NDUFA9

id: Q16795
gene_symbol: NDUFA9
product_type: PROTEIN
status: INITIALIZED
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: >-
  NDUFA9 (NADH:ubiquinone oxidoreductase subunit A9; also called the 39 kDa
  subunit, CI-39kD) is an accessory (supernumerary) subunit of mitochondrial
  respiratory Complex I (NADH:ubiquinone oxidoreductase). It sits at the junction
  between the peripheral (matrix) arm and the membrane arm, near the Q-module,
  and adopts a short-chain dehydrogenase/reductase (SDR) NAD(P)-binding
  Rossmann-like fold. NDUFA9 binds a structural NADPH dinucleotide cofactor
  that is not turned over catalytically; the subunit itself is not
  part of the electron-transfer wire and does not carry a redox-active Fe-S
  cluster. Its role is structural: it stabilises the Q-module/junction and is
  required for proper assembly of a functional Complex I. Through Complex I it
  contributes to mitochondrial electron transport from NADH to ubiquinone and
  hence to oxidative phosphorylation. The mature protein (after cleavage of a
  mitochondrial targeting presequence) resides in the mitochondrial inner
  membrane as an integral component of Complex I. Biallelic loss-of-function
  variants cause mitochondrial Complex I deficiency (nuclear type 26 / MC1DN26),
  a severe mitochondrial disease with phenotypes including Leigh syndrome and
  neonatally fatal encephalopathy.
existing_annotations:
- term:
    id: GO:0005739
    label: mitochondrion
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: is_active_in
  review:
    summary: >-
      Phylogenetic (IBA) localization of NDUFA9 to the mitochondrion. NDUFA9 is a
      nucleus-encoded Complex I subunit with a cleaved N-terminal mitochondrial
      targeting presequence and is a bona fide mitochondrial protein. Correct but
      generic; the more informative location is the mitochondrial inner membrane
      (GO:0005743), where the mature protein resides as part of Complex I.
    action: KEEP_AS_NON_CORE
    reason: >-
      Accurate compartment assignment but superseded in specificity by the
      inner-membrane and respiratory-chain-complex-I annotations. Retained as
      non-core supporting localization.
    supported_by:
    - reference_id: file:human/NDUFA9/NDUFA9-uniprot.txt
      supporting_text: "Accessory subunit of the mitochondrial membrane respiratory"
- term:
    id: GO:0006744
    label: ubiquinone biosynthetic process
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: >-
      Phylogenetic (IBA) annotation to ubiquinone biosynthetic process. This is
      incorrect for NDUFA9. Complex I uses ubiquinone as an electron acceptor and
      reduces it to ubiquinol; it does not synthesize ubiquinone (that pathway is
      carried out by the COQ enzymes). NDUFA9 is a non-catalytic accessory subunit
      and has no role in ubiquinone biosynthesis. The IBA propagation likely
      conflated "acts on ubiquinone" with "makes ubiquinone".
    action: REMOVE
    reason: >-
      Biologically wrong process. NDUFA9/Complex I reduces ubiquinone as part of
      electron transport (GO:0006120), and does not participate in ubiquinone
      biosynthesis. No literature supports a biosynthetic role.
    propagation_review:
      root_cause: TERM_SCOPING_PROBLEM
      failure_modes:
      - ROLE_CONFLATION
      source_entities:
      - source_id: PomBase:SPCC1840.09
        comment: >-
          Fission yeast Complex I-related family member; the biosynthetic-process
          term conflates acting on ubiquinone with synthesizing it.
      - source_id: SGD:S000004281
        comment: Budding yeast family source in the same IBA propagation.
    supported_by:
    - reference_id: PMID:9878551
      supporting_text: "the transport of electrons from NADH to ubiquinone, which is"
- term:
    id: GO:0044877
    label: protein-containing complex binding
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: enables
  review:
    summary: >-
      Phylogenetic (IBA) annotation to protein-containing complex binding. NDUFA9
      is a constitutive subunit of Complex I rather than an external ligand that
      binds a complex; the informative statement is that it is part_of respiratory
      chain complex I (GO:0045271). "protein-containing complex binding" is
      uninformative here and does not capture its structural role.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Not wrong in the trivial sense (it contacts other Complex I subunits), but
      it is over-annotation of a subunit that is a stable constituent of the
      complex. Its role is better represented as part_of Complex I (GO:0045271)
      and structural molecule activity.
    propagation_review:
      root_cause: TERM_SCOPING_PROBLEM
      failure_modes:
      - GRANULARITY_MISMATCH
      source_entities:
      - source_id: PANTHER:PTN000252522
        comment: >-
          Family node from which the generic "protein-containing complex binding"
          MF was propagated; for a constitutive subunit, part_of Complex I is the
          informative statement rather than binding the complex.
    supported_by:
    - reference_id: file:human/NDUFA9/NDUFA9-uniprot.txt
      supporting_text: "Complex I is composed of 45 different subunits."
- term:
    id: GO:0005759
    label: mitochondrial matrix
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: >-
      IEA subcellular-location mapping to mitochondrial matrix, mirroring the
      UniProt SUBCELLULAR LOCATION annotation (Mitochondrion matrix, ECO:0000305
      from PubMed:12611891). NDUFA9 is part of Complex I, which is embedded in the
      inner membrane with its accessory subunits (including NDUFA9 at the
      peripheral-arm/membrane-arm junction) facing the matrix; structural data
      place it as an integral part of the inner-membrane-bound complex. The
      inner-membrane annotation (GO:0005743) is the more accurate location.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Historically-derived "matrix" call reflecting the matrix-facing peripheral
      arm, but NDUFA9 is a bound subunit of the inner-membrane Complex I. The
      IDA/IEA inner-membrane annotations (GO:0005743) are preferred; matrix is
      kept as over-annotated rather than removed since UniProt still records it.
    supported_by:
    - reference_id: file:human/NDUFA9/NDUFA9-uniprot.txt
      supporting_text: "Mitochondrion matrix"
- term:
    id: GO:1902600
    label: proton transmembrane transport
  evidence_type: IEA
  original_reference_id: GO_REF:0000108
  qualifier: involved_in
  review:
    summary: >-
      IEA inferred by inter-ontology logical inference from the molecular-function
      annotation GO:0008137 (NADH dehydrogenase (ubiquinone) activity), which
      links to proton translocation. Complex I as a whole couples NADH:ubiquinone
      oxidoreduction to proton pumping across the inner membrane, but this
      activity is a property of the intact enzyme (driven by the membrane-arm ND
      subunits), not of the non-catalytic accessory subunit NDUFA9. The inference
      is only as valid as the GO:0008137 annotation it derives from, which is
      itself an over-annotation for NDUFA9.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Complex-level proton transport should not be propagated to a structural
      accessory subunit that does not perform catalysis or proton translocation.
      Inherited from the questionable GO:0008137 annotation; better captured at
      the level of the ND core subunits.
    supported_by:
    - reference_id: file:human/NDUFA9/NDUFA9-uniprot.txt
      supporting_text: "chain NADH dehydrogenase (Complex I), that is believed not to be"
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:17500595
  qualifier: enables
  review:
    summary: >-
      IPI protein binding with huntingtin (HTT, UniProtKB:P42858) from a
      high-throughput screen for huntingtin-interacting proteins. This is a bare
      "protein binding" term that conveys no specific molecular function, and the
      interaction is from a broad interactome/modifier study rather than a
      characterized NDUFA9 function. UniProt records the HTT interaction in its
      INTERACTION section.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Uninformative "protein binding"; per curation policy such IPIs are marked as
      over-annotated rather than removed. The interaction is real per the
      interactome data but does not define NDUFA9's core function.
    supported_by:
    - reference_id: file:human/NDUFA9/NDUFA9-uniprot.txt
      supporting_text: "Q16795; P42858: HTT;"
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:19103604
  qualifier: enables
  review:
    summary: >-
      IPI protein binding with NOA1 (hNOA1, UniProtKB:Q8NC60), a mitochondrial
      GTPase that co-purifies with Complex I. The paper reports that hNOA1
      interacts with Complex I and regulates Complex I-dependent respiration;
      NDUFA9 was identified among the interacting Complex I subunits. This is a
      bare "protein binding" term.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Uninformative "protein binding". The NOA1-Complex I association is
      biologically plausible but the term does not describe a molecular function
      of NDUFA9; marked over-annotated per policy.
    supported_by:
    - reference_id: PMID:19103604
      supporting_text: "hNOA1 interacts with both"
    - reference_id: file:human/NDUFA9/NDUFA9-uniprot.txt
      supporting_text: "Q16795; Q8NC60: NOA1;"
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:22309213
  qualifier: enables
  review:
    summary: >-
      IPI protein binding with BLOC1S1/GCN5L1 (UniProtKB:P78537). This study
      identified GCN5L1/BLOC1S1 as a mitochondrial acetyltransferase-programme
      component; UniProt records that NDUFA9 interacts with BLOC1S1 and that
      BLOC1S1 is required for NDUFA9 acetylation. This is a bare "protein binding"
      term.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Uninformative "protein binding". The BLOC1S1 interaction relates to
      acetylation of NDUFA9 rather than to a molecular function it enables; marked
      over-annotated per policy.
    supported_by:
    - reference_id: file:human/NDUFA9/NDUFA9-uniprot.txt
      supporting_text: "Interacts with BLOC1S1 (PubMed:22309213). Interacts"
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:32296183
  qualifier: enables
  review:
    summary: >-
      IPI protein binding from the HuRI human binary interactome map (yeast
      two-hybrid). Two rows derive from this reference; this one pairs NDUFA9 with
      CYSRT1 (UniProtKB:A8MQ03), a keratin-associated/cysteine-rich protein.
      Y2H-derived binary interactions with non-mitochondrial keratin-family
      proteins are commonly spurious/non-physiological for a matrix-facing Complex
      I subunit. Bare "protein binding" term.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Uninformative "protein binding" from a large-scale binary screen; the CYSRT1
      pairing has no evident biological relevance to NDUFA9's mitochondrial role.
      Marked over-annotated per policy rather than removed.
    supported_by:
    - reference_id: file:human/NDUFA9/NDUFA9-uniprot.txt
      supporting_text: "Q16795; A8MQ03: CYSRT1;"
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:32296183
  qualifier: enables
  review:
    summary: >-
      Second IPI from the HuRI binary interactome (PMID:32296183), pairing NDUFA9
      with KRTAP6-2 (UniProtKB:Q3LI66), a keratin-associated protein. As with the
      CYSRT1 pairing, this is a large-scale Y2H binary interaction with a
      non-mitochondrial keratin-family protein and is likely non-physiological.
      Bare "protein binding" term.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Uninformative "protein binding" from a high-throughput binary screen; the
      KRTAP6-2 pairing lacks biological relevance to NDUFA9's Complex I function.
      Marked over-annotated per policy.
    supported_by:
    - reference_id: file:human/NDUFA9/NDUFA9-uniprot.txt
      supporting_text: "Q16795; Q3LI66: KRTAP6-2;"
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:32814053
  qualifier: enables
  review:
    summary: >-
      IPI protein binding with huntingtin (HTT, UniProtKB:P42858 per GOA WITH/FROM) from a
      neurodegenerative-disease interactome mapping study. This is another bare
      "protein binding" annotation; the interaction with huntingtin (HTT, P42858)
      is already captured (PMID:17500595) and is recorded in the UniProt
      INTERACTION section.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Uninformative "protein binding" from a disease-interactome screen; redundant
      with the HTT interaction and not indicative of a molecular function. Marked
      over-annotated per policy.
    supported_by:
    - reference_id: file:human/NDUFA9/NDUFA9-uniprot.txt
      supporting_text: "Q16795; P42858: HTT;"
- term:
    id: GO:0005743
    label: mitochondrial inner membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: is_active_in
  review:
    summary: >-
      IEA orthology transfer (Ensembl Compara, from mouse Q9DC69) placing NDUFA9
      at the mitochondrial inner membrane. This is the correct anatomical location
      for a Complex I subunit and is independently supported by the ComplexPortal
      IDA (GO:0005743, PMID:28844695). NDUFA9 is an integral part of the
      inner-membrane-embedded Complex I.
    action: ACCEPT
    reason: >-
      Accurate and specific location, concordant with experimental (IDA) and
      structural evidence for Complex I in the inner mitochondrial membrane.
    supported_by:
    - reference_id: file:human/NDUFA9/NDUFA9-uniprot.txt
      supporting_text: "Accessory subunit of the mitochondrial membrane respiratory"
- term:
    id: GO:0045271
    label: respiratory chain complex I
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: part_of
  review:
    summary: >-
      IEA orthology transfer (Ensembl Compara, from mouse Q9DC69) that NDUFA9 is
      part of respiratory chain complex I. This is the defining, well-established
      structural membership of NDUFA9 and is corroborated by multiple IDA
      annotations (PMID:12611891, 17209039, 27626371, 31536960, 9878551) and cryo-EM
      structures.
    action: ACCEPT
    reason: >-
      Core structural annotation. NDUFA9 is an accessory subunit of Complex I;
      membership is supported by immunopurification, proteomics and structural
      studies.
    supported_by:
    - reference_id: file:human/NDUFA9/NDUFA9-uniprot.txt
      supporting_text: "Complex I 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: >-
      IDA (ComplexPortal) localization to mitochondrial inner membrane, from the
      cryo-EM structure of the human respiratory megacomplex I2III2IV2, in which
      NDUFA9 is assigned as an individual subunit of Complex I within the inner
      membrane. This is the correct, specific anatomical location.
    action: ACCEPT
    reason: >-
      Directly supported by structural determination of Complex I in the
      respiratory (super)complex; the most accurate location term for NDUFA9.
    supported_by:
    - reference_id: PMID:28844695
      supporting_text: "precise assignment of individual subunits of"
- term:
    id: GO:0009060
    label: aerobic respiration
  evidence_type: NAS
  original_reference_id: PMID:30030361
  qualifier: involved_in
  review:
    summary: >-
      NAS (ComplexPortal) annotation to aerobic respiration, based on Complex I's
      role as the entry point of the OXPHOS electron transport chain. As a subunit
      of Complex I, NDUFA9 participates in aerobic respiration. This is a
      high-level process term; the more precise process for NDUFA9's contribution
      is mitochondrial electron transport, NADH to ubiquinone (GO:0006120).
    action: KEEP_AS_NON_CORE
    reason: >-
      Correct but broad; NDUFA9 contributes to aerobic respiration only via its
      structural role in Complex I. Retained as non-core; the specific electron
      transport process term is core.
    supported_by:
    - reference_id: PMID:30030361
      supporting_text: "'supernumerary' subunits that play essential roles in assembly, regulation "
- 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: >-
      NAS (ComplexPortal) annotation to proton motive force-driven mitochondrial
      ATP synthesis. Complex I generates part of the proton-motive force that
      drives ATP synthase, but ATP synthesis is performed by Complex V; NDUFA9 as
      a non-catalytic accessory subunit contributes only indirectly and distally
      to this process. This is an over-broad process for a structural subunit.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Downstream/complex-level process not directly enabled by NDUFA9. Its
      contribution is limited to structural stabilization of Complex I, upstream of
      ATP synthesis; better captured by GO:0006120.
    supported_by:
    - reference_id: PMID:30030361
      supporting_text: "'supernumerary' subunits that play essential roles in assembly, regulation "
- term:
    id: GO:0045271
    label: respiratory chain complex I
  evidence_type: IPI
  original_reference_id: PMID:28844695
  qualifier: part_of
  review:
    summary: >-
      IPI (ComplexPortal) evidence that NDUFA9 is part_of respiratory chain complex
      I, from the cryo-EM megacomplex structure in which NDUFA9 is resolved as an
      individual Complex I subunit. Core, well-supported structural membership.
    action: ACCEPT
    reason: >-
      Structural evidence directly places NDUFA9 within Complex I; a defining
      component annotation.
    supported_by:
    - reference_id: PMID:28844695
      supporting_text: "precise assignment of individual subunits of"
- term:
    id: GO:0005739
    label: mitochondrion
  evidence_type: HTP
  original_reference_id: PMID:34800366
  qualifier: located_in
  review:
    summary: >-
      High-throughput (HTP) proteomics localization to mitochondrion, from a
      quantitative high-confidence human mitochondrial proteome study. Consistent
      with NDUFA9 being a mitochondrial Complex I subunit, though generic relative
      to the inner-membrane/Complex I annotations.
    action: KEEP_AS_NON_CORE
    reason: >-
      Correct but non-specific compartment; superseded by the inner-membrane and
      Complex I localizations. Retained as supporting non-core evidence.
    supported_by:
    - reference_id: file:human/NDUFA9/NDUFA9-uniprot.txt
      supporting_text: "Accessory subunit of the mitochondrial membrane respiratory"
- term:
    id: GO:0045271
    label: respiratory chain complex I
  evidence_type: IDA
  original_reference_id: PMID:12611891
  qualifier: part_of
  review:
    summary: >-
      IDA that NDUFA9 (the 39 kDa subunit) is part of Complex I, from one-step
      immunopurification of human NADH dehydrogenase and mass spectrometry
      identification of its subunits. NDUFA9 is identified as one of the human
      Complex I polypeptides. Core structural annotation.
    action: ACCEPT
    reason: >-
      Direct experimental identification of NDUFA9 as a Complex I subunit by
      immunopurification/MS.
    supported_by:
    - reference_id: PMID:12611891
      supporting_text: "isolating this multisubunit"
- term:
    id: GO:0045271
    label: respiratory chain complex I
  evidence_type: IDA
  original_reference_id: PMID:17209039
  qualifier: part_of
  review:
    summary: >-
      IDA that NDUFA9 is part of Complex I, from a study tracing tagged NDUFS3 to
      define stepwise Complex I assembly intermediates; NDUFA9 is detected in
      Complex I subcomplexes. Supports both structural membership and involvement
      in the assembly pathway.
    action: ACCEPT
    reason: >-
      Experimental identification of NDUFA9 within assembling Complex I; consistent
      with its role in Complex I biogenesis.
    supported_by:
    - reference_id: PMID:17209039
      supporting_text: "stepwise assembly of CI"
- term:
    id: GO:0045271
    label: respiratory chain complex I
  evidence_type: IDA
  original_reference_id: PMID:27626371
  qualifier: part_of
  review:
    summary: >-
      IDA that NDUFA9 is part of Complex I, from the systematic gene-editing study
      of human Complex I accessory subunits. Knockout cell lines showed that most
      accessory subunits (including NDUFA9) are strictly required for assembly of a
      functional complex, and loss of a subunit destabilizes co-module subunits.
      Establishes NDUFA9 both as a component and as functionally required.
    action: ACCEPT
    reason: >-
      Direct experimental demonstration that NDUFA9 is an integral, functionally
      important accessory subunit of Complex I.
    supported_by:
    - reference_id: PMID:27626371
      supporting_text: "25 subunits are strictly"
    - reference_id: PMID:27626371
      supporting_text: "affects the stability of other subunits residing in the same"
- term:
    id: GO:0045271
    label: respiratory chain complex I
  evidence_type: IDA
  original_reference_id: PMID:31536960
  qualifier: part_of
  review:
    summary: >-
      IDA that NDUFA9 is part of Complex I, from the human mitochondrial
      interactome study during neuronal reprogramming; NDUFA9 is detected in
      complexes with other Complex I (FS3, FS7), Complex III and Complex IV
      subunits within respirasome-containing assemblies. Supports Complex I
      membership.
    action: ACCEPT
    reason: >-
      Interactome/proteomics evidence placing NDUFA9 within Complex I and the
      respiratory supercomplex; concordant structural membership.
    supported_by:
    - reference_id: PMID:31536960
      supporting_text: "NDUFA9, FS3, FS7)"
- term:
    id: GO:0045271
    label: respiratory chain complex I
  evidence_type: IDA
  original_reference_id: PMID:9878551
  qualifier: part_of
  review:
    summary: >-
      IDA that NDUFA9 is part of Complex I, from the cDNA characterization of the
      nuclear-encoded human Complex I subunits, which places these subunits
      (including the 39 kDa/NDUFA9 subunit) within the inner-membrane
      NADH:ubiquinone oxidoreductase. Supports structural membership.
    action: ACCEPT
    reason: >-
      Establishes NDUFA9 as a characterized nuclear-encoded subunit of human
      Complex I located in the inner mitochondrial membrane.
    supported_by:
    - reference_id: PMID:9878551
      supporting_text: "multiprotein complex located in the inner mitochondrial membrane"
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:31536960
  qualifier: enables
  review:
    summary: >-
      IPI protein binding with RAB5IF (UniProtKB:Q9BUV8) identified in the
      mitochondrial interactome study; UniProt records that NDUFA9 interacts with
      RAB5IF. This is a bare "protein binding" term that does not describe a
      molecular function of NDUFA9.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Uninformative "protein binding" from interactome mapping; marked
      over-annotated per policy rather than removed.
    supported_by:
    - reference_id: file:human/NDUFA9/NDUFA9-uniprot.txt
      supporting_text: "Interacts with RAB5IF (PubMed:31536960)."
- term:
    id: GO:0044877
    label: protein-containing complex binding
  evidence_type: IDA
  original_reference_id: PMID:23209302
  qualifier: enables
  review:
    summary: >-
      IDA (MGI) protein-containing complex binding. The cited reference
      (PMID:23209302) concerns KIF14 regulation of Rap1a-Radil signaling in breast
      cancer and does not, in its abstract, describe a characterized molecular
      function of NDUFA9. The term is uninformative for NDUFA9, whose relevant
      "complex" relationship is being a constitutive part_of Complex I (GO:0045271)
      rather than binding an external complex.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Uninformative complex-binding term; NDUFA9's role is as a stable Complex I
      subunit. Marked over-annotated rather than removed (the underlying
      experimental support cannot be fully verified from the abstract-only cache).
    supported_by:
    - reference_id: file:human/NDUFA9/NDUFA9-uniprot.txt
      supporting_text: "Complex I is composed of 45 different subunits."
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:28985504
  qualifier: enables
  review:
    summary: >-
      IPI protein binding with CLOCK (UniProtKB:O15516). UniProt records that
      NDUFA9 interacts with CLOCK and is acetylated by CLOCK in a circadian manner.
      This is a bare "protein binding" term; the interaction relates to
      post-translational acetylation of NDUFA9 rather than a molecular function it
      enables.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Uninformative "protein binding"; the CLOCK interaction underlies circadian
      acetylation of NDUFA9 but the MF term itself is uninformative. Marked
      over-annotated per policy.
    supported_by:
    - reference_id: file:human/NDUFA9/NDUFA9-uniprot.txt
      supporting_text: "Interacts with CLOCK (PubMed:28985504)."
- term:
    id: GO:0007623
    label: circadian rhythm
  evidence_type: IDA
  original_reference_id: PMID:28985504
  qualifier: involved_in
  review:
    summary: >-
      IDA involvement in circadian rhythm, based on the finding that NDUFA9 is
      acetylated by CLOCK in a circadian manner (UniProt PTM, PubMed:28985504). The
      evidence establishes that NDUFA9 is a circadian-regulated target (an
      output/substrate of the clock), not that NDUFA9 is a component of the
      circadian oscillator or regulates rhythmicity. "involved_in circadian rhythm"
      over-reads a PTM observation.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      NDUFA9 is a substrate of circadian CLOCK-mediated acetylation, i.e. a
      downstream target rather than a functional participant in generating
      circadian rhythm. Peripheral to its core Complex I role and an over-read of
      the acetylation data.
    supported_by:
    - reference_id: file:human/NDUFA9/NDUFA9-uniprot.txt
      supporting_text: "Acetylated by CLOCK in a circadian manner"
- term:
    id: GO:0005759
    label: mitochondrial matrix
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-163217
  qualifier: located_in
  review:
    summary: >-
      Reactome TAS localization to mitochondrial matrix for the Complex I reaction
      "Complex I oxidises NADH to NAD+, reduces CoQ to CoQH2". As with the other
      matrix annotations, NDUFA9 is a subunit of inner-membrane Complex I whose
      peripheral arm faces the matrix; the more precise location is the
      mitochondrial inner membrane (GO:0005743).
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Matrix call reflects the matrix-facing catalytic module of Complex I but
      NDUFA9 is an inner-membrane-associated subunit; inner-membrane annotations
      are preferred. One of several redundant Reactome matrix annotations.
    supported_by:
    - reference_id: file:human/NDUFA9/NDUFA9-uniprot.txt
      supporting_text: "Mitochondrion matrix"
- term:
    id: GO:0005759
    label: mitochondrial matrix
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-6799178
  qualifier: located_in
  review:
    summary: >-
      Reactome TAS matrix localization associated with a Complex I biogenesis
      reaction. Redundant with the other matrix annotations; NDUFA9 is an
      inner-membrane Complex I subunit and GO:0005743 is the preferred location.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Redundant Reactome matrix annotation for an inner-membrane subunit; kept as
      over-annotated in favor of the inner-membrane location.
    supported_by:
    - reference_id: file:human/NDUFA9/NDUFA9-uniprot.txt
      supporting_text: "Mitochondrion matrix"
- term:
    id: GO:0005759
    label: mitochondrial matrix
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-6799179
  qualifier: located_in
  review:
    summary: >-
      Reactome TAS matrix localization associated with a Complex I biogenesis
      reaction. Redundant with the other matrix annotations; NDUFA9 is an
      inner-membrane Complex I subunit and GO:0005743 is the preferred location.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Redundant Reactome matrix annotation for an inner-membrane subunit; kept as
      over-annotated in favor of the inner-membrane location.
    supported_by:
    - reference_id: file:human/NDUFA9/NDUFA9-uniprot.txt
      supporting_text: "Mitochondrion matrix"
- term:
    id: GO:0005759
    label: mitochondrial matrix
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-6799191
  qualifier: located_in
  review:
    summary: >-
      Reactome TAS matrix localization associated with a Complex I biogenesis
      reaction. Redundant with the other matrix annotations; NDUFA9 is an
      inner-membrane Complex I subunit and GO:0005743 is the preferred location.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Redundant Reactome matrix annotation for an inner-membrane subunit; kept as
      over-annotated in favor of the inner-membrane location.
    supported_by:
    - reference_id: file:human/NDUFA9/NDUFA9-uniprot.txt
      supporting_text: "Mitochondrion matrix"
- term:
    id: GO:0005759
    label: mitochondrial matrix
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-6799196
  qualifier: located_in
  review:
    summary: >-
      Reactome TAS matrix localization associated with a Complex I biogenesis
      reaction. Redundant with the other matrix annotations; NDUFA9 is an
      inner-membrane Complex I subunit and GO:0005743 is the preferred location.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Redundant Reactome matrix annotation for an inner-membrane subunit; kept as
      over-annotated in favor of the inner-membrane location.
    supported_by:
    - reference_id: file:human/NDUFA9/NDUFA9-uniprot.txt
      supporting_text: "Mitochondrion matrix"
- term:
    id: GO:0005759
    label: mitochondrial matrix
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-6799197
  qualifier: located_in
  review:
    summary: >-
      Reactome TAS matrix localization associated with a Complex I biogenesis
      reaction. Redundant with the other matrix annotations; NDUFA9 is an
      inner-membrane Complex I subunit and GO:0005743 is the preferred location.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Redundant Reactome matrix annotation for an inner-membrane subunit; kept as
      over-annotated in favor of the inner-membrane location.
    supported_by:
    - reference_id: file:human/NDUFA9/NDUFA9-uniprot.txt
      supporting_text: "Mitochondrion matrix"
- term:
    id: GO:0005759
    label: mitochondrial matrix
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-6799202
  qualifier: located_in
  review:
    summary: >-
      Reactome TAS matrix localization associated with a Complex I biogenesis
      reaction. Redundant with the other matrix annotations; NDUFA9 is an
      inner-membrane Complex I subunit and GO:0005743 is the preferred location.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Redundant Reactome matrix annotation for an inner-membrane subunit; kept as
      over-annotated in favor of the inner-membrane location.
    supported_by:
    - reference_id: file:human/NDUFA9/NDUFA9-uniprot.txt
      supporting_text: "Mitochondrion matrix"
- term:
    id: GO:0005759
    label: mitochondrial matrix
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-6799203
  qualifier: located_in
  review:
    summary: >-
      Reactome TAS matrix localization associated with a Complex I biogenesis
      reaction. Redundant with the other matrix annotations; NDUFA9 is an
      inner-membrane Complex I subunit and GO:0005743 is the preferred location.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Redundant Reactome matrix annotation for an inner-membrane subunit; kept as
      over-annotated in favor of the inner-membrane location.
    supported_by:
    - reference_id: file:human/NDUFA9/NDUFA9-uniprot.txt
      supporting_text: "Mitochondrion matrix"
- term:
    id: GO:0005759
    label: mitochondrial matrix
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-6800868
  qualifier: located_in
  review:
    summary: >-
      Reactome TAS matrix localization associated with a Complex I biogenesis
      reaction ("NDUF subunits bind to form the IP subcomplex"). Redundant with the
      other matrix annotations; NDUFA9 is an inner-membrane Complex I subunit and
      GO:0005743 is the preferred location.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Redundant Reactome matrix annotation for an inner-membrane subunit; kept as
      over-annotated in favor of the inner-membrane location.
    supported_by:
    - reference_id: file:human/NDUFA9/NDUFA9-uniprot.txt
      supporting_text: "Mitochondrion matrix"
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: HDA
  original_reference_id: PMID:21630459
  qualifier: located_in
  review:
    summary: >-
      HDA nucleus localization from a proteomic characterization of the human
      sperm nucleus. NDUFA9 is a mitochondrial Complex I subunit with an N-terminal
      mitochondrial targeting sequence and no known nuclear function; its detection
      in a sperm-nucleus proteome most likely reflects mitochondrial/contaminating
      material rather than a genuine nuclear localization.
    action: REMOVE
    reason: >-
      Nuclear localization is not supported for this mitochondrial inner-membrane
      Complex I subunit and is inconsistent with its targeting sequence and
      structural role. Likely a proteomic contaminant/artifact; no functional
      nuclear role is described.
    supported_by:
    - reference_id: file:human/NDUFA9/NDUFA9-uniprot.txt
      supporting_text: "Accessory subunit of the mitochondrial membrane respiratory"
- term:
    id: GO:0005759
    label: mitochondrial matrix
  evidence_type: IDA
  original_reference_id: PMID:8486360
  qualifier: located_in
  review:
    summary: >-
      IDA (UniProt) mitochondrial matrix localization, from the cDNA
      characterization identifying this transcript as the human homologue of the
      bovine 39-kDa nuclear-encoded NADH:ubiquinone oxidoreductase subunit. This is
      the historical UniProt matrix call for NDUFA9. As above, the matrix location
      reflects the matrix-facing peripheral arm; the inner membrane (GO:0005743) is
      the more precise location for this Complex I subunit.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Retained matrix annotation for the inner-membrane Complex I subunit; the
      inner-membrane location terms are preferred. Kept as over-annotated in line
      with UniProt's recorded subcellular location.
    supported_by:
    - reference_id: PMID:8486360
      supporting_text: "human homologue of the bovine 39-kDa nuclear-encoded"
- term:
    id: GO:0003954
    label: NADH dehydrogenase activity
  evidence_type: IMP
  original_reference_id: PMID:11112787
  qualifier: enables
  review:
    summary: >-
      IMP annotation of NADH dehydrogenase activity, from a study using monoclonal
      antibodies (including one against the 39 kDa/NDUFA9 subunit) to distinguish
      catalytic versus assembly defects in Complex I deficiency. The measured NADH
      dehydrogenase activity is a property of the intact Complex I holoenzyme, and
      UniProt explicitly states NDUFA9 is an accessory subunit "believed not to be
      involved in catalysis". Attributing the catalytic MF directly to NDUFA9
      over-reads the complex-level assay.
    action: MODIFY
    reason: >-
      NDUFA9 is non-catalytic; the redox activity belongs to the core (Q-module/N-
      module) subunits, not this accessory subunit. NDUFA9's contribution to the
      assay is structural (its loss disrupts assembly and thereby activity), so the
      informative MF is structural molecule activity, with the process captured by
      GO:0006120. The catalytic MF should not be assigned to NDUFA9.
    proposed_replacement_terms:
    - id: GO:0005198
      label: structural molecule activity
    supported_by:
    - reference_id: file:human/NDUFA9/NDUFA9-uniprot.txt
      supporting_text: "chain NADH dehydrogenase (Complex I), that is believed not to be"
    - reference_id: PMID:11112787
      supporting_text: "distinguish catalytic versus assembly"
- 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 involvement in mitochondrial electron transport, NADH to ubiquinone. As a
      required accessory subunit of Complex I (NADH:ubiquinone oxidoreductase),
      whose main function is the transport of electrons from NADH to ubiquinone,
      NDUFA9 is properly annotated to this process. This is the core biological
      process for NDUFA9's contribution to respiration.
    action: ACCEPT
    reason: >-
      Correct and appropriately specific process term. NDUFA9 contributes to
      NADH-to-ubiquinone electron transport via its structural role in Complex I;
      this is its core biological-process annotation.
    supported_by:
    - reference_id: PMID:9878551
      supporting_text: "the transport of electrons from NADH to ubiquinone, which is"
- term:
    id: GO:0008137
    label: NADH dehydrogenase (ubiquinone) activity
  evidence_type: NAS
  original_reference_id: PMID:9878551
  qualifier: enables
  review:
    summary: >-
      NAS annotation of NADH dehydrogenase (ubiquinone) activity, propagated to
      NDUFA9 as a Complex I subunit. This catalytic MF is a property of the intact
      Complex I holoenzyme, not of the non-catalytic accessory subunit NDUFA9,
      which UniProt states is "believed not to be involved in catalysis".
    action: MODIFY
    reason: >-
      Catalytic activity of the whole complex should not be assigned to a
      structural accessory subunit. NDUFA9's role is structural; replace with
      structural molecule activity. The process-level contribution is captured by
      GO:0006120.
    proposed_replacement_terms:
    - id: GO:0005198
      label: structural molecule activity
    supported_by:
    - reference_id: file:human/NDUFA9/NDUFA9-uniprot.txt
      supporting_text: "chain NADH dehydrogenase (Complex I), that is believed not to be"
- term:
    id: GO:0031966
    label: mitochondrial membrane
  evidence_type: IDA
  original_reference_id: PMID:17209039
  qualifier: located_in
  review:
    summary: >-
      IDA mitochondrial membrane localization, from the study tracing Complex I
      assembly intermediates. Correct but less specific than mitochondrial inner
      membrane (GO:0005743), which is the precise compartment for Complex I.
    action: MODIFY
    reason: >-
      Correct membrane localization but insufficiently specific; NDUFA9 resides in
      the mitochondrial inner membrane as part of Complex I. Replace/generalize to
      the more precise inner-membrane term.
    proposed_replacement_terms:
    - id: GO:0005743
      label: mitochondrial inner membrane
    supported_by:
    - reference_id: PMID:17209039
      supporting_text: "stepwise assembly of CI"
- term:
    id: GO:0003954
    label: NADH dehydrogenase activity
  evidence_type: NAS
  original_reference_id: PMID:8486360
  qualifier: enables
  review:
    summary: >-
      NAS annotation of NADH dehydrogenase activity from the original cDNA
      identification of NDUFA9 as the human homologue of the bovine 39-kDa Complex I
      subunit. As with the other catalytic MF annotations, this reflects the
      activity of the whole complex; NDUFA9 itself is non-catalytic.
    action: MODIFY
    reason: >-
      Redundant catalytic MF assigned to a non-catalytic accessory subunit;
      replace with structural molecule activity. Duplicate of the IMP GO:0003954
      annotation (PMID:11112787).
    proposed_replacement_terms:
    - id: GO:0005198
      label: structural molecule activity
    supported_by:
    - reference_id: file:human/NDUFA9/NDUFA9-uniprot.txt
      supporting_text: "chain NADH dehydrogenase (Complex I), that is believed not to be"
- term:
    id: GO:0006814
    label: sodium ion transport
  evidence_type: NAS
  original_reference_id: PMID:8486360
  qualifier: involved_in
  review:
    summary: >-
      NAS annotation to sodium ion transport. This is incorrect for human
      NDUFA9/Complex I. Mammalian mitochondrial Complex I is a proton-pumping
      NADH:ubiquinone oxidoreductase; it does not transport sodium. Na+-translocating
      NADH:quinone oxidoreductases (Na+-NQR) are a distinct bacterial enzyme family.
      The annotation appears to be a legacy mis-assignment.
    action: REMOVE
    reason: >-
      No evidence that human NDUFA9 or human Complex I transports sodium; the
      coupling ion for mammalian Complex I is the proton, not Na+. Biologically
      wrong process.
    supported_by:
    - reference_id: PMID:9878551
      supporting_text: "translocation of protons from the mitochondrial matrix to the"
- term:
    id: GO:0008137
    label: NADH dehydrogenase (ubiquinone) activity
  evidence_type: NAS
  original_reference_id: PMID:8486360
  qualifier: enables
  review:
    summary: >-
      NAS annotation of NADH dehydrogenase (ubiquinone) activity from the original
      cDNA identification of NDUFA9. Duplicate of the GO:0008137 NAS annotation
      (PMID:9878551); this catalytic MF belongs to the holoenzyme, not the
      non-catalytic accessory subunit NDUFA9.
    action: MODIFY
    reason: >-
      Catalytic MF assigned to a structural accessory subunit; replace with
      structural molecule activity. Redundant with the other GO:0008137 annotation.
    proposed_replacement_terms:
    - id: GO:0005198
      label: structural molecule activity
    supported_by:
    - reference_id: file:human/NDUFA9/NDUFA9-uniprot.txt
      supporting_text: "chain NADH dehydrogenase (Complex I), that is believed not to be"
- term:
    id: GO:0032981
    label: mitochondrial respiratory chain complex I assembly
  evidence_type: IMP
  original_reference_id: PMID:27626371
  qualifier: involved_in
  review:
    summary: >-
      Proposed new annotation. NDUFA9 is required for proper assembly of a
      functional Complex I: gene-editing knockout studies show that most accessory
      subunits, including NDUFA9, are strictly required for assembly of a functional
      complex, and loss of a subunit destabilizes co-module subunits. UniProt
      states NDUFA9 is "Required for proper complex I assembly", and pathogenic
      NDUFA9 variants cause a Complex I assembly defect with accumulation of
      assembly intermediates. This process is not currently in the GOA set but is
      strongly supported.
    action: NEW
    reason: >-
      Captures NDUFA9's core biological role (assembly/stabilization of Complex I),
      which is better supported than the catalytic MF annotations and complements
      the electron-transport process term.
    supported_by:
    - reference_id: PMID:27626371
      supporting_text: "25 subunits are strictly"
    - reference_id: file:human/NDUFA9/NDUFA9-uniprot.txt
      supporting_text: "involved in catalysis. Required for proper complex I assembly"
core_functions:
- description: >-
    NDUFA9 is a structural accessory (supernumerary) subunit of mitochondrial
    respiratory Complex I. It sits at the junction of the peripheral (Q-module)
    and membrane arms and stabilizes the complex; it is non-catalytic and binds a
    structural NADPH dinucleotide cofactor that is not turned over. Through
    its structural role it is required for proper assembly of a functional
    Complex I and thereby contributes to mitochondrial electron transport from
    NADH to ubiquinone.
  molecular_function:
    id: GO:0005198
    label: structural molecule 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:0005743
    label: mitochondrial inner membrane
  in_complex:
    id: GO:0045271
    label: respiratory chain complex I
  supported_by:
  - reference_id: file:human/NDUFA9/NDUFA9-uniprot.txt
    supporting_text: "involved in catalysis. Required for proper complex I assembly"
  - reference_id: PMID:27626371
    supporting_text: "25 subunits are strictly"
  - reference_id: PMID:9878551
    supporting_text: "the transport of electrons from NADH to ubiquinone, which is"
references:
- id: GO_REF:0000033
  title: Annotation inferences using phylogenetic trees
  findings: []
- id: GO_REF:0000044
  title: Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location
    vocabulary mapping, accompanied by conservative changes to GO terms applied by
    UniProt
  findings: []
- 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: PMID:11112787
  title: Human complex I defects can be resolved by monoclonal antibody analysis into
    distinct subunit assembly patterns.
  findings: []
- id: PMID:12611891
  title: The subunit composition of the human NADH dehydrogenase obtained by rapid
    one-step immunopurification.
  findings: []
- id: PMID:17209039
  title: Identification of mitochondrial complex I assembly intermediates by tracing
    tagged NDUFS3 demonstrates the entry point of mitochondrial subunits.
  findings: []
- id: PMID:17500595
  title: Huntingtin interacting proteins are genetic modifiers of neurodegeneration.
  findings: []
- id: PMID:19103604
  title: hNOA1 interacts with complex I and DAP3 and regulates mitochondrial respiration
    and apoptosis.
  findings: []
- id: PMID:21630459
  title: Proteomic characterization of the human sperm nucleus.
  findings: []
- id: PMID:22309213
  title: 'Identification of a molecular component of the mitochondrial acetyltransferase
    programme: a novel role for GCN5L1.'
  findings: []
- id: PMID:23209302
  title: KIF14 negatively regulates Rap1a-Radil signaling during breast cancer progression.
  findings: []
- id: PMID:27626371
  title: Accessory subunits are integral for assembly and function of human mitochondrial
    complex I.
  findings: []
- id: PMID:28844695
  title: Architecture of Human Mitochondrial Respiratory Megacomplex I(2)III(2)IV(2).
  findings: []
- id: PMID:28985504
  title: CLOCK Acetylates ASS1 to Drive Circadian Rhythm of Ureagenesis.
  findings: []
- id: PMID:30030361
  title: Assembly of mammalian oxidative phosphorylation complexes I-V and supercomplexes.
  findings: []
- id: PMID:31536960
  title: Rewiring of the Human Mitochondrial Interactome during Neuronal Reprogramming
    Reveals Regulators of the Respirasome and Neurogenesis.
  findings: []
- id: PMID:32296183
  title: A reference map of the human binary protein interactome.
  findings: []
- id: PMID:32814053
  title: Interactome Mapping Provides a Network of Neurodegenerative Disease Proteins
    and Uncovers Widespread Protein Aggregation in Affected Brains.
  findings: []
- id: PMID:34800366
  title: Quantitative high-confidence human mitochondrial proteome and its dynamics
    in cellular context.
  findings: []
- id: PMID:8486360
  title: Construction and evaluation of a hncDNA library of human 12p transcribed
    sequences derived from a somatic cell hybrid.
  findings: []
- id: PMID:9878551
  title: 'cDNA of eight nuclear encoded subunits of NADH:ubiquinone oxidoreductase:
    human complex I cDNA characterization completed.'
  findings: []
- id: Reactome:R-HSA-163217
  title: Complex I oxidises NADH to NAD+, reduces CoQ to CoQH2
  findings: []
- id: Reactome:R-HSA-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: []
- id: file:human/NDUFA9/NDUFA9-uniprot.txt
  title: UniProtKB entry Q16795 (NDUA9_HUMAN)
  findings: []