id: Q99807
gene_symbol: COQ7
product_type: PROTEIN
status: INITIALIZED
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: >-
  COQ7 (also called CLK-1, the clock-1 homolog) is the mitochondrial di-iron
  hydroxylase that catalyzes the penultimate step of coenzyme Q (ubiquinone,
  CoQ10) biosynthesis. It hydroxylates 5-demethoxyubiquinol / 5-methoxy-2-methyl-
  3-(all-trans-polyprenyl)benzoquinone (DMQ) at the C6 position to give a
  3-demethyl-ubiquinol, the substrate for the final COQ3-catalyzed O-methylation
  that produces CoQ. It has a ferritin-like fold with a carboxylate-bridged
  di-iron center (it binds two iron ions per subunit and is NOT a flavin- or
  heme-dependent enzyme); substrate binding mediates reduction of the diiron
  center by NADH and initiates molecular oxygen activation for hydroxylation. COQ7
  is a peripheral inner-mitochondrial-membrane protein on the matrix face and is a
  component of the eukaryotic CoQ biosynthetic complex (COQ metabolon / synthome)
  together with COQ3, COQ4, COQ5, COQ6 and COQ9; the lipid-binding protein COQ9
  binds COQ7 and presents the hydrophobic DMQ substrate to it. A distinct pool of
  uncleaved COQ7 localizes to the nucleus and chromatin, where it participates in
  a mitochondria-to-nucleus retrograde signaling program that modulates reactive
  oxygen species metabolism and the mitochondrial unfolded protein response
  independently of ubiquinone biosynthesis. In humans, loss-of-function variants
  cause autosomal recessive primary coenzyme Q10 deficiency (COQ10D8) and distal
  hereditary motor neuronopathy (HMNR9); the clk-1/COQ7 ortholog influences
  lifespan in invertebrate and mouse models.
alternative_products:
- name: '1'
  id: Q99807-1
- name: '2'
  id: Q99807-2
  sequence_note: VSP_039068
existing_annotations:
- term:
    id: GO:0005743
    label: mitochondrial inner membrane
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: is_active_in
  review:
    summary: >-
      COQ7 is a peripheral protein of the mitochondrial inner membrane on the
      matrix side, consistent with its role in the CoQ biosynthetic complex. This
      is the correct core location and is supported by direct assay (ComplexPortal
      IDA) and phylogeny across the COQ7 family.
    action: ACCEPT
    supported_by:
    - reference_id: file:human/COQ7/COQ7-uniprot.txt
      supporting_text: "SUBCELLULAR LOCATION: Mitochondrion inner membrane"
- term:
    id: GO:0160224
    label: 3-demethoxyubiquinone 3-hydroxylase (NADH) activity
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: enables
  review:
    summary: >-
      This is the core molecular function of COQ7 and matches the enzyme's Rhea
      reaction. Well supported by phylogeny across the conserved COQ7/CLK-1 family
      and by direct human biochemistry.
    action: ACCEPT
    supported_by:
    - reference_id: PMID:23445365
      supporting_text: >-
        GB1-hCLK-1 functions as a 5-demethoxyubiquinone-hydroxylase, utilizing its
        carboxylate-bridged diiron center.
- term:
    id: GO:0006744
    label: ubiquinone biosynthetic process
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: >-
      Core biological process. COQ7 performs the penultimate (C6 hydroxylation)
      step of ubiquinone biosynthesis. Strongly supported across the family and by
      human/mammalian biochemistry and disease genetics.
    action: ACCEPT
- term:
    id: GO:2000377
    label: regulation of reactive oxygen species metabolic process
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: >-
      Supported for the moonlighting nuclear pool of COQ7/CLK-1, which regulates a
      ROS-defensive gene expression program independently of ubiquinone synthesis.
      This is a genuine but non-core, secondary function distinct from the enzyme's
      biosynthetic role, so keep it as non-core.
    action: KEEP_AS_NON_CORE
    supported_by:
    - reference_id: PMID:25961505
      supporting_text: >-
        nuclear CLK-1/COQ7 can potentially regulate metabolic pathways that alter
        cellular ROS production independently of ubiquinone
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: is_active_in
  review:
    summary: >-
      A distinct uncleaved pool of COQ7/CLK-1 does localize to the nucleus and act
      there (PMID:25961505), so the phylogenetically-inferred nuclear localization is
      not wrong. But this is a derived moonlighting function, not the ancestral/core
      activity of the family (the mitochondrial CoQ hydroxylase); keep the nuclear
      localization as non-core.
    action: KEEP_AS_NON_CORE
    supported_by:
    - reference_id: PMID:25961505
      supporting_text: >-
        We have uncovered a distinct nuclear form of CLK-1 that independently
        regulates lifespan.
- term:
    id: GO:0008340
    label: determination of adult lifespan
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: >-
      clk-1/COQ7 influences lifespan in C. elegans and heterozygous mice, partly
      through altered CoQ/ROS metabolism and partly through the nuclear moonlighting
      pool. This is a real, conserved organismal phenotype but downstream of the
      core enzymatic function; retain as non-core.
    action: KEEP_AS_NON_CORE
    supported_by:
    - reference_id: PMID:25961505
      supporting_text: >-
        nuclear CLK-1 can regulate longevity and that this is unrelated to the
        mitochondrial role of CLK-1 in ubiquinone biosynthesis.
- term:
    id: GO:0004497
    label: monooxygenase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: enables
  review:
    summary: >-
      Correct but generic parent term. COQ7 is a monooxygenase (it incorporates one
      oxygen atom into DMQ), but the specific child GO:0160224 (3-demethoxyubiquinone
      3-hydroxylase (NADH) activity) captures the actual reaction and is already
      annotated. Note COQ7 is a carboxylate-bridged di-iron monooxygenase, not a
      flavin- or heme-dependent one. Over-annotation relative to the specific term.
    action: MARK_AS_OVER_ANNOTATED
    proposed_replacement_terms:
    - id: GO:0160224
      label: 3-demethoxyubiquinone 3-hydroxylase (NADH) activity
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: >-
      Nuclear localization is experimentally supported for a subpool of COQ7
      (PMID:25961505) and is captured by the UniProt Nucleus subcellular location.
      Genuine but non-core relative to the mitochondrial inner-membrane site of the
      biosynthetic function.
    action: KEEP_AS_NON_CORE
- term:
    id: GO:0005694
    label: chromosome
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: >-
      The nuclear pool of COQ7 associates directly with chromatin (PMID:25961505),
      consistent with this SubCell-derived Chromosome location. Non-core moonlighting
      localization.
    action: KEEP_AS_NON_CORE
    supported_by:
    - reference_id: PMID:25961505
      supporting_text: >-
        the nuclear pool of COQ7 can directly associate with chromatin
- term:
    id: GO:0005739
    label: mitochondrion
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: >-
      Correct but less specific than the mitochondrial inner membrane annotation.
      Keep as non-core; the informative location is GO:0005743.
    action: KEEP_AS_NON_CORE
- term:
    id: GO:0005743
    label: mitochondrial inner membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: >-
      Correct core location, redundant with the experimentally-supported inner
      membrane annotations. Accept.
    action: ACCEPT
    supported_by:
    - reference_id: file:human/COQ7/COQ7-uniprot.txt
      supporting_text: "SUBCELLULAR LOCATION: Mitochondrion inner membrane"
- term:
    id: GO:0006744
    label: ubiquinone biosynthetic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: involved_in
  review:
    summary: >-
      Correct core biological process, redundant with the experimental IDA/IMP
      annotations. Accept.
    action: ACCEPT
- term:
    id: GO:0016709
    label: oxidoreductase activity, acting on paired donors, with incorporation or
      reduction of molecular oxygen, NAD(P)H as one donor, and incorporation of one
      atom of oxygen
  evidence_type: IEA
  original_reference_id: GO_REF:0000104
  qualifier: enables
  review:
    summary: >-
      Accurate parent term describing the class of NAD(P)H-dependent, single-oxygen-
      incorporating oxygenase reaction that COQ7 performs, but less informative than
      the specific GO:0160224. Over-annotation relative to the specific activity.
    action: MARK_AS_OVER_ANNOTATED
    proposed_replacement_terms:
    - id: GO:0160224
      label: 3-demethoxyubiquinone 3-hydroxylase (NADH) activity
- term:
    id: GO:0031314
    label: extrinsic component of mitochondrial inner membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000104
  qualifier: located_in
  review:
    summary: >-
      This is a more precise topological description than "mitochondrial inner
      membrane": COQ7 is a peripheral (extrinsic) membrane protein on the matrix
      side of the inner membrane. Accurate and informative; accept.
    action: ACCEPT
    supported_by:
    - reference_id: file:human/COQ7/COQ7-uniprot.txt
      supporting_text: "Peripheral membrane protein"
- term:
    id: GO:0160224
    label: 3-demethoxyubiquinone 3-hydroxylase (NADH) activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: enables
  review:
    summary: >-
      Core molecular function, redundant with the experimental EXP/IDA annotations
      and derived here from the Rhea/EC mapping (RHEA:81211, EC:1.14.13.253). Accept.
    action: ACCEPT
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:27499296
  qualifier: enables
  review:
    summary: >-
      Bare "protein binding" (IPI to COQ synthome partners identified in the
      mitochondrial interaction map). The interaction is real but the term is
      uninformative; the biologically meaningful content (membership in the CoQ
      biosynthetic complex and the COQ9->COQ7 substrate-presentation interaction) is
      captured by GO:0110142 and by the core functions. Over-annotated; do not use
      as a core function.
    action: MARK_AS_OVER_ANNOTATED
    supported_by:
    - reference_id: PMID:27499296
      supporting_text: >-
        we identified a dynamic human CoQ biosynthetic complex involving
- term:
    id: GO:0009410
    label: response to xenobiotic stimulus
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: >-
      Electronic ortholog transfer from rat (UniProtKB:Q63619) via Ensembl Compara.
      There is no direct evidence that human COQ7 functions in a xenobiotic response,
      and this is not part of its characterized biology. Weak, uninformative
      electronic transfer; flag as over-annotation rather than a core function.
    action: MARK_AS_OVER_ANNOTATED
- term:
    id: GO:0005743
    label: mitochondrial inner membrane
  evidence_type: IDA
  original_reference_id: PMID:27499296
  qualifier: located_in
  review:
    summary: >-
      Direct assignment of COQ7 to the mitochondrial inner membrane by ComplexPortal
      from the CoQ biosynthetic complex characterization. This is the correct core
      location. Accept.
    action: ACCEPT
    supported_by:
    - reference_id: file:human/COQ7/COQ7-uniprot.txt
      supporting_text: "SUBCELLULAR LOCATION: Mitochondrion inner membrane"
- term:
    id: GO:0006744
    label: ubiquinone biosynthetic process
  evidence_type: NAS
  original_reference_id: PMID:28927698
  qualifier: involved_in
  review:
    summary: >-
      Author statement (review of CoQ biosynthesis) placing COQ7 in ubiquinone
      biosynthesis. Correct core process. Accept.
    action: ACCEPT
- term:
    id: GO:0110142
    label: ubiquinone biosynthesis complex
  evidence_type: IPI
  original_reference_id: PMID:27499296
  qualifier: part_of
  review:
    summary: >-
      COQ7 is a component of the eukaryotic CoQ biosynthetic complex (COQ metabolon /
      synthome), whose definition explicitly includes COQ3, COQ4, COQ5, COQ6, COQ7
      and COQ9. This complex membership is the informative counterpart to the bare
      "protein binding" annotations. Accept as core complex membership.
    action: ACCEPT
    supported_by:
    - reference_id: PMID:38425362
      supporting_text: >-
        These include COQ3, COQ4, COQ5, COQ6, COQ7 and COQ9
- term:
    id: GO:0005743
    label: mitochondrial inner membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-2162186
  qualifier: located_in
  review:
    summary: >-
      Reactome-derived location for a specific CoQ pathway reaction event. Correct
      core inner-membrane location (one of several redundant Reactome duplicates).
      Accept.
    action: ACCEPT
- term:
    id: GO:0005743
    label: mitochondrial inner membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-2162187
  qualifier: located_in
  review:
    summary: >-
      Redundant Reactome-derived inner-membrane location for another CoQ pathway
      event. Correct core location. Accept.
    action: ACCEPT
- term:
    id: GO:0005743
    label: mitochondrial inner membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-2162188
  qualifier: located_in
  review:
    summary: >-
      Redundant Reactome-derived inner-membrane location. Correct core location.
      Accept.
    action: ACCEPT
- term:
    id: GO:0005743
    label: mitochondrial inner membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-2162193
  qualifier: located_in
  review:
    summary: >-
      Redundant Reactome-derived inner-membrane location. Correct core location.
      Accept.
    action: ACCEPT
- term:
    id: GO:0005743
    label: mitochondrial inner membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-2162194
  qualifier: located_in
  review:
    summary: >-
      Reactome event "COQ7:COQ9 octamer hydroxylates DMQ10H2" — directly describes
      the COQ7 catalytic step at the inner membrane. Correct core inner-membrane
      location (one of several redundant Reactome duplicates). Accept.
    action: ACCEPT
- term:
    id: GO:0005743
    label: mitochondrial inner membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-2162195
  qualifier: located_in
  review:
    summary: >-
      Redundant Reactome-derived inner-membrane location. Correct core location.
      Accept.
    action: ACCEPT
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: EXP
  original_reference_id: PMID:25961505
  qualifier: located_in
  review:
    summary: >-
      Experimental evidence (immunostaining, fractionation) that an uncleaved pool of
      COQ7 localizes to the nucleus. Genuine moonlighting localization; retain as
      non-core relative to the mitochondrial biosynthetic function.
    action: KEEP_AS_NON_CORE
    supported_by:
    - reference_id: PMID:25961505
      supporting_text: >-
        endogenous and exogenously expressed COQ7 display both mitochondrial and
        nuclear immunostaining in HeLa cells
- term:
    id: GO:0005694
    label: chromosome
  evidence_type: EXP
  original_reference_id: PMID:25961505
  qualifier: located_in
  review:
    summary: >-
      Experimentally supported: nuclear COQ7 is enriched in the chromatin fraction
      and associates directly with chromatin/DNA-protein complexes. Non-core
      moonlighting localization.
    action: KEEP_AS_NON_CORE
    supported_by:
    - reference_id: PMID:25961505
      supporting_text: >-
        the uncleaved form of COQ7, but not the R28A mutant, was enriched in the
        chromatin fraction
- term:
    id: GO:0160224
    label: 3-demethoxyubiquinone 3-hydroxylase (NADH) activity
  evidence_type: EXP
  original_reference_id: PMID:23445365
  qualifier: enables
  review:
    summary: >-
      Direct biochemical demonstration on purified human CLK-1/COQ7 that it is a
      5-demethoxyubiquinone hydroxylase using a carboxylate-bridged diiron center,
      with substrate-mediated NADH reduction and O2 activation. This is the strongest
      evidence for the core molecular function. Accept.
    action: ACCEPT
    supported_by:
    - reference_id: PMID:23445365
      supporting_text: >-
        The binding of DMQn (n = 0 or 2) to GB1-hCLK-1 mediates reduction of the
        diiron center by nicotinamide adenine dinucleotide (NADH) and initiates O2
        activation for subsequent DMQ hydroxylation.
- term:
    id: GO:0005739
    label: mitochondrion
  evidence_type: IDA
  original_reference_id: PMID:25961505
  qualifier: is_active_in
  review:
    summary: >-
      Direct evidence of mitochondrial localization/activity. Correct but less
      specific than the mitochondrial inner membrane; retain as non-core.
    action: KEEP_AS_NON_CORE
    supported_by:
    - reference_id: PMID:25961505
      supporting_text: >-
        endogenous and exogenously expressed COQ7 display both mitochondrial and
        nuclear immunostaining in HeLa cells
- term:
    id: GO:0006744
    label: ubiquinone biosynthetic process
  evidence_type: IDA
  original_reference_id: PMID:38425362
  qualifier: involved_in
  review:
    summary: >-
      In vitro reconstitution of the human/tetrapod COQ metabolon demonstrates COQ7
      performing its C6 hydroxylation step within ubiquinone biosynthesis. Direct
      support for the core biological process. Accept.
    action: ACCEPT
    supported_by:
    - reference_id: PMID:38425362
      supporting_text: >-
        COQ7 is an NADH-dependent hydroxylase that possesses a carboxylate-bridged
        diiron centre and converts 5 to 6
- term:
    id: GO:0160224
    label: 3-demethoxyubiquinone 3-hydroxylase (NADH) activity
  evidence_type: IDA
  original_reference_id: PMID:38425362
  qualifier: enables
  review:
    summary: >-
      In vitro reconstitution confirms COQ7 as the NADH-dependent, diiron-dependent
      hydroxylase catalyzing the C6 step, with COQ9 enhancing its catalytic
      efficiency. Direct support for the core molecular function. Accept.
    action: ACCEPT
    supported_by:
    - reference_id: PMID:38425362
      supporting_text: >-
        addition of COQ9 increased catalytic efficiency by 1.5-fold, substantiating
        its role for COQ7 function
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:30661980
  qualifier: enables
  review:
    summary: >-
      Bare "protein binding" IPI to COQ9 (O75208). The meaningful biology is that
      COQ9 binds and presents the lipophilic DMQ substrate to COQ7; this is captured
      by complex membership (GO:0110142) and the core functions. Uninformative as a
      standalone MF; over-annotated.
    action: MARK_AS_OVER_ANNOTATED
    supported_by:
    - reference_id: PMID:25339443
      supporting_text: >-
        COQ9 specifically interacts with COQ7 through a series of conserved residues.
- term:
    id: GO:0005739
    label: mitochondrion
  evidence_type: HTP
  original_reference_id: PMID:34800366
  qualifier: located_in
  review:
    summary: >-
      High-throughput mitochondrial proteome (MitoCoP) places COQ7 in mitochondria.
      Correct but less specific than the inner membrane; retain as non-core.
    action: KEEP_AS_NON_CORE
- term:
    id: GO:0006744
    label: ubiquinone biosynthetic process
  evidence_type: IMP
  original_reference_id: PMID:28409910
  qualifier: involved_in
  review:
    summary: >-
      Patient/mutation study: pathogenic COQ7 variants (V141E, L111P) reduce protein
      stability and ubiquinone levels, and DHB bypass can restore synthesis in cells
      lacking COQ7 activity — direct genetic evidence that COQ7 is required for
      ubiquinone biosynthesis. Core biological process. Accept.
    action: ACCEPT
    supported_by:
    - reference_id: PMID:28409910
      supporting_text: >-
        mutations in the ubiquinone biosynthetic gene COQ7
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:25339443
  qualifier: enables
  review:
    summary: >-
      Bare "protein binding" IPI to COQ9 (O75208) from the study defining the
      COQ9-COQ7 interaction. Real and important interaction, but "protein binding" is
      uninformative; the biology (COQ9 presenting substrate to COQ7 within the COQ
      complex) is captured by GO:0110142 and the core functions. Over-annotated.
    action: MARK_AS_OVER_ANNOTATED
    supported_by:
    - reference_id: PMID:25339443
      supporting_text: >-
        suggesting that COQ9 might serve to present its bound lipid to COQ7.
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: IDA
  original_reference_id: GO_REF:0000054
  qualifier: located_in
  review:
    summary: >-
      LIFEdb intracellular-localization curation reporting nuclear localization of a
      COQ7 fusion protein. Consistent with the experimentally-confirmed nuclear pool
      (PMID:25961505). Non-core moonlighting localization.
    action: KEEP_AS_NON_CORE
- term:
    id: GO:0005506
    label: iron ion binding
  evidence_type: IDA
  original_reference_id: PMID:23445365
  qualifier: enables
  review:
    summary: >-
      Proposed new annotation. GOA currently carries only the generic GO:0046872
      metal ion binding (IEA from keyword). COQ7 binds a carboxylate-bridged di-iron
      center (two iron ions per subunit), directly demonstrated for the purified human
      enzyme, so GO:0005506 iron ion binding is the accurate specific metal-binding
      MF and should be added.
    action: NEW
    supported_by:
    - reference_id: file:human/COQ7/COQ7-uniprot.txt
      supporting_text: "Note=Binds 2 iron ions per subunit."
    - reference_id: PMID:23445365
      supporting_text: >-
        GB1-hCLK-1 functions as a 5-demethoxyubiquinone-hydroxylase, utilizing its
        carboxylate-bridged diiron center.
core_functions:
- description: >-
    COQ7 is the carboxylate-bridged di-iron hydroxylase that catalyzes the
    penultimate step of coenzyme Q biosynthesis, hydroxylating 5-demethoxyubiquinol
    (DMQ) at the C6 position using NADH and molecular oxygen. Substrate binding
    mediates NADH reduction of its diiron center, which then activates O2 for
    hydroxylation.
  molecular_function:
    id: GO:0160224
    label: 3-demethoxyubiquinone 3-hydroxylase (NADH) activity
  directly_involved_in:
  - id: GO:0006744
    label: ubiquinone biosynthetic process
  locations:
  - id: GO:0005743
    label: mitochondrial inner membrane
  in_complex:
    id: GO:0110142
    label: ubiquinone biosynthesis complex
  supported_by:
  - reference_id: PMID:23445365
    supporting_text: >-
      GB1-hCLK-1 functions as a 5-demethoxyubiquinone-hydroxylase, utilizing its
      carboxylate-bridged diiron center.
  - reference_id: PMID:38425362
    supporting_text: >-
      COQ7 is an NADH-dependent hydroxylase that possesses a carboxylate-bridged
      diiron centre and converts 5 to 6
- description: >-
    COQ7 binds a carboxylate-bridged di-iron center (two iron ions per subunit) via
    a ferritin-like fold; this diiron cofactor is essential for catalysis and O2
    activation and is not replaced by flavin or heme.
  molecular_function:
    id: GO:0005506
    label: iron ion binding
  directly_involved_in:
  - id: GO:0006744
    label: ubiquinone biosynthetic process
  locations:
  - id: GO:0005743
    label: mitochondrial inner membrane
  supported_by:
  - reference_id: file:human/COQ7/COQ7-uniprot.txt
    supporting_text: "Note=Binds 2 iron ions per subunit."
  - reference_id: PMID:23445365
    supporting_text: >-
      GB1-hCLK-1 functions as a 5-demethoxyubiquinone-hydroxylase, utilizing its
      carboxylate-bridged diiron center.
proposed_new_terms: []
suggested_questions:
- question: >-
    What controls the partitioning of COQ7 between the mitochondrial (biosynthetic)
    and nuclear (retrograde-signaling) pools, and is the nuclear moonlighting
    function relevant to human COQ7 disease phenotypes?
- question: >-
    How is COQ7 hydroxylase activity regulated post-translationally (e.g. by
    phosphorylation and by COQ8-dependent kinase activity within the synthome)?
suggested_experiments:
- description: >-
    Reconstitute the human COQ7:COQ9 complex with defined DMQ substrates and measure
    how disease variants (e.g. V141E, L111P, R54Q) affect diiron-center assembly,
    NADH-coupled O2 activation, and hydroxylation kinetics.
- description: >-
    Use compartment-restricted COQ7 alleles (mitochondria-only vs nucleus-only) to
    dissect which human phenotypes depend on the biosynthetic activity versus the
    nuclear ROS/UPRmt signaling role.
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: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:0000054
  title: Gene Ontology annotation based on curation of intracellular localizations
    of expressed fusion proteins in living cells
  findings: []
- id: GO_REF:0000104
  title: Electronic Gene Ontology annotations created by transferring manual GO annotations
    between related proteins based on shared sequence features
  findings: []
- id: GO_REF:0000107
  title: Automatic transfer of experimentally verified manual GO annotation data to
    orthologs using Ensembl Compara
  findings: []
- id: GO_REF:0000120
  title: Combined Automated Annotation using Multiple IEA Methods
  findings: []
- id: PMID:23445365
  title: 'Aging-associated enzyme human clock-1: substrate-mediated reduction of the
    diiron center for 5-demethoxyubiquinone hydroxylation.'
  findings:
  - statement: >-
      Purified human CLK-1/COQ7 is a 5-demethoxyubiquinone hydroxylase that uses a
      carboxylate-bridged diiron center; substrate (DMQ) binding mediates NADH
      reduction of the diiron center and initiates O2 activation for hydroxylation.
    reference_section_type: ABSTRACT
    supporting_text: >-
      GB1-hCLK-1 functions as a 5-demethoxyubiquinone-hydroxylase, utilizing its
      carboxylate-bridged diiron center.
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      PMID verified against cached record; primary biochemical demonstration of the
      core di-iron hydroxylase activity of human COQ7/CLK-1.
- id: PMID:25339443
  title: Mitochondrial COQ9 is a lipid-binding protein that associates with COQ7 to
    enable coenzyme Q biosynthesis.
  findings:
  - statement: >-
      COQ9 is a lipid-binding protein that specifically interacts with COQ7 through
      conserved residues around its lipid-binding site, and is proposed to present
      its bound lipid (DMQ) substrate to COQ7 to enable CoQ biosynthesis.
    reference_section_type: ABSTRACT
    supporting_text: >-
      COQ9 specifically interacts with COQ7 through a series of conserved residues.
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Abstract-only in cache (full_text_available: false); abstract directly supports
      the COQ9->COQ7 substrate-presentation interaction.
- id: PMID:25961505
  title: A nuclear role for the respiratory enzyme CLK-1 in regulating mitochondrial
    stress responses and longevity.
  findings:
  - statement: >-
      A distinct uncleaved pool of COQ7/CLK-1 localizes to the nucleus and chromatin
      and regulates ROS metabolism, the UPRmt, and longevity independently of its
      mitochondrial ubiquinone-biosynthetic function.
    reference_section_type: RESULTS
    supporting_text: >-
      COQ7 has a biologically relevant nuclear role that is independent of its
      characterised mitochondrial function in ubiquinone biosynthesis.
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Full text cached; establishes the moonlighting nuclear/chromatin localization
      and ROS/lifespan signaling role (basis for the non-core nucleus/chromosome and
      ROS-regulation annotations).
- id: PMID:27499296
  title: Mitochondrial Protein Interaction Mapping Identifies Regulators of Respiratory
    Chain Function.
  findings:
  - statement: >-
      Systematic mitochondrial protein interaction mapping identified a dynamic human
      CoQ biosynthetic complex, placing COQ7 within the CoQ synthome at the inner
      mitochondrial membrane.
    reference_section_type: ABSTRACT
    supporting_text: >-
      we identified a dynamic human CoQ biosynthetic complex involving
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Full text cached; source for ComplexPortal COQ7 inner-membrane and
      ubiquinone-biosynthesis-complex (GO:0110142) annotations.
- id: PMID:28409910
  title: Pathogenicity of two COQ7 mutations and responses to 2,4-dihydroxybenzoate
    bypass treatment.
  findings:
  - statement: >-
      Pathogenic COQ7 variants (V141E, L111P) reduce protein stability and ubiquinone
      levels; 2,4-dihydroxybenzoate can restore ubiquinone synthesis in cells lacking
      COQ7 activity, confirming COQ7's requirement in ubiquinone biosynthesis.
    reference_section_type: ABSTRACT
    supporting_text: >-
      mutations in the ubiquinone biosynthetic gene COQ7
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Full text cached; genetic/functional support (IMP) for the ubiquinone
      biosynthetic process annotation and for disease (COQ10D8).
- id: PMID:28927698
  title: Biochemistry of Mitochondrial Coenzyme Q Biosynthesis.
  findings:
  - statement: >-
      Review of mitochondrial CoQ biosynthesis and the CoQ biosynthetic complex,
      within which COQ7 catalyzes a hydroxylation step.
    reference_section_type: ABSTRACT
    supporting_text: >-
      questions framed by the recently discovered CoQ biosynthetic complex
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: >-
      Full text cached; authoritative review (NAS source for ubiquinone biosynthetic
      process).
- id: PMID:30661980
  title: An Isoprene Lipid-Binding Protein Promotes Eukaryotic Coenzyme Q Biosynthesis.
  findings:
  - statement: >-
      Structural/biochemical study of the COQ9 isoprene-lipid-binding protein and its
      interface with COQ7, supporting a lipid-presentation role in CoQ biosynthesis.
    reference_section_type: RESULTS
    supporting_text: >-
      COQ9 interaction and interface with COQ7 suggest a lipid presentation role
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: >-
      Full text cached; source of a COQ9-COQ7 protein-binding (IPI) annotation;
      informative content is the COQ9->COQ7 lipid presentation, not bare binding.
- id: PMID:34800366
  title: Quantitative high-confidence human mitochondrial proteome and its dynamics
    in cellular context.
  findings:
  - statement: >-
      High-confidence human mitochondrial proteome (MitoCoP) that includes COQ7 among
      mitochondrial proteins.
    reference_section_type: ABSTRACT
    supporting_text: >-
      defined a mitochondrial high-confidence proteome of >1,100 proteins (MitoCoP)
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: >-
      Full text cached; high-throughput proteomic support (HTP) for mitochondrial
      localization only.
- id: PMID:38425362
  title: In vitro construction of the COQ metabolon unveils the molecular determinants
    of coenzyme Q biosynthesis.
  findings:
  - statement: >-
      In vitro reconstitution of the animal COQ metabolon shows COQ7 is an
      NADH-dependent, carboxylate-bridged-diiron hydroxylase performing the C6 step,
      with COQ9 enhancing its catalytic efficiency, within a COQ3/4/5/6/7/9 complex.
    reference_section_type: RESULTS
    supporting_text: >-
      COQ7 is an NADH-dependent hydroxylase that possesses a carboxylate-bridged
      diiron centre and converts 5 to 6
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Full text cached; direct IDA support for the core molecular function and
      biological process and for COQ metabolon membership.
- id: file:human/COQ7/COQ7-uniprot.txt
  title: UniProt entry Q99807 (COQ7_HUMAN)
  findings:
  - statement: >-
      COQ7 is an NADPH-dependent 3-demethoxyubiquinone 3-hydroxylase that binds two
      iron ions per subunit and localizes as a peripheral protein to the matrix side
      of the mitochondrial inner membrane.
    reference_section_type: OTHER
    supporting_text: "Note=Binds 2 iron ions per subunit."
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Authoritative UniProt record; source for enzyme naming, di-iron cofactor,
      subcellular location, and disease associations.
- id: Reactome:R-HSA-2162186
  title: COQ3 methylates DeMQ10H2
  findings: []
- id: Reactome:R-HSA-2162187
  title: COQ6 hydroxylates DHB
  findings: []
- id: Reactome:R-HSA-2162188
  title: COQ5 methylates MDMQ10H2
  findings: []
- id: Reactome:R-HSA-2162193
  title: COQ3 methylates DHDB
  findings: []
- id: Reactome:R-HSA-2162194
  title: COQ7:COQ9 octamer hydroxylates DMQ10H2
  findings: []
- id: Reactome:R-HSA-2162195
  title: COQ4 decarboxylates MHDB
  findings: []