id: PMID:9878551
      supporting_text: Now all currently known 41 proteins of human NADH:ubiquinone
        oxidoreductase have been characterized
- term:
    id: GO:0006120
    label: mitochondrial electron transport, NADH to ubiquinone
  evidence_type: IMP
  original_reference_id: PMID:22499348
  qualifier: involved_in
  review:
    summary: IMP annotation of the core electron-transport process, based on NDUFS8
      patient variants that decrease Complex I enzyme activity, with WT cDNA rescue of
      complex I activity confirming pathogenicity.
    action: ACCEPT
    reason: Strong experimental support that NDUFS8 is required for NADH-to-ubiquinone
      electron transport (Complex I activity); a core function.
    supported_by:
    - reference_id: PMID:22499348
      supporting_text: Expression of wild-type cDNA in mutant cell lines rescued complex
        I activity and assembly, thus providing a functional validation of their
        pathogenicity.
- term:
    id: GO:0008137
    label: NADH dehydrogenase (ubiquinone) activity
  evidence_type: IMP
  original_reference_id: PMID:22499348
  qualifier: enables
  review:
    summary: IMP annotation to the Complex I catalytic activity based on NDUFS8 variants
      that reduce enzyme activity, rescued by WT cDNA. This underpins the UniProt EC
      7.1.1.2 / CATALYTIC ACTIVITY assignment for NDUFS8.
    action: ACCEPT
    reason: Experimentally supported core molecular function; NDUFS8 is required for the
      NADH:ubiquinone oxidoreductase activity of Complex I.
    supported_by:
    - reference_id: PMID:22499348
      supporting_text: rescued complex I activity and assembly, thus providing a
        functional validation of their pathogenicity
- term:
    id: GO:0032981
    label: mitochondrial respiratory chain complex I assembly
  evidence_type: IMP
  original_reference_id: PMID:22499348
  qualifier: involved_in
  review:
    summary: IMP annotation to Complex I assembly, based on NDUFS8 variants that impair
      complex I assembly, rescued by WT cDNA. UniProt notes NDUFS8 is essential for both
      catalytic activity and assembly of Complex I.
    action: ACCEPT
    reason: Experimentally supported role in Complex I assembly; a core function of this
      subunit.
    supported_by:
    - reference_id: PMID:22499348
      supporting_text: rescued complex I activity and assembly
    - reference_id: file:human/NDUFS8/NDUFS8-uniprot.txt
      supporting_text: Essential for the catalytic activity and assembly of complex I
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:31536960
  qualifier: enables
  review:
    summary: IPI annotation recording a physical interaction of NDUFS8 with RAB5IF
      (UniProtKB:Q9BUV8) detected in a mitochondrial interactome/co-fractionation study.
      Bare protein binding is uninformative about molecular function.
    action: MARK_AS_OVER_ANNOTATED
    reason: Per curation policy, the generic protein binding term does not convey a
      specific molecular function. The interaction is real but the term is uninformative;
      retain but flag as over-annotated rather than remove the experimental IPI.
    supported_by:
    - reference_id: file:human/NDUFS8/NDUFS8-uniprot.txt
      supporting_text: Interacts with RAB5IF (PubMed:31536960)
- term:
    id: GO:0005759
    label: mitochondrial matrix
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-163217
  qualifier: located_in
  review:
    summary: Reactome TAS annotation to mitochondrial matrix. NDUFS8 is an inner-membrane
      peripheral subunit facing the matrix; the matrix assignment is a coarse
      localization that is less precise than the annotated inner-membrane location.
    action: MARK_AS_OVER_ANNOTATED
    reason: UniProt places NDUFS8 as an inner-membrane peripheral protein on the matrix
      side, not a soluble matrix protein. The more informative and accurate
      inner-membrane term (GO:0005743) is already annotated; the matrix term
      over-generalizes the location.
    supported_by:
    - reference_id: file:human/NDUFS8/NDUFS8-uniprot.txt
      supporting_text: Peripheral membrane protein
- term:
    id: GO:0005759
    label: mitochondrial matrix
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-6788523
  qualifier: located_in
  review:
    summary: Reactome TAS annotation to mitochondrial matrix (from a Complex I biogenesis
      reaction). Coarse localization for an inner-membrane peripheral subunit.
    action: MARK_AS_OVER_ANNOTATED
    reason: Same rationale as the other Reactome matrix annotations; the inner-membrane
      location (GO:0005743) is more accurate and already annotated.
    supported_by:
    - reference_id: file:human/NDUFS8/NDUFS8-uniprot.txt
      supporting_text: Peripheral membrane protein
- term:
    id: GO:0005759
    label: mitochondrial matrix
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-6799178
  qualifier: located_in
  review:
    summary: Reactome TAS annotation to mitochondrial matrix (Complex I assembly
      intermediate reaction). Coarse localization for an inner-membrane peripheral
      subunit.
    action: MARK_AS_OVER_ANNOTATED
    reason: The inner-membrane location (GO:0005743) is more accurate and already
      annotated; matrix over-generalizes.
    supported_by:
    - reference_id: file:human/NDUFS8/NDUFS8-uniprot.txt
      supporting_text: Peripheral membrane protein
- term:
    id: GO:0005759
    label: mitochondrial matrix
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-6799179
  qualifier: located_in
  review:
    summary: Reactome TAS annotation to mitochondrial matrix (Complex I assembly
      reaction). Coarse localization for an inner-membrane peripheral subunit.
    action: MARK_AS_OVER_ANNOTATED
    reason: The inner-membrane location (GO:0005743) is more accurate and already
      annotated; matrix over-generalizes.
    supported_by:
    - reference_id: file:human/NDUFS8/NDUFS8-uniprot.txt
      supporting_text: Peripheral membrane protein
- term:
    id: GO:0005759
    label: mitochondrial matrix
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-6799191
  qualifier: located_in
  review:
    summary: Reactome TAS annotation to mitochondrial matrix (Complex I assembly
      reaction). Coarse localization for an inner-membrane peripheral subunit.
    action: MARK_AS_OVER_ANNOTATED
    reason: The inner-membrane location (GO:0005743) is more accurate and already
      annotated; matrix over-generalizes.
    supported_by:
    - reference_id: file:human/NDUFS8/NDUFS8-uniprot.txt
      supporting_text: Peripheral membrane protein
- term:
    id: GO:0005759
    label: mitochondrial matrix
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-6799196
  qualifier: located_in
  review:
    summary: Reactome TAS annotation to mitochondrial matrix (Complex I assembly
      reaction). Coarse localization for an inner-membrane peripheral subunit.
    action: MARK_AS_OVER_ANNOTATED
    reason: The inner-membrane location (GO:0005743) is more accurate and already
      annotated; matrix over-generalizes.
    supported_by:
    - reference_id: file:human/NDUFS8/NDUFS8-uniprot.txt
      supporting_text: Peripheral membrane protein
- term:
    id: GO:0005759
    label: mitochondrial matrix
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-6799197
  qualifier: located_in
  review:
    summary: Reactome TAS annotation to mitochondrial matrix (Complex I assembly
      reaction). Coarse localization for an inner-membrane peripheral subunit.
    action: MARK_AS_OVER_ANNOTATED
    reason: The inner-membrane location (GO:0005743) is more accurate and already
      annotated; matrix over-generalizes.
    supported_by:
    - reference_id: file:human/NDUFS8/NDUFS8-uniprot.txt
      supporting_text: Peripheral membrane protein
- term:
    id: GO:0005759
    label: mitochondrial matrix
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-6799202
  qualifier: located_in
  review:
    summary: Reactome TAS annotation to mitochondrial matrix (Complex I assembly
      reaction). Coarse localization for an inner-membrane peripheral subunit.
    action: MARK_AS_OVER_ANNOTATED
    reason: The inner-membrane location (GO:0005743) is more accurate and already
      annotated; matrix over-generalizes.
    supported_by:
    - reference_id: file:human/NDUFS8/NDUFS8-uniprot.txt
      supporting_text: Peripheral membrane protein
- term:
    id: GO:0005759
    label: mitochondrial matrix
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-6799203
  qualifier: located_in
  review:
    summary: Reactome TAS annotation to mitochondrial matrix (Complex I assembly
      reaction). Coarse localization for an inner-membrane peripheral subunit.
    action: MARK_AS_OVER_ANNOTATED
    reason: The inner-membrane location (GO:0005743) is more accurate and already
      annotated; matrix over-generalizes.
    supported_by:
    - reference_id: file:human/NDUFS8/NDUFS8-uniprot.txt
      supporting_text: Peripheral membrane protein
- term:
    id: GO:0005759
    label: mitochondrial matrix
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-6800868
  qualifier: located_in
  review:
    summary: Reactome TAS annotation to mitochondrial matrix (IP subcomplex formation
      reaction). Coarse localization for an inner-membrane peripheral subunit.
    action: MARK_AS_OVER_ANNOTATED
    reason: The inner-membrane location (GO:0005743) is more accurate and already
      annotated; matrix over-generalizes.
    supported_by:
    - reference_id: file:human/NDUFS8/NDUFS8-uniprot.txt
      supporting_text: Peripheral membrane protein
- term:
    id: GO:0032981
    label: mitochondrial respiratory chain complex I assembly
  evidence_type: IMP
  original_reference_id: PMID:11112787
  qualifier: involved_in
  review:
    summary: IMP annotation to Complex I assembly from a study distinguishing catalytic
      versus assembly defects among Complex I patients, including an NDUFS8 case, using
      monoclonal antibodies and sucrose-gradient analysis.
    action: ACCEPT
    reason: Experimental support that NDUFS8 defects affect Complex I assembly; consistent
      with the established role of this subunit in assembly/stability.
    supported_by:
    - reference_id: PMID:11112787
      supporting_text: helps distinguish catalytic versus assembly defects and further
        distinguishes between mutations in different subunits
- term:
    id: GO:0032981
    label: mitochondrial respiratory chain complex I assembly
  evidence_type: IMP
  original_reference_id: PMID:15159508
  qualifier: involved_in
  review:
    summary: IMP annotation to Complex I assembly from a late-onset Leigh syndrome case
      with NDUFS8 mutations; Western blot showed reduced NDUFS8 and other Complex I
      subunits, indicating NDUFS8 is essential for assembly/stability of the complex.
    action: ACCEPT
    reason: Direct patient-based evidence that NDUFS8 is required for Complex I assembly
      or stability; a core function.
    supported_by:
    - reference_id: PMID:15159508
      supporting_text: this subunit is essential for either the assembly or stability of
        complex I
- term:
    id: GO:0003954
    label: NADH dehydrogenase activity
  evidence_type: IMP
  original_reference_id: PMID:14749350
  qualifier: contributes_to
  review:
    summary: IMP annotation (contributes_to) to NADH dehydrogenase activity from a
      BN-PAGE study of Complex I assembly/stability in complex I-deficient patients.
    action: ACCEPT
    reason: Consistent with NDUFS8 contributing to the whole-complex NADH dehydrogenase
      activity; the contributes_to qualifier is appropriate.
    supported_by:
    - reference_id: PMID:14749350
      supporting_text: an important decrease in the levels of intact complex I in
        patients harboring mutations in nuclear-encoded complex I subunits
- term:
    id: GO:0003954
    label: NADH dehydrogenase activity
  evidence_type: IMP
  original_reference_id: PMID:15159508
  qualifier: contributes_to
  review:
    summary: IMP annotation (contributes_to) to NADH dehydrogenase activity from the
      NDUFS8 late-onset Leigh syndrome case with partial Complex I defect.
    action: ACCEPT
    reason: NDUFS8 contributes to the whole-complex NADH dehydrogenase activity, which
      is reduced in this patient; contributes_to qualifier is appropriate.
    supported_by:
    - reference_id: PMID:15159508
      supporting_text: one patient with late-onset disease and partial complex I defect
- term:
    id: GO:0005739
    label: mitochondrion
  evidence_type: IDA
  original_reference_id: PMID:9666055
  qualifier: located_in
  review:
    summary: IDA annotation localizing the TYKY (NDUFS8) subunit to mitochondria, based
      on immunodetection in placental mitochondria. Correct organelle-level localization.
    action: ACCEPT
    reason: Direct immunodetection of the mature TYKY subunit in mitochondria; consistent
      with the more specific inner-membrane annotations.
    supported_by:
    - reference_id: PMID:9666055
      supporting_text: Immunodetection of the TYKY subunit in placental mitochondria
        after two-dimensional gel electrophoresis
- term:
    id: GO:0006120
    label: mitochondrial electron transport, NADH to ubiquinone
  evidence_type: NAS
  original_reference_id: PMID:9666055
  qualifier: involved_in
  review:
    summary: NAS annotation of the core Complex I electron-transport process, based on
      characterization of the NDUFS8/TYKY subunit of the mitochondrial NADH:ubiquinone
      oxidoreductase.
    action: ACCEPT
    reason: Correct core process; redundant with the stronger IMP/IBA annotations to
      GO:0006120.
    supported_by:
    - reference_id: PMID:9666055
      supporting_text: TYKY subunit of the human mitochondrial NADH:ubiquinone
        oxidoreductase (Complex I)
- term:
    id: GO:0008137
    label: NADH dehydrogenase (ubiquinone) activity
  evidence_type: IMP
  original_reference_id: PMID:9837812
  qualifier: contributes_to
  review:
    summary: IMP annotation (contributes_to) to the Complex I catalytic activity from the
      first report of a nuclear-encoded Complex I (NDUFS8) mutation causing Leigh
      syndrome with isolated complex I deficiency.
    action: ACCEPT
    reason: NDUFS8 contributes to the NADH:ubiquinone oxidoreductase activity, which is
      deficient in these patients; contributes_to is appropriate for a whole-complex
      activity.
    supported_by:
    - reference_id: PMID:9837812
      supporting_text: two compound heterozygous transitions in a patient with
        neuropathologically proven Leigh syndrome
- term:
    id: GO:0006120
    label: mitochondrial electron transport, NADH to ubiquinone
  evidence_type: NAS
  original_reference_id: PMID:9878551
  qualifier: involved_in
  review:
    summary: NAS annotation to the core Complex I electron-transport process, based on
      the statement that the main function of complex I is transport of electrons from
      NADH to ubiquinone.
    action: ACCEPT
    reason: Correct core process; redundant with the IMP/IBA annotations to GO:0006120.
    supported_by:
    - reference_id: PMID:9878551
      supporting_text: Its main function is the transport of electrons from NADH to
        ubiquinone
- term:
    id: GO:0008137
    label: NADH dehydrogenase (ubiquinone) activity
  evidence_type: NAS
  original_reference_id: PMID:9878551
  qualifier: enables
  review:
    summary: NAS annotation to the Complex I catalytic activity, based on the
      NADH:ubiquinone oxidoreductase characterization. Redundant with the experimentally
      supported GO:0008137 annotations.
    action: ACCEPT
    reason: Correct core molecular function of the complex to which NDUFS8 belongs.
    supported_by:
    - reference_id: PMID:9878551
      supporting_text: NADH:ubiquinone oxidoreductase (complex I)
core_functions:
- description: NDUFS8 coordinates two [4Fe-4S] clusters via its two ferredoxin-type
    domains, providing electron-carrier redox centers within the peripheral (IP) arm of
    Complex I.
  supported_by:
  - reference_id: file:human/NDUFS8/NDUFS8-uniprot.txt
    supporting_text: Note=Binds 2 [4Fe-4S] cluster.
  molecular_function:
    id: GO:0051539
    label: 4 iron, 4 sulfur cluster binding
  directly_involved_in:
  - id: GO:0006120
    label: mitochondrial electron transport, NADH to ubiquinone
  in_complex:
    id: GO:0045271
    label: respiratory chain complex I
  locations:
  - id: GO:0005743
    label: mitochondrial inner membrane
- description: As a core subunit of Complex I, NDUFS8 is required for the NADH:ubiquinone
    oxidoreductase (EC 7.1.1.2) catalytic activity that transfers electrons from NADH to
    ubiquinone; NDUFS8 patient variants reduce this activity and are rescued by wild-type
    cDNA.
  supported_by:
  - reference_id: PMID:22499348
    supporting_text: Expression of wild-type cDNA in mutant cell lines rescued complex I
      activity and assembly, thus providing a functional validation of their
      pathogenicity.
  - reference_id: file:human/NDUFS8/NDUFS8-uniprot.txt
    supporting_text: Essential for the catalytic activity and assembly of complex I
  molecular_function:
    id: GO:0008137
    label: NADH dehydrogenase (ubiquinone) activity
  directly_involved_in:
  - id: GO:0006120
    label: mitochondrial electron transport, NADH to ubiquinone
  in_complex:
    id: GO:0045271
    label: respiratory chain complex I
  locations:
  - id: GO:0005743
    label: mitochondrial inner membrane
proposed_new_terms: []
suggested_questions:
- question: Do the two NDUFS8-coordinated [4Fe-4S] clusters correspond specifically to
    N6a and N6b in the electron-transfer wire of human Complex I, and does either directly
    gate electron transfer to N2/ubiquinone?
- question: Is the NDUFS8-RAB5IF (C20orf24/Q9BUV8) interaction a stable
    assembly/regulatory interaction, and does it warrant a more specific
    molecular-function annotation than protein binding?
suggested_experiments:
- description: Site-directed mutagenesis of the eight cluster-ligating cysteines followed
    by EPR to assign the N6a/N6b clusters to NDUFS8 and measure their redox potentials
    and role in electron transfer.
- description: Blue-native PAGE and cryo-EM of NDUFS8-knockout cells reconstituted with
    wild-type versus patient-variant NDUFS8 to define which assembly intermediate stalls
    and quantify the catalytic contribution of each Fe-S cluster.
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: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: file:human/NDUFS8/NDUFS8-uniprot.txt
  title: UniProtKB entry O00217 (NDUS8_HUMAN)
  findings: []
- id: PMID:11112787
  title: Human complex I defects can be resolved by monoclonal antibody analysis into
    distinct subunit assembly patterns.
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: PubMed-verified; NDUFS8 among patients analyzed; supports assembly-vs-catalytic
      distinction and complex I membership.
- id: PMID:12611891
  title: The subunit composition of the human NADH dehydrogenase obtained by rapid
    one-step immunopurification.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: PubMed-verified; biochemical identification of NDUFS8 as a subunit of
      immunopurified human complex I; basis for UniProt SUBUNIT/localization.
- id: PMID:14749350
  title: Differences in assembly or stability of complex I and other mitochondrial
    OXPHOS complexes in inherited complex I deficiency.
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: PubMed-verified; BN-PAGE study of complex I assembly/stability in
      patients with nuclear complex I subunit mutations.
- id: PMID:15159508
  title: Late-onset Leigh syndrome in a patient with mitochondrial complex I NDUFS8
    mutations.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: PubMed-verified; NDUFS8 compound heterozygous mutations cause
      late-onset Leigh syndrome; subunit essential for assembly/stability.
- id: PMID:22499348
  title: Molecular diagnosis in mitochondrial complex I deficiency using exome sequencing.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: PubMed-verified; NDUFS8 variants functionally validated by WT cDNA
      rescue of complex I activity and assembly; underpins UniProt FUNCTION and EC
      7.1.1.2.
- id: PMID:28844695
  title: Architecture of Human Mitochondrial Respiratory Megacomplex I(2)III(2)IV(2).
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: PubMed-verified; cryo-EM structure with precise assignment of
      individual human complex I subunits; structural basis for complex membership and
      inner-membrane location.
- id: PMID:30030361
  title: Assembly of mammalian oxidative phosphorylation complexes I-V and supercomplexes.
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: PubMed-verified review of OXPHOS assembly; source of the ComplexPortal
      NAS aerobic-respiration and PMF-ATP-synthesis process annotations.
- id: PMID:31536960
  title: Rewiring of the Human Mitochondrial Interactome during Neuronal Reprogramming
    Reveals Regulators of the Respirasome and Neurogenesis.
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: PubMed-verified; mitochondrial co-fractionation/interactome study;
      source of the NDUFS8-RAB5IF interaction and a complex I membership annotation.
- id: PMID:34800366
  title: Quantitative high-confidence human mitochondrial proteome and its dynamics
    in cellular context.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: PubMed-verified high-confidence mitochondrial proteome; supports
      mitochondrial localization (HTP).
- id: PMID:9666055
  title: Genomic structure of the human NDUFS8 gene coding for the iron-sulfur TYKY
    subunit of the mitochondrial NADH:ubiquinone oxidoreductase.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: PubMed-verified; characterizes the NDUFS8/TYKY gene and protein,
      mitochondrial localization, and tissue expression.
- id: PMID:9837812
  title: The first nuclear-encoded complex I mutation in a patient with Leigh syndrome.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: PubMed-verified; first nuclear complex I (NDUFS8) mutation in Leigh
      syndrome; notes two 4Fe4S ferredoxin consensus patterns.
- id: PMID:9878551
  title: 'cDNA of eight nuclear encoded subunits of NADH:ubiquinone oxidoreductase:
    human complex I cDNA characterization completed.'
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: PubMed-verified; completes cDNA characterization of human complex I
      subunits; states complex I function is NADH-to-ubiquinone electron transport.
- 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-6799178
  title: Intermediate 1 binds HP subcomplex to form Intermediate 2
  findings: []
- id: Reactome:R-HSA-6799179
  title: Peripheral arm subunits bind the 815kDa complex to form a 980kDa complex
  findings: []
- id: Reactome:R-HSA-6799191
  title: Intermediate 2 binds MT-ND1:NDUFAF5:NDUFAF6 to form a 315kDa subcomplex
  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-6799197
  title: ND4, ND5 bind the 550kDa complex to form the 815kDa complex
  findings: []
- id: Reactome:R-HSA-6799202
  title: The 315kDa subcomplex binds the 370kDa subcomplex to form the 550kDa complex
  findings: []
- id: Reactome:R-HSA-6799203
  title: IP subcomplex binds NDUFAF3, NDUFAF4, TIMMDC1 to form Intermediate 1
  findings: []
- id: Reactome:R-HSA-6800868
  title: NDUF subunits bind to form the IP subcomplex
  findings: []