id: Q9P0J0
gene_symbol: NDUFA13
product_type: PROTEIN
status: IN_PROGRESS
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: >-
  NDUFA13 (also known as GRIM-19 and Complex I-B16.6) is a 144-residue, ~16.7 kDa
  nuclear-encoded accessory ("supernumerary") subunit of the peripheral/matrix arm of
  mitochondrial Complex I (NADH:ubiquinone oxidoreductase, the first enzyme of the
  respiratory electron transport chain). It is a genuine, stable structural component
  of the mature holoenzyme but does not itself catalyze NADH oxidation, quinone
  reduction, or proton translocation; instead it stabilizes the complex and is
  strictly required for its assembly and electron-transfer activity, so its loss
  causes Complex I instability and mitochondrial disease. NDUFA13 anchors to the
  inner mitochondrial membrane on the matrix side via a single transmembrane helix.
  In addition to this structural role, NDUFA13/GRIM-19 has a well-documented
  moonlighting function in cell-death regulation: it was originally isolated as a
  mediator of interferon-beta/retinoic-acid-induced tumor-cell death and is a specific
  negative regulator of the transcription factor STAT3, binding the STAT3
  transactivation domain and repressing STAT3-dependent transcription. It also
  associates with the mitochondrial serine protease HtrA2/OMI to promote apoptosis,
  acts as a chaperone that recruits STAT3 into mitochondria and integrates it into
  Complex I, and interacts with NOD2/CARD15 in innate immune signaling. A small pool
  localizes to the nucleus and cytoplasm, particularly upon interferon/retinoic-acid
  treatment.
alternative_products:
- name: '1'
  id: Q9P0J0-1
- name: '2'
  id: Q9P0J0-2
  sequence_note: VSP_056644
existing_annotations:
- 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) inference of Complex I membership. Correct: NDUFA13 is a
      bona fide accessory subunit of respiratory chain complex I, corroborated by
      direct experimental identification of the protein in immunopurified human
      Complex I. This is a core structural aspect of the gene.
    action: ACCEPT
    supported_by:
    - reference_id: PMID:12611891
      supporting_text: These polypeptides include the GRIM-19 protein
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: >-
      Electronic SubCell mapping of the UniProt Nucleus annotation. This is a real
      but secondary (moonlighting-associated) localization: a GRIM-19 pool is nuclear,
      particularly upon IFN/RA treatment. Duplicates the experimental EXP nucleus
      annotation (PMID:12628925). Keep, but as non-core since the core function is
      in the mitochondrion.
    action: KEEP_AS_NON_CORE
    supported_by:
    - reference_id: PMID:10924506
      supporting_text: GRIM-19 is primarily a nuclear protein
- term:
    id: GO:0005743
    label: mitochondrial inner membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: located_in
  review:
    summary: >-
      Electronic (IEA) inner-membrane localization. Correct and core: NDUFA13 is a
      single-pass inner-membrane protein (matrix side) that is part of membrane-arm-
      anchored Complex I. Strongly supported by multiple experimental annotations.
    action: ACCEPT
    supported_by:
    - reference_id: file:human/NDUFA13/NDUFA13-uniprot.txt
      supporting_text: Mitochondrion inner membrane
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:15753091
  qualifier: enables
  review:
    summary: >-
      Bare "protein binding" (IPI) from the NOD2/CARD15 interaction. The interaction
      itself is biologically meaningful (GRIM-19 is required for NOD2-mediated NF-kB
      activation in intestinal epithelium), but GO:0005515 is uninformative as a
      molecular function. Per policy, retained rather than removed, but flagged as an
      over-annotation; the meaningful biology is a non-core innate-immunity role.
    action: MARK_AS_OVER_ANNOTATED
    supported_by:
    - reference_id: PMID:15753091
      supporting_text: interacts with endogenous NOD2
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:17297443
  qualifier: enables
  review:
    summary: >-
      Bare "protein binding" (IPI) from the HtrA2/OMI interaction. The interaction is
      genuine and functionally important (GRIM-19 associates with HtrA2 to augment
      IFN/RA-dependent apoptosis and XIAP destruction), but GO:0005515 conveys no
      specific molecular function. Retained per policy but marked over-annotated; the
      meaningful role is captured in the apoptosis annotations below.
    action: MARK_AS_OVER_ANNOTATED
    supported_by:
    - reference_id: PMID:17297443
      supporting_text: GRIM-19 physically interacts with HtrA2
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:17500595
  qualifier: enables
  review:
    summary: >-
      Bare "protein binding" (IPI) with huntingtin (HTT) from a large-scale
      huntingtin-interacting-protein screen. Uninformative as a molecular function and
      of uncertain physiological relevance for NDUFA13. Retained per policy, flagged
      as over-annotation.
    action: MARK_AS_OVER_ANNOTATED
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:31617661
  qualifier: enables
  review:
    summary: >-
      Bare "protein binding" (IPI) with HTRA2 from a high-throughput interactome map
      of mitochondrial intermembrane-space proteases. Consistent with the HtrA2
      association but uninformative as an MF. Retained per policy, flagged as
      over-annotation.
    action: MARK_AS_OVER_ANNOTATED
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:32814053
  qualifier: enables
  review:
    summary: >-
      Bare "protein binding" (IPI) with HTT from a large-scale interactome/aggregation
      map of neurodegenerative-disease proteins. Uninformative as a molecular function
      and of uncertain relevance to NDUFA13's biology. Retained per policy, flagged as
      over-annotation.
    action: MARK_AS_OVER_ANNOTATED
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:40205054
  qualifier: enables
  review:
    summary: >-
      Bare "protein binding" (IPI) with HTRA2 from a multimodal cell-map / structural
      genomics interactome. Uninformative as an MF. Retained per policy, flagged as
      over-annotation.
    action: MARK_AS_OVER_ANNOTATED
- term:
    id: GO:0005739
    label: mitochondrion
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: located_in
  review:
    summary: >-
      Electronic (IEA) mitochondrial localization. Correct and core, though coarse
      relative to the more specific inner-membrane/Complex I annotations. Extensively
      supported by experimental evidence.
    action: ACCEPT
    supported_by:
    - reference_id: PMID:15367666
      supporting_text: its primary localization in the mitochondria
- term:
    id: GO:0045271
    label: respiratory chain complex I
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: part_of
  review:
    summary: >-
      Electronic (IEA) Complex I membership, redundant with the experimental IDA/IMP
      and IBA annotations. Core structural aspect. Accept.
    action: ACCEPT
    supported_by:
    - reference_id: PMID:27626371
      supporting_text: Accessory subunits are integral for assembly and function of human
- term:
    id: GO:0005743
    label: mitochondrial inner membrane
  evidence_type: IDA
  original_reference_id: PMID:28844695
  qualifier: located_in
  review:
    summary: >-
      Direct (IDA, ComplexPortal) inner-membrane localization of NDUFA13 from cryo-EM
      of the human respiratory megacomplex, which precisely assigns individual Complex
      I subunits within the inner membrane. Core mitochondrial localization. Accept.
    action: ACCEPT
    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: >-
      Complex-level aerobic-respiration BP asserted (NAS, ComplexPortal) for the
      Complex I subunit. True at the holoenzyme level but high/general; more specific
      to NDUFA13's role is mitochondrial electron transport (NADH to ubiquinone).
      Keep as a non-core, complex-level process annotation.
    action: KEEP_AS_NON_CORE
    supported_by:
    - reference_id: PMID:30030361
      supporting_text: 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: >-
      Complex-level BP (NAS, ComplexPortal). Complex I contributes to the proton
      gradient that drives ATP synthesis, but ATP synthesis itself is performed by
      Complex V, and NDUFA13 is a non-catalytic accessory subunit. This is an
      over-annotation at the level of the individual subunit.
    action: MARK_AS_OVER_ANNOTATED
- term:
    id: GO:0045271
    label: respiratory chain complex I
  evidence_type: IPI
  original_reference_id: PMID:28844695
  qualifier: part_of
  review:
    summary: >-
      ComplexPortal IPI assignment of NDUFA13 to Complex I from the human megacomplex
      cryo-EM structure. Duplicates the IDA membership annotation. Core structural
      aspect. Accept.
    action: ACCEPT
    supported_by:
    - reference_id: PMID:28844695
      supporting_text: precise assignment of individual subunits of
- term:
    id: GO:0005739
    label: mitochondrion
  evidence_type: IDA
  original_reference_id: GO_REF:0000052
  qualifier: located_in
  review:
    summary: >-
      Immunofluorescence-based (HPA) mitochondrial localization. Correct and core,
      consistent with all other evidence. Coarser than inner-membrane/Complex I.
      Accept.
    action: ACCEPT
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: EXP
  original_reference_id: PMID:12628925
  qualifier: located_in
  review:
    summary: >-
      Experimental nuclear localization. GRIM-19 has a documented nuclear pool (and
      was originally described as primarily nuclear), associated with its moonlighting
      STAT3/cell-death role. Genuine but non-core relative to the mitochondrial
      structural function.
    action: KEEP_AS_NON_CORE
    supported_by:
    - reference_id: PMID:10924506
      supporting_text: GRIM-19 is primarily a nuclear protein
- term:
    id: GO:0005743
    label: mitochondrial inner membrane
  evidence_type: EXP
  original_reference_id: PMID:12628925
  qualifier: located_in
  review:
    summary: >-
      Experimental inner-membrane localization. Core: NDUFA13 co-localizes with
      mitochondrial markers and is an inner-membrane Complex I subunit. Accept.
    action: ACCEPT
    supported_by:
    - reference_id: PMID:12628925
      supporting_text: co-localizes with mitochondrial
- term:
    id: GO:0005743
    label: mitochondrial inner membrane
  evidence_type: EXP
  original_reference_id: PMID:15059901
  qualifier: located_in
  review:
    summary: >-
      Experimental inner-membrane localization (from the OLFM4/GW112 study, which
      also examined GRIM-19 localization). Core mitochondrial localization. Accept.
    action: ACCEPT
- term:
    id: GO:0005743
    label: mitochondrial inner membrane
  evidence_type: EXP
  original_reference_id: PMID:15367666
  qualifier: located_in
  review:
    summary: >-
      Experimental inner-membrane / mitochondrial localization from the study showing
      GRIM-19 is a functional Complex I component essential for assembly. Core. Accept.
    action: ACCEPT
    supported_by:
    - reference_id: PMID:15367666
      supporting_text: its primary localization in the mitochondria
- term:
    id: GO:0005739
    label: mitochondrion
  evidence_type: HTP
  original_reference_id: PMID:34800366
  qualifier: located_in
  review:
    summary: >-
      High-throughput mitochondrial-proteome localization. Correct and core, coarse
      relative to inner-membrane/Complex I annotations. Accept.
    action: ACCEPT
- term:
    id: GO:0045271
    label: respiratory chain complex I
  evidence_type: IDA
  original_reference_id: PMID:12611891
  qualifier: part_of
  review:
    summary: >-
      Direct experimental identification (mass spectrometry of immunopurified human
      NADH dehydrogenase) of GRIM-19 as a Complex I subunit. This is a key primary
      demonstration of Complex I membership and a core structural aspect. Accept.
    action: ACCEPT
    supported_by:
    - reference_id: PMID:12611891
      supporting_text: These polypeptides include the GRIM-19 protein
- term:
    id: GO:0045271
    label: respiratory chain complex I
  evidence_type: IDA
  original_reference_id: PMID:17209039
  qualifier: part_of
  review:
    summary: >-
      Direct identification of NDUFA13 in Complex I / assembly-intermediate analysis
      (NDUFS3-tracing study). Core structural aspect of Complex I membership. Accept.
    action: ACCEPT
- term:
    id: GO:0045271
    label: respiratory chain complex I
  evidence_type: IMP
  original_reference_id: PMID:25901006
  qualifier: part_of
  review:
    summary: >-
      Complex I membership supported by mutational/patient evidence: the germline
      R57H mutation reduces NDUFA13 protein and causes Complex I instability, showing
      NDUFA13 is an integral component of the holoenzyme. Core. Accept.
    action: ACCEPT
    supported_by:
    - reference_id: PMID:25901006
      supporting_text: >-
        the abundances of NDUFA13 protein, CI holoenzyme and super complexes were
        drastically reduced
- term:
    id: GO:0045271
    label: respiratory chain complex I
  evidence_type: IDA
  original_reference_id: PMID:27626371
  qualifier: part_of
  review:
    summary: >-
      Direct identification of NDUFA13 as an integral accessory subunit of human
      Complex I via CRISPR-knockout + quantitative proteomics. Primary support for
      Complex I membership. Core. Accept.
    action: ACCEPT
    supported_by:
    - reference_id: PMID:27626371
      supporting_text: 25 subunits are strictly required for assembly of a functional complex
- term:
    id: GO:0045732
    label: positive regulation of protein catabolic process
  evidence_type: IGI
  original_reference_id: PMID:17297443
  qualifier: involved_in
  review:
    summary: >-
      GRIM-19 augments HtrA2-driven destruction of the antiapoptotic protein XIAP,
      i.e. positively regulates protein catabolism in the apoptotic context. A genuine
      moonlighting (apoptosis) function. Keep as non-core.
    action: KEEP_AS_NON_CORE
    supported_by:
    - reference_id: PMID:17297443
      supporting_text: >-
        the HtrA2-driven destruction of the antiapoptotic protein X-linked inhibitor of
        apoptosis (XIAP) is augmented
- term:
    id: GO:0061133
    label: endopeptidase activator activity
  evidence_type: IC
  original_reference_id: PMID:17297443
  qualifier: enables
  review:
    summary: >-
      Curator-inferred (IC, from the positive regulation of protein catabolism) MF:
      GRIM-19 augments the serine-protease HtrA2's destruction of XIAP. Reflects the
      moonlighting HtrA2/apoptosis axis rather than the core Complex I structural role.
      Retained as a non-core moonlighting molecular function.
    action: KEEP_AS_NON_CORE
    supported_by:
    - reference_id: PMID:17297443
      supporting_text: GRIM-19 physically interacts with HtrA2 and augments cell death
- term:
    id: GO:1900119
    label: positive regulation of execution phase of apoptosis
  evidence_type: IGI
  original_reference_id: PMID:17297443
  qualifier: involved_in
  review:
    summary: >-
      GRIM-19 promotes IFN/RA-dependent cell death via its HtrA2 interaction. This is
      the well-documented pro-apoptotic moonlighting function for which GRIM-19 was
      originally discovered. Genuine but non-core relative to the Complex I structural
      role. Keep as non-core.
    action: KEEP_AS_NON_CORE
    supported_by:
    - reference_id: PMID:17297443
      supporting_text: augments cell death in an IFN/all-trans retinoic acid (RA)-dependent manner
- term:
    id: GO:0005743
    label: mitochondrial inner membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9839110
  qualifier: located_in
  review:
    summary: >-
      Reactome (TAS) inner-membrane localization. Correct and core. Accept.
    action: ACCEPT
- term:
    id: GO:0032981
    label: mitochondrial respiratory chain complex I assembly
  evidence_type: IMP
  original_reference_id: PMID:25901006
  qualifier: involved_in
  review:
    summary: >-
      NDUFA13 is required for Complex I assembly/stability: loss (patient R57H mutation
      or silencing) causes CI instability with reduced holoenzyme and supercomplex.
      This is a core biological process for the gene. Accept.
    action: ACCEPT
    supported_by:
    - reference_id: PMID:25901006
      supporting_text: induces CI instability
- term:
    id: GO:0035458
    label: cellular response to interferon-beta
  evidence_type: IDA
  original_reference_id: PMID:17297443
  qualifier: involved_in
  review:
    summary: >-
      GRIM-19 is an IFN-beta/retinoic-acid-induced gene product mediating the cellular
      response to IFN-beta in the cell-death pathway. Genuine moonlighting function;
      non-core relative to the structural Complex I role. Keep as non-core.
    action: KEEP_AS_NON_CORE
    supported_by:
    - reference_id: PMID:17297443
      supporting_text: novel interferon (IFN)-retinoid regulated cell death
- term:
    id: GO:0071300
    label: cellular response to retinoic acid
  evidence_type: IDA
  original_reference_id: PMID:17297443
  qualifier: involved_in
  review:
    summary: >-
      GRIM-19 mediates cellular responses to retinoic acid (in combination with
      IFN-beta) in the apoptotic pathway. Genuine moonlighting function; non-core.
      Keep as non-core.
    action: KEEP_AS_NON_CORE
    supported_by:
    - reference_id: PMID:17297443
      supporting_text: IFN/all-trans retinoic acid (RA)-dependent manner
- term:
    id: GO:0045039
    label: protein insertion into mitochondrial inner membrane
  evidence_type: IDA
  original_reference_id: PMID:23271731
  qualifier: involved_in
  review:
    summary: >-
      GRIM-19 acts as a chaperone that recruits STAT3 into mitochondria and enhances
      its integration into Complex I in the inner membrane. This underpins the
      annotation, but the term is broader than the specific STAT3-chaperone role
      (GRIM-19 is not a general inner-membrane insertase). A genuine, non-core
      moonlighting activity tied to the STAT3 axis.
    action: KEEP_AS_NON_CORE
    supported_by:
    - reference_id: PMID:23271731
      supporting_text: acts as a chaperone to recruit STAT3 into mitochondria
- term:
    id: GO:0005743
    label: mitochondrial inner membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-163217
  qualifier: located_in
  review:
    summary: Reactome (TAS) inner-membrane localization. Correct and core. Accept.
    action: ACCEPT
- term:
    id: GO:0005743
    label: mitochondrial inner membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-6799178
  qualifier: located_in
  review:
    summary: Reactome (TAS) inner-membrane localization. Correct and core. Accept.
    action: ACCEPT
- term:
    id: GO:0005743
    label: mitochondrial inner membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-6799179
  qualifier: located_in
  review:
    summary: Reactome (TAS) inner-membrane localization. Correct and core. Accept.
    action: ACCEPT
- term:
    id: GO:0005743
    label: mitochondrial inner membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-6799191
  qualifier: located_in
  review:
    summary: Reactome (TAS) inner-membrane localization. Correct and core. Accept.
    action: ACCEPT
- term:
    id: GO:0005743
    label: mitochondrial inner membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-6799196
  qualifier: located_in
  review:
    summary: Reactome (TAS) inner-membrane localization. Correct and core. Accept.
    action: ACCEPT
- term:
    id: GO:0005743
    label: mitochondrial inner membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-6799197
  qualifier: located_in
  review:
    summary: Reactome (TAS) inner-membrane localization. Correct and core. Accept.
    action: ACCEPT
- term:
    id: GO:0005743
    label: mitochondrial inner membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-6799202
  qualifier: located_in
  review:
    summary: Reactome (TAS) inner-membrane localization. Correct and core. Accept.
    action: ACCEPT
- term:
    id: GO:0005743
    label: mitochondrial inner membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9839073
  qualifier: located_in
  review:
    summary: Reactome (TAS) inner-membrane localization. Correct and core. Accept.
    action: ACCEPT
- term:
    id: GO:0005739
    label: mitochondrion
  evidence_type: IDA
  original_reference_id: PMID:16826196
  qualifier: located_in
  review:
    summary: >-
      Direct mitochondrial localization from the study establishing an essential role
      of Complex I (GRIM-19/NDUFS3) in IFN-beta/RA-induced cancer-cell death. Core
      mitochondrial localization. Accept.
    action: ACCEPT
- term:
    id: GO:0031966
    label: mitochondrial membrane
  evidence_type: IDA
  original_reference_id: PMID:17209039
  qualifier: located_in
  review:
    summary: >-
      Direct mitochondrial-membrane localization, coarser parent of the more specific
      inner-membrane annotations. Correct and core. Accept.
    action: ACCEPT
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:12867595
  qualifier: enables
  review:
    summary: >-
      Bare "protein binding" (IPI) from the STAT3 interaction. This is arguably the
      most functionally important GRIM-19 interaction (specific STAT3 binding, driving
      transcriptional repression), but GO:0005515 itself is uninformative as a
      molecular function. Retained per policy but marked over-annotated; the biology is
      captured by the STAT3 transcription-repression annotation and by the core
      function synthesis.
    action: MARK_AS_OVER_ANNOTATED
    supported_by:
    - reference_id: PMID:12867595
      supporting_text: the transcription factor STAT3 (signal transducer and activator of
- term:
    id: GO:0005524
    label: ATP binding
  evidence_type: NAS
  original_reference_id: PMID:10924506
  qualifier: enables
  review:
    summary: >-
      "ATP binding" asserted non-experimentally (NAS) from the discovery paper, which
      does not demonstrate nucleotide binding. NDUFA13 is a non-catalytic accessory
      subunit with no recognized nucleotide-binding motif, and UniProt does not list
      ATP binding among its functions. This is an over-annotation.
    action: MARK_AS_OVER_ANNOTATED
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: IDA
  original_reference_id: PMID:10924506
  qualifier: located_in
  review:
    summary: >-
      Direct nucleoplasm localization from the discovery paper, which found GRIM-19 to
      be primarily nuclear. Genuine but tied to the moonlighting (STAT3/cell-death)
      pool rather than the core mitochondrial function. Keep as non-core.
    action: KEEP_AS_NON_CORE
    supported_by:
    - reference_id: PMID:10924506
      supporting_text: GRIM-19 is primarily a nuclear protein
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IDA
  original_reference_id: PMID:10924506
  qualifier: located_in
  review:
    summary: >-
      Direct cytoplasmic localization from the discovery paper. Coarse; a cytoplasmic
      pool is consistent with the nuclear/cytoplasmic distribution of the moonlighting
      GRIM-19 protein. Genuine but non-core relative to the mitochondrial structural
      role. Keep as non-core.
    action: KEEP_AS_NON_CORE
- term:
    id: GO:0005739
    label: mitochondrion
  evidence_type: IDA
  original_reference_id: PMID:12611891
  qualifier: located_in
  review:
    summary: >-
      Direct mitochondrial localization from the study identifying GRIM-19 in
      immunopurified human Complex I. Core mitochondrial localization. Accept.
    action: ACCEPT
    supported_by:
    - reference_id: PMID:12611891
      supporting_text: These polypeptides include the GRIM-19 protein
- term:
    id: GO:0045892
    label: negative regulation of DNA-templated transcription
  evidence_type: IDA
  original_reference_id: PMID:12867595
  qualifier: involved_in
  review:
    summary: >-
      GRIM-19 is a specific inhibitor of STAT3-dependent transcription (it binds the
      STAT3 transactivation domain and represses target-gene expression without
      blocking STAT3 phosphorylation or DNA binding). This is a genuine, well-supported
      moonlighting function. The generic "negative regulation of DNA-templated
      transcription" is less precise than the STAT-specific process; a more informative
      term is GO:1904893 (negative regulation of receptor signaling pathway via STAT).
    action: MODIFY
    proposed_replacement_terms:
    - id: GO:1904893
      label: negative regulation of receptor signaling pathway via STAT
    supported_by:
    - reference_id: PMID:12867595
      supporting_text: GRIM-19 inhibits transcription driven by activation of STAT3, but not STAT1
- term:
    id: GO:0098803
    label: respiratory chain complex
  evidence_type: IDA
  original_reference_id: PMID:12611891
  qualifier: located_in
  review:
    summary: >-
      Membership in a respiratory chain complex, the parent class of the more specific
      respiratory chain complex I annotation. Correct but redundant/general; the
      specific GO:0045271 (respiratory chain complex I) annotation is preferred.
    action: MARK_AS_OVER_ANNOTATED
    supported_by:
    - reference_id: PMID:12611891
      supporting_text: These polypeptides include the GRIM-19 protein
core_functions:
- description: >-
    NDUFA13 (GRIM-19) is a non-catalytic accessory (supernumerary) structural subunit
    of the peripheral/matrix arm of mitochondrial Complex I, anchored to the inner
    mitochondrial membrane on the matrix side by a single transmembrane helix. It does
    not itself catalyze NADH oxidation, quinone reduction, or proton translocation;
    it provides a structural molecule activity that stabilizes the mature holoenzyme
    and is strictly required for Complex I assembly and electron-transfer activity,
    thereby contributing to the complex-level NADH:ubiquinone oxidoreductase activity
    that transfers electrons from NADH to ubiquinone.
  molecular_function:
    id: GO:0005198
    label: structural molecule 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:0005743
    label: mitochondrial inner membrane
  in_complex:
    id: GO:0045271
    label: respiratory chain complex I
  supported_by:
  - reference_id: file:human/NDUFA13/NDUFA13-uniprot.txt
    supporting_text: >-
      Accessory subunit of the mitochondrial membrane respiratory
  - reference_id: PMID:27626371
    supporting_text: 25 subunits are strictly required for assembly of a functional complex
  - reference_id: PMID:25901006
    supporting_text: induces CI instability
- description: >-
    Moonlighting cell-death / STAT3-regulatory function: NDUFA13 was originally
    discovered as GRIM-19, a mediator of interferon-beta/retinoic-acid-induced
    tumor-cell death. A nuclear/cytoplasmic pool acts as a specific negative regulator
    of STAT3, binding the STAT3 transactivation domain (Ser727-dependent) and
    repressing STAT3-dependent transcription without blocking STAT3 phosphorylation or
    DNA binding. This is a genuine, experimentally supported secondary function that is
    distinct from, and non-core relative to, the structural Complex I role.
  molecular_function:
    id: GO:0005198
    label: structural molecule activity
  directly_involved_in:
  - id: GO:1904893
    label: negative regulation of receptor signaling pathway via STAT
  - id: GO:1900119
    label: positive regulation of execution phase of apoptosis
  locations:
  - id: GO:0005634
    label: nucleus
  supported_by:
  - reference_id: PMID:12867595
    supporting_text: GRIM-19 inhibits transcription driven by activation of STAT3, but not STAT1
  - reference_id: PMID:12867595
    supporting_text: our studies identify a specific inhibitor of STAT3
  - reference_id: PMID:17297443
    supporting_text: augments cell death in an IFN/all-trans retinoic acid (RA)-dependent manner
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:0000052
  title: Gene Ontology annotation based on curation of immunofluorescence data
  findings: []
- id: GO_REF:0000120
  title: Combined Automated Annotation using Multiple IEA Methods
  findings: []
- id: PMID:10924506
  title: Identification of GRIM-19, a novel cell death-regulatory gene induced by
    the interferon-beta and retinoic acid combination, using a genetic approach.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Discovery paper: isolated GRIM-19 in an antisense-knockout screen for mediators
      of IFN-beta/RA-induced tumor-cell death; found it primarily nuclear and
      IFN/RA-inducible. Underpins the moonlighting cell-death role and the
      nuclear/cytoplasmic localization annotations. The NAS 'ATP binding' asserted here
      is not experimentally demonstrated. Abstract-only in cache.
- 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: >-
      Mass-spec identification of GRIM-19 as a subunit of immunopurified human Complex
      I; primary support for Complex I membership and mitochondrial localization.
      Abstract-only in cache.
- id: PMID:12628925
  title: GRIM-19, a death-regulatory gene product, suppresses Stat3 activity via functional
    interaction.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Independent Y2H identification of GRIM-19 as a specific Stat3-interacting
      negative regulator; also documents mitochondrial co-localization and a nuclear
      pool. Supports the STAT3 moonlighting function and localization annotations.
      Abstract-only in cache.
- id: PMID:12867595
  title: The cell death regulator GRIM-19 is an inhibitor of signal transducer and
    activator of transcription 3.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Primary demonstration that GRIM-19 specifically binds STAT3 (via the TAD/Ser727)
      and represses STAT3-dependent transcription without blocking STAT3
      phosphorylation or DNA binding. Basis for the negative-regulation-of-transcription
      (STAT3) annotation. Full text available and verified.
- id: PMID:15059901
  title: GW112, a novel antiapoptotic protein that promotes tumor growth.
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: >-
      OLFM4/GW112 study that also examined GRIM-19 subcellular localization
      (mitochondrial). Supports inner-membrane localization. Abstract-only in cache.
- id: PMID:15367666
  title: GRIM-19, a cell death regulatory protein, is essential for assembly and function
    of mitochondrial complex I.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Gene-targeting study: GRIM-19 knockout is embryonic-lethal; GRIM-19 is in native
      Complex I and its loss destroys CI assembly and electron-transfer activity.
      Strong support for the core structural/assembly role and mitochondrial
      localization. Abstract-only in cache.
- id: PMID:15753091
  title: GRIM-19 interacts with nucleotide oligomerization domain 2 and serves as
    downstream effector of anti-bacterial function in intestinal epithelial cells.
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: >-
      Y2H + functional study: GRIM-19 interacts with NOD2/CARD15 and is required for
      NOD2-mediated NF-kB activation and antibacterial responses in intestinal
      epithelium. Source of the NOD2 protein-binding IPI; a non-core innate-immunity
      function. Abstract-only in cache.
- id: PMID:16826196
  title: 'Coupling mitochondrial respiratory chain to cell death: an essential role
    of mitochondrial complex I in the interferon-beta and retinoic acid-induced cancer
    cell death.'
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: >-
      Links Complex I (GRIM-19/NDUFS3) to IFN-beta/RA-induced apoptosis via ROS;
      source of a mitochondrial-localization IDA and support for the moonlighting
      cell-death role. Abstract-only in cache.
- id: PMID:17209039
  title: Identification of mitochondrial complex I assembly intermediates by tracing
    tagged NDUFS3 demonstrates the entry point of mitochondrial subunits.
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: >-
      Complex I assembly-intermediate study (NDUFS3-GFP tracing); supports NDUFA13
      Complex I membership and mitochondrial-membrane localization. Abstract-only in
      cache.
- id: PMID:17297443
  title: GRIM-19 associates with the serine protease HtrA2 for promoting cell death.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      GRIM-19 binds HtrA2/OMI and augments IFN/RA-dependent apoptosis and HtrA2-driven
      XIAP destruction. Primary support for the pro-apoptotic moonlighting annotations
      (positive regulation of execution phase of apoptosis, positive regulation of
      protein catabolism, endopeptidase activator activity, cellular responses to
      IFN-beta/RA). Abstract-only in cache.
- id: PMID:17500595
  title: Huntingtin interacting proteins are genetic modifiers of neurodegeneration.
  findings: []
  reference_review:
    relevance: LOW
    correctness: LOW_QUALITY
    review_notes: >-
      Large-scale huntingtin-interactor screen; source of a bare HTT protein-binding
      IPI of uncertain physiological relevance to NDUFA13. Uninformative as a molecular
      function.
- id: PMID:23271731
  title: The import of the transcription factor STAT3 into mitochondria depends on
    GRIM-19, a component of the electron transport chain.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Shows GRIM-19 acts as a chaperone recruiting STAT3 into mitochondria and
      integrating it into Complex I; basis for the 'protein insertion into
      mitochondrial inner membrane' IDA (broader than the specific STAT3-chaperone
      role). Full text available and verified.
- id: PMID:25901006
  title: Mutation in NDUFA13/GRIM19 leads to early onset hypotonia, dyskinesia and
    sensorial deficiencies, and mitochondrial complex I instability.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      First germline NDUFA13 pathogenic mutation (R57H, MC1DN28): reduces NDUFA13
      protein and holoenzyme/supercomplex levels and causes CI instability. Primary
      support for the core assembly/stability role and Complex I membership.
      Abstract-only in cache.
- id: PMID:27626371
  title: Accessory subunits are integral for assembly and function of human mitochondrial
    complex I.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      CRISPR-knockout + quantitative proteomics defining accessory subunits (including
      NDUFA13) as integral, non-catalytic components required for assembly/function of
      human Complex I. Primary support for the core structural function and the
      'believed not to be involved in catalysis' framing. Abstract-only in cache.
- 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: >-
      Cryo-EM of the human respiratory megacomplex with precise assignment of
      individual Complex I subunits; supports NDUFA13 Complex I membership and
      inner-membrane localization (ComplexPortal curation). Abstract-only in cache.
- id: PMID:30030361
  title: Assembly of mammalian oxidative phosphorylation complexes I-V and supercomplexes.
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: >-
      Review of OXPHOS/supercomplex assembly; basis for the ComplexPortal NAS
      complex-level BP annotations (aerobic respiration, proton-motive-force ATP
      synthesis). Abstract-only in cache.
- id: PMID:31617661
  title: Global Interactome Mapping of Mitochondrial Intermembrane Space Proteases
    Identifies a Novel Function for HTRA2.
  findings: []
  reference_review:
    relevance: LOW
    correctness: LOW_QUALITY
    review_notes: >-
      High-throughput interactome map of IMS proteases; source of a bare HTRA2
      protein-binding IPI. Consistent with the HtrA2 association but uninformative as a
      molecular function.
- id: PMID:32814053
  title: Interactome Mapping Provides a Network of Neurodegenerative Disease Proteins
    and Uncovers Widespread Protein Aggregation in Affected Brains.
  findings: []
  reference_review:
    relevance: LOW
    correctness: LOW_QUALITY
    review_notes: >-
      Large-scale interactome/aggregation map; source of a bare HTT protein-binding
      IPI of uncertain relevance to NDUFA13. Uninformative as a molecular function.
- id: PMID:34800366
  title: Quantitative high-confidence human mitochondrial proteome and its dynamics
    in cellular context.
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: >-
      High-throughput mitochondrial-proteome study; supports mitochondrial
      localization (coarse relative to inner-membrane/Complex I).
- id: PMID:40205054
  title: Multimodal cell maps as a foundation for structural and functional genomics.
  findings: []
  reference_review:
    relevance: LOW
    correctness: LOW_QUALITY
    review_notes: >-
      Multimodal cell-map / structural-genomics interactome; source of a bare HTRA2
      protein-binding IPI. Uninformative as a molecular function.
- 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-9839073
  title: HTRA2 binds NDUFA13 (GRIM-19)
  findings: []
- id: Reactome:R-HSA-9839110
  title: HTRA2 degrades NDUFA13 (GRIM-19)
  findings: []