id: Q9BRT2
gene_symbol: UQCC2
product_type: PROTEIN
status: INITIALIZED
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: >-
  UQCC2 (ubiquinol-cytochrome c reductase complex assembly factor 2; also known as MNF1,
  M19 and C6orf125) is a small (126 aa) nuclear-encoded mitochondrial assembly factor for
  respiratory chain Complex III (cytochrome bc1 / ubiquinol-cytochrome c oxidoreductase).
  It is imported into mitochondria via an N-terminal transit peptide and localises
  predominantly to the mitochondrial inner membrane, with additional pools reported in the
  matrix and mitochondrial nucleoid. UQCC2 is the human ortholog of Saccharomyces cerevisiae
  Cbp6p and partners with UQCC1 (the ortholog of Cbp3p); the two proteins are mutually
  required for each other's stability. The UQCC1-UQCC2 module activates translation of, and
  stabilises, the mitochondrially-encoded cytochrome b subunit (MT-CYB), delivering it to an
  early Complex III assembly intermediate. UQCC2 is non-catalytic. Loss-of-function causes
  mitochondrial complex III deficiency, nuclear type 7 (MC3DN7), presenting with severe
  intrauterine growth retardation, neonatal lactic acidosis and renal tubular dysfunction.
existing_annotations:
- term:
    id: GO:0005759
    label: mitochondrial matrix
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: is_active_in
  review:
    summary: >-
      Phylogenetic (IBA) assertion that UQCC2 acts in the mitochondrial matrix. Consistent
      with experimental localisation of the human ortholog: protease-protection experiments
      sublocalise M19/UQCC2 to the matrix space, and UniProt lists mitochondrion matrix as a
      primary location.
    action: ACCEPT
    reason: >-
      Matrix localisation is directly supported by protease-protection data for human UQCC2
      and is consistent with the UniProt SUBCELLULAR LOCATION. A soluble/peripheral matrix
      pool is compatible with the predominant inner-membrane association of the CIII assembly
      module.
    supported_by:
    - reference_id: PMID:19643811
      supporting_text: >-
        protease-protection experiment showed
        it to be sublocalized in the matrix space
- term:
    id: GO:0034551
    label: mitochondrial respiratory chain complex III assembly
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: >-
      Phylogenetic (IBA) assertion of the core function: UQCC2 is a Complex III assembly
      factor. This is the central, experimentally established role of the gene and matches
      the mirrored IDA annotation from PMID:24385928.
    action: ACCEPT
    reason: >-
      This is the core biological process for UQCC2, established both by orthology to the
      yeast CIII assembly factor Cbp6p and by direct functional studies in human cells
      showing UQCC2 loss causes Complex III deficiency.
    supported_by:
    - reference_id: PMID:24385928
      supporting_text: >-
        role of UQCC2 as a complex III assembly factor that cooperates with UQCC1
- term:
    id: GO:0005739
    label: mitochondrion
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: >-
      Electronic UniProt SubCell mapping to mitochondrion. Correct and well supported by
      multiple experimental studies; the most general and least controversial localisation.
    action: ACCEPT
    reason: >-
      Mitochondrial localisation is confirmed by mass spectrometry, immunofluorescence
      (HPA), and targeted experimental studies; this IEA is fully corroborated.
    supported_by:
    - reference_id: PMID:19643811
      supporting_text: >-
        Human
        M19 (hM19) is present in mitochondria
- term:
    id: GO:0005743
    label: mitochondrial inner membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: >-
      Electronic UniProt SubCell mapping to the mitochondrial inner membrane. UniProt notes
      UQCC2 is predominantly expressed in the inner membrane, consistent with its role in
      membrane insertion of nascent cytochrome b during CIII assembly.
    action: ACCEPT
    reason: >-
      The inner membrane is the predominant reported location and is where the UQCC1-UQCC2
      module operates on the membrane-integral MT-CYB; supported by the UniProt record.
    supported_by:
    - reference_id: file:human/UQCC2/UQCC2-uniprot.txt
      supporting_text: Predominantly expressed in the mitochondrial inner
        membrane.
- term:
    id: GO:0005758
    label: mitochondrial intermembrane space
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: >-
      Electronic UniProt SubCell mapping to the intermembrane space. In UniProt this
      location carries only by-similarity (ECO:0000250) evidence; it is plausible but less
      strongly supported than the matrix/inner-membrane pools.
    action: ACCEPT
    reason: >-
      Listed as a UniProt subcellular location (by similarity). Not contradicted by
      experimental data; retained as a peripheral/minor localisation rather than a core role.
    supported_by:
    - reference_id: file:human/UQCC2/UQCC2-uniprot.txt
      supporting_text: Mitochondrion intermembrane space {ECO:0000250}.
- term:
    id: GO:0005759
    label: mitochondrial matrix
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: >-
      Electronic UniProt SubCell mapping to the matrix. Duplicates the IBA/IDA-supported
      matrix localisation (protease-protection of human UQCC2 places it in the matrix space).
    action: ACCEPT
    reason: >-
      Matrix localisation is experimentally supported for human UQCC2; this IEA duplicate is
      consistent and acceptable.
    supported_by:
    - reference_id: PMID:19643811
      supporting_text: >-
        protease-protection experiment showed
        it to be sublocalized in the matrix space
- term:
    id: GO:0042645
    label: mitochondrial nucleoid
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: >-
      Electronic UniProt SubCell mapping to the mitochondrial nucleoid. Supported by the
      original M19 characterisation showing co-localisation with mtDNA and co-fractionation
      with known nucleoid components.
    action: ACCEPT
    reason: >-
      Nucleoid association is experimentally documented (PMID:19643811). Although later work
      showed nucleoids are not disturbed in UQCC2-deficient patient cells (arguing the
      nucleoid link is not the core function), the localisation itself is valid.
    supported_by:
    - reference_id: PMID:19643811
      supporting_text: >-
        co-localized with signals
        arising from mitochondrial DNA (mtDNA), suggesting the inclusion of M19 in the
        mtDNA-protein complex (mitochondrial nucleoids)
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:32296183
  qualifier: enables
  review:
    summary: >-
      High-throughput binary interactome (HuRI) IPI. The reported preys (CDKN2D, EXOC8,
      GNG13, MKRN3, MRFAP1, NRDE2, SNAP25, TRAPPC2, TXN2, ZNF765, plus UQCC1) are largely
      non-mitochondrial and are not connected to Complex III assembly; these are uninformative
      and likely include screen artifacts.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Bare `protein binding` conveys no functional information, and the bulk of the preys from
      this systematic screen are non-mitochondrial proteins with no known relationship to
      UQCC2 biology. Per curation policy this bare-protein-binding IPI is marked as
      over-annotated rather than removed.
    supported_by:
    - reference_id: PMID:32296183
      supporting_text: A reference map of the human binary protein interactome.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:33961781
  qualifier: enables
  review:
    summary: >-
      Proteome-scale interaction network (BioPlex) IPI with UQCC1 (Q9NVA1). This recovers the
      biologically meaningful partner of UQCC2, but the GO term itself (`protein binding`) is
      uninformative.
    action: ACCEPT
    reason: >-
      The recorded partner is UQCC1, the genuine functional binding partner, so the evidence
      is sound; however `protein binding` is not a core molecular function. Kept as supporting
      interaction evidence rather than used in core_functions.
    supported_by:
    - reference_id: PMID:24385928
      supporting_text: revealed efficient co-isolation of UQCC1
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:40205054
  qualifier: enables
  review:
    summary: >-
      Multimodal cell-map / interaction-network IPI with UQCC1 (Q9NVA1), again recovering the
      correct functional partner. `protein binding` remains uninformative as a term.
    action: ACCEPT
    reason: >-
      The prey is UQCC1, the established partner; the interaction is real and consistent with
      the UQCC1-UQCC2 module. Retained as interaction evidence, not as a core molecular
      function.
    supported_by:
    - reference_id: PMID:24385928
      supporting_text: revealed efficient co-isolation of UQCC1
- term:
    id: GO:0005739
    label: mitochondrion
  evidence_type: IDA
  original_reference_id: GO_REF:0000052
  qualifier: located_in
  review:
    summary: >-
      Direct immunofluorescence localisation (Human Protein Atlas) to mitochondrion. Consistent
      with all other localisation evidence.
    action: ACCEPT
    reason: >-
      Independent IDA (imaging) confirmation of mitochondrial localisation; fully consistent
      with the mass-spectrometry and targeted studies.
    supported_by:
    - reference_id: PMID:19643811
      supporting_text: >-
        Human
        M19 (hM19) is present in mitochondria
- term:
    id: GO:0005739
    label: mitochondrion
  evidence_type: HTP
  original_reference_id: PMID:34800366
  qualifier: located_in
  review:
    summary: >-
      High-throughput mitochondrial proteome study assigns UQCC2 to the mitochondrion.
      Corroborates the curated mitochondrial localisation.
    action: ACCEPT
    reason: >-
      Consistent high-throughput confirmation of mitochondrial localisation; no conflict with
      other evidence.
    supported_by:
    - reference_id: PMID:34800366
      supporting_text: Quantitative high-confidence human mitochondrial proteome and its dynamics
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:24385928
  qualifier: enables
  review:
    summary: >-
      IPI with UQCC1 (Q9NVA1) from the primary functional paper. Co-affinity purification
      (UQCC2-TAP and reciprocal UQCC1-TAP) demonstrates a direct, functionally central
      interaction between UQCC2 and UQCC1.
    action: ACCEPT
    reason: >-
      This is the biologically meaningful, experimentally validated interaction underlying the
      UQCC1-UQCC2 assembly module. Although the term is bare `protein binding`, the partner
      (UQCC1) is the correct, core functional partner, so the annotation is accepted as valid
      supporting evidence.
    supported_by:
    - reference_id: PMID:24385928
      supporting_text: revealed efficient co-isolation of UQCC1
    - reference_id: PMID:24385928
      supporting_text: UQCC2 interacts with UQCC1
- term:
    id: GO:0034551
    label: mitochondrial respiratory chain complex III assembly
  evidence_type: IDA
  original_reference_id: PMID:24385928
  qualifier: involved_in
  review:
    summary: >-
      Direct experimental evidence (patient fibroblasts, lentiviral rescue, siRNA knockdown,
      BN-PAGE) that UQCC2 is required for assembly of Complex III. This is the core function
      of the gene.
    action: ACCEPT
    reason: >-
      Loss of UQCC2 causes severe Complex III deficiency that is rescued by re-expression of
      wild-type UQCC2, establishing a direct requirement in CIII assembly. Core BP.
    supported_by:
    - reference_id: PMID:24385928
      supporting_text: >-
        role of UQCC2 as a complex III assembly factor that cooperates with UQCC1
    - reference_id: PMID:24385928
      supporting_text: >-
        UQCC1 and UQCC2 are critical factors required for the expression of cytochrome b and
        complex III biogenesis
- term:
    id: GO:0070131
    label: positive regulation of mitochondrial translation
  evidence_type: IDA
  original_reference_id: PMID:24385928
  qualifier: involved_in
  review:
    summary: >-
      UQCC2 (with UQCC1) activates translation of, and stabilises, mtDNA-encoded cytochrome b
      (MT-CYB). Patient cells show a specific defect in cytochrome b protein synthesis/stability
      despite normal MT-CYB mRNA levels, consistent with a positive role in mitochondrial
      translation of this transcript.
    action: ACCEPT
    reason: >-
      The UQCC1-UQCC2 module functions analogously to the yeast Cbp3p-Cbp6p translational
      activators of cytochrome b; the human data (specific loss of cytochrome b protein with
      unaffected mRNA) support a positive-regulation-of-mitochondrial-translation role for the
      MT-CYB transcript.
    supported_by:
    - reference_id: PMID:24385928
      supporting_text: >-
        activate translation of mtDNA-encoded cytochrome b, bind and stabilize the newly
        synthesized protein
    - reference_id: PMID:24385928
      supporting_text: MT-CYB mRNA levels were unaffected in patient cells
    - reference_id: PMID:24385928
      supporting_text: >-
        a striking and specific defect in cytochrome b protein levels was observed
- term:
    id: GO:0002082
    label: regulation of oxidative phosphorylation
  evidence_type: IMP
  original_reference_id: PMID:22363741
  qualifier: involved_in
  review:
    summary: >-
      RNAi and over-expression of M19/UQCC2 modulate mitochondrial oxygen consumption and ATP
      production, indicating regulation of respiratory chain / oxidative phosphorylation
      activity. This is a downstream consequence of its role in Complex III assembly.
    action: ACCEPT
    reason: >-
      Perturbing UQCC2 changes OXPHOS output (O2 consumption, ATP production), which is
      consistent with regulation of oxidative phosphorylation. This effect is mechanistically
      downstream of the core CIII-assembly function.
    supported_by:
    - reference_id: PMID:22363741
      supporting_text: >-
        M19
        modulates mitochondrial oxygen consumption and ATP production
- term:
    id: GO:0005739
    label: mitochondrion
  evidence_type: IDA
  original_reference_id: PMID:22363741
  qualifier: located_in
  review:
    summary: >-
      Direct localisation of M19/UQCC2 to mitochondria, mediated by an N-terminal 13-residue
      targeting sequence. Consistent with all other localisation evidence.
    action: ACCEPT
    reason: >-
      Independent IDA confirmation of mitochondrial localisation and identification of the
      mitochondrial targeting signal.
    supported_by:
    - reference_id: PMID:22363741
      supporting_text: >-
        13-long amino acid sequence located at
        the N-terminus of M19 that targets the protein to mitochondria
- term:
    id: GO:0005743
    label: mitochondrial inner membrane
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: located_in
  review:
    summary: >-
      Sequence-similarity transfer (from mouse ortholog Q9CQY6) of inner-membrane localisation.
      Consistent with UniProt noting UQCC2 is predominantly expressed in the inner membrane.
    action: ACCEPT
    reason: >-
      Inner membrane is the predominant reported location; the ISS transfer from the mouse
      ortholog is concordant with the human UniProt record.
    supported_by:
    - reference_id: file:human/UQCC2/UQCC2-uniprot.txt
      supporting_text: Predominantly expressed in the mitochondrial inner
        membrane.
- term:
    id: GO:0005758
    label: mitochondrial intermembrane space
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: located_in
  review:
    summary: >-
      Sequence-similarity transfer (from mouse ortholog Q9CQY6) of intermembrane-space
      localisation. Duplicates the IEA IMS annotation; a plausible peripheral pool.
    action: ACCEPT
    reason: >-
      Concordant with the UniProt subcellular location list (by similarity). Retained as a
      minor/peripheral localisation, not a core role.
    supported_by:
    - reference_id: file:human/UQCC2/UQCC2-uniprot.txt
      supporting_text: Mitochondrion intermembrane space {ECO:0000250}.
- term:
    id: GO:0005759
    label: mitochondrial matrix
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: located_in
  review:
    summary: >-
      Sequence-similarity transfer (from mouse ortholog Q9CQY6) of matrix localisation.
      Concordant with the protease-protection evidence placing human UQCC2 in the matrix space.
    action: ACCEPT
    reason: >-
      Matrix localisation is experimentally supported for the human protein and by orthology;
      the ISS transfer is consistent.
    supported_by:
    - reference_id: PMID:19643811
      supporting_text: >-
        protease-protection experiment showed
        it to be sublocalized in the matrix space
- term:
    id: GO:0050796
    label: regulation of insulin secretion
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: involved_in
  review:
    summary: >-
      Sequence-similarity transfer of a physiological role in insulin secretion. In INS-1
      pancreatic beta-cells M19/UQCC2 plays a permissive role in insulin secretion under basal
      glucose conditions, an indirect consequence of its modulation of respiratory chain
      activity.
    action: KEEP_AS_NON_CORE
    reason: >-
      This is a downstream, tissue-specific physiological effect that operates through altered
      OXPHOS/ATP output rather than a direct molecular role of UQCC2. Retained as a non-core
      annotation.
    supported_by:
    - reference_id: PMID:22363741
      supporting_text: >-
        plays a permissive role on insulin secretion under basal
        glucose conditions in INS-1 pancreatic
- term:
    id: GO:2001014
    label: regulation of skeletal muscle cell differentiation
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: involved_in
  review:
    summary: >-
      Sequence-similarity transfer of a role in muscle differentiation. In C2C12 myogenic
      cells M19/UQCC2 acts on late muscle differentiation, an indirect effect of its
      modulation of mitochondrial ATP production.
    action: KEEP_AS_NON_CORE
    reason: >-
      A downstream, tissue-specific developmental effect mediated by altered respiratory chain
      activity, not a direct molecular function of UQCC2. Retained as non-core.
    supported_by:
    - reference_id: PMID:22363741
      supporting_text: >-
        acts on late muscle differentiation in myogenic
        C2C12 cells
- term:
    id: GO:0042645
    label: mitochondrial nucleoid
  evidence_type: IDA
  original_reference_id: PMID:19643811
  qualifier: located_in
  review:
    summary: >-
      Direct experimental evidence: tagged M19/UQCC2 co-localises with mtDNA and co-fractionates
      with known nucleoid components, placing it in the mitochondrial nucleoid. This is the
      original characterisation of the protein.
    action: ACCEPT
    reason: >-
      Well-supported IDA nucleoid association. Note that this is a localisation rather than the
      core CIII-assembly function, and later work found nucleoids are undisturbed in
      UQCC2-deficient patient cells; nonetheless the localisation is valid.
    supported_by:
    - reference_id: PMID:19643811
      supporting_text: >-
        co-localized with signals
        arising from mitochondrial DNA (mtDNA), suggesting the inclusion of M19 in the
        mtDNA-protein complex (mitochondrial nucleoids)
core_functions:
- description: >-
    Mitochondrial Complex III (cytochrome bc1) assembly factor that, in a complex with UQCC1,
    activates translation of and stabilises the mtDNA-encoded cytochrome b subunit (MT-CYB) and
    delivers it into early Complex III assembly intermediates in the mitochondrial inner
    membrane. UQCC2 is non-catalytic, so no molecular_function term is assigned (only bare
    `protein binding` is available in GOA).
  directly_involved_in:
  - id: GO:0034551
    label: mitochondrial respiratory chain complex III assembly
  locations:
  - id: GO:0005743
    label: mitochondrial inner membrane
  - id: GO:0005739
    label: mitochondrion
  supported_by:
  - reference_id: PMID:24385928
    supporting_text: >-
      role of UQCC2 as a complex III assembly factor that cooperates with UQCC1
  - reference_id: file:human/UQCC2/UQCC2-uniprot.txt
    supporting_text: Predominantly expressed in the mitochondrial inner
      membrane.
proposed_new_terms: []
suggested_questions:
- question: >-
    Does UQCC2 have any role beyond MT-CYB translation/stabilisation, and is its nucleoid
    association functionally meaningful or merely a consequence of its inner-membrane/matrix
    localisation near mtDNA?
- question: >-
    Which residues of UQCC2 mediate the UQCC1 interaction and MT-CYB stabilisation, and could a
    more specific molecular function term (e.g. a translational-activator or chaperone activity)
    be justified beyond `protein binding`?
suggested_experiments:
- description: >-
    Structural/crosslinking analysis of the human UQCC1-UQCC2 (and COMA/COMB/COMC) complexes
    bound to nascent MT-CYB to define UQCC2's precise molecular role and any specific activity.
- description: >-
    Ribosome profiling / mitochondrial translation assays in UQCC2-null versus rescued cells to
    quantify the MT-CYB translational-activation defect independently of protein stability.
references:
- id: GO_REF:0000024
  title: Manual transfer of experimentally-verified manual GO annotation data to orthologs
    by curator judgment of sequence similarity
  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:0000052
  title: Gene Ontology annotation based on curation of immunofluorescence data
  findings: []
- id: PMID:19643811
  title: Association of a novel mitochondrial protein M19 with mitochondrial nucleoids.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      PubMed-verified. Original characterisation of M19/UQCC2; establishes mitochondrial and
      nucleoid/matrix localisation (protease-protection, mtDNA co-localisation). Abstract-only
      in cache; supporting quotes taken from the abstract.
- id: PMID:22363741
  title: M19 modulates skeletal muscle differentiation and insulin secretion in pancreatic
    β-cells through modulation of respiratory chain activity.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      PubMed-verified, full text available. Shows M19/UQCC2 modulates O2 consumption and ATP
      production and, via respiratory chain activity, influences muscle differentiation and
      insulin secretion. Source for the OXPHOS-regulation, insulin-secretion and
      muscle-differentiation annotations.
- id: PMID:24385928
  title: Mutations in the UQCC1-interacting protein, UQCC2, cause human complex III
    deficiency associated with perturbed cytochrome b protein expression.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      PubMed-verified, full text available. Definitive functional paper: establishes UQCC2 as
      a Complex III assembly factor, its interaction with UQCC1, its role in cytochrome b
      (MT-CYB) expression, and causation of MC3DN7. Primary support for the core function.
- id: PMID:32296183
  title: A reference map of the human binary protein interactome.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: >-
      PubMed-verified. Systematic binary (HuRI) interactome; most reported UQCC2 preys are
      non-mitochondrial and unrelated to CIII assembly, so the resulting bare `protein binding`
      annotation is uninformative/over-annotated.
- id: PMID:33961781
  title: Dual proteome-scale networks reveal cell-specific remodeling of the human
    interactome.
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: >-
      PubMed-verified. Proteome-scale network recovers the UQCC2-UQCC1 interaction (prey
      Q9NVA1), corroborating the functional partner, though the GO term is bare `protein
      binding`.
- 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: >-
      PubMed-verified. High-throughput mitochondrial proteome study supporting mitochondrial
      localisation of UQCC2.
- id: PMID:40205054
  title: Multimodal cell maps as a foundation for structural and functional genomics.
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: >-
      PubMed-verified. Multimodal cell-map/interaction study recovering the UQCC2-UQCC1
      interaction (prey Q9NVA1); corroborates the functional partner.
- id: file:human/UQCC2/UQCC2-uniprot.txt
  title: UniProtKB entry Q9BRT2 (UQCC2_HUMAN)
  findings: []