id: Q6UW78
gene_symbol: UQCC3
product_type: PROTEIN
status: INITIALIZED
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: >-
  UQCC3 (ubiquinol-cytochrome-c reductase complex assembly factor 3; formerly
  C11orf83) is a small (93-residue) single-pass mitochondrial inner-membrane
  protein and the functional human equivalent of yeast Cbp4p. It is a
  non-catalytic assembly factor for respiratory chain Complex III (cytochrome
  bc1 / ubiquinol-cytochrome c reductase): acting downstream of UQCC1/UQCC2, it
  mediates recruitment and stabilization of the cytochrome b (MT-CYB) subunit
  within the early bc1 core assembly intermediate, and is therefore required for
  Complex III assembly, holocomplex accumulation, and mitochondrial electron
  transport from ubiquinol to cytochrome c. UQCC3 also binds cardiolipin (via its
  intermembrane-space-facing α-helices), influences mitochondrial cardiolipin
  composition and cristae morphology, and helps stabilize bc1-containing
  respiratory supercomplexes (notably the III2/IV supercomplex). Its N-terminus
  sits in the matrix, followed by a transmembrane helix and an
  intermembrane-space-facing C-terminal lipid-binding region; the protein is
  cleaved by the OMA1 metalloprotease upon mitochondrial depolarization. Loss of
  function causes mitochondrial complex III deficiency, nuclear type 9 (MC3DN9),
  presenting with severe lactic acidosis, hypoglycemia, hypotonia, and delayed
  psychomotor development.
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: >-
      Phylogenetic (IBA) inference that UQCC3 is active in the mitochondrial inner
      membrane. This is the correct compartment for this Complex III assembly
      factor and is strongly corroborated by direct experimental localization.
    action: ACCEPT
    reason: >-
      Well supported by direct (IDA) localization in two primary studies and by
      the UniProt subcellular location; UQCC3 is a single-pass inner-membrane
      protein where Complex III assembly occurs. This is a core cellular
      component annotation.
    supported_by:
    - reference_id: PMID:25605331
      supporting_text: >-
        is a mitochondrial inner membrane protein facing the intermembrane space
    - reference_id: file:human/UQCC3/UQCC3-uniprot.txt
      supporting_text: Mitochondrion inner membrane
- term:
    id: GO:0006122
    label: mitochondrial electron transport, ubiquinol to cytochrome c
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: >-
      Phylogenetic inference that UQCC3 is involved in Complex III-mediated
      electron transport from ubiquinol to cytochrome c. UQCC3 is a non-catalytic
      assembly factor, so it participates in this process only indirectly, by
      building and stabilizing Complex III; loss of UQCC3 abolishes Complex III
      activity.
    action: KEEP_AS_NON_CORE
    reason: >-
      Defensible (UQCC3 loss impairs electron transport because Complex III is not
      assembled), but UQCC3 is not part of the electron-transfer machinery itself;
      the core function is Complex III assembly. Keep as a non-core process
      annotation reflecting the downstream physiological consequence.
    supported_by:
    - reference_id: file:human/UQCC3/UQCC3-uniprot.txt
      supporting_text: >-
        Required for the assembly of the ubiquinol-cytochrome c reductase complex
- 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 inference that UQCC3 is involved in mitochondrial respiratory
      chain Complex III assembly. This is the central, well-established function of
      UQCC3 and matches its yeast ortholog Cbp4p.
    action: ACCEPT
    reason: >-
      This is the core biological process for UQCC3, independently supported by IMP
      evidence (patient-cell and knockdown studies) and by InterPro-based IEA. UQCC3
      acts downstream of UQCC1/UQCC2 to stabilize the cytochrome-b-containing bc1
      core assembly intermediate.
    supported_by:
    - reference_id: PMID:25008109
      supporting_text: >-
        UQCC3 functions in the complex III assembly pathway downstream of UQCC1 and
        UQCC2
    - reference_id: PMID:25605331
      supporting_text: >-
        involved in the early stages of its assembly by stabilizing the bc1 core
        complex
- term:
    id: GO:0005743
    label: mitochondrial inner membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: >-
      Electronic annotation mapped from the UniProt Swiss-Prot subcellular location
      "Mitochondrion inner membrane". Correct and consistent with the experimental
      localization.
    action: ACCEPT
    reason: >-
      The UniProt subcellular location it is derived from is itself experimentally
      supported (IDA in two studies). This is the correct compartment.
    supported_by:
    - reference_id: file:human/UQCC3/UQCC3-uniprot.txt
      supporting_text: Mitochondrion inner membrane
- term:
    id: GO:0034551
    label: mitochondrial respiratory chain complex III assembly
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: involved_in
  review:
    summary: >-
      InterPro2GO electronic annotation (InterPro:IPR027896, the UQCC3 family) to
      Complex III assembly. The UQCC3 family signature is diagnostic of exactly this
      function, so the mapping is appropriate.
    action: ACCEPT
    reason: >-
      The InterPro entry IPR027896 is specific to the UQCC3 family whose defining
      function is Complex III assembly; the IEA is consistent with experimental and
      phylogenetic evidence. Core biological process.
    supported_by:
    - reference_id: PMID:25605331
      supporting_text: >-
        involved in the early stages of its assembly by stabilizing the bc1 core
        complex
- term:
    id: GO:0005739
    label: mitochondrion
  evidence_type: IDA
  original_reference_id: GO_REF:0000052
  qualifier: located_in
  review:
    summary: >-
      Direct immunofluorescence localization (Human Protein Atlas) to the
      mitochondrion. Correct but less specific than the mitochondrial inner
      membrane localization.
    action: ACCEPT
    reason: >-
      Accurate direct localization; the parent compartment (mitochondrion) is
      subsumed by the more specific inner-membrane annotation but is not wrong.
      Retained as a valid, if broader, CC annotation.
    supported_by:
    - reference_id: PMID:25605331
      supporting_text: >-
        is a mitochondrial inner membrane protein facing the intermembrane space
- term:
    id: GO:0005739
    label: mitochondrion
  evidence_type: HTP
  original_reference_id: PMID:34800366
  qualifier: located_in
  review:
    summary: >-
      High-throughput mitochondrial proteomics assigns UQCC3 to the mitochondrion.
      Consistent with the curated inner-membrane localization.
    action: ACCEPT
    reason: >-
      High-throughput proteomic detection agrees with the direct localization data;
      correct though broader than the mitochondrial inner membrane term.
    supported_by:
    - reference_id: file:human/UQCC3/UQCC3-uniprot.txt
      supporting_text: Mitochondrion inner membrane
- term:
    id: GO:0006122
    label: mitochondrial electron transport, ubiquinol to cytochrome c
  evidence_type: IMP
  original_reference_id: PMID:25008109
  qualifier: involved_in
  review:
    summary: >-
      Mutant-phenotype evidence: patient fibroblasts carrying a UQCC3 loss-of-function
      variant have reduced Complex III activity and holocomplex levels, and cytochrome
      b is absent from the high-molecular-weight complex, impairing ubiquinol-to-cytochrome
      c electron transport. UQCC3 mediates this process indirectly, as a non-catalytic
      assembly factor.
    action: KEEP_AS_NON_CORE
    reason: >-
      The IMP is valid — UQCC3 loss impairs Complex III-mediated electron transport — but
      UQCC3 does not itself carry electrons; the phenotype is a downstream consequence of
      failed Complex III assembly. Kept as non-core, with assembly (GO:0034551) as the core
      process.
    supported_by:
    - reference_id: PMID:25008109
      supporting_text: >-
        reduced complex III activity and lower levels
    - reference_id: PMID:25008109
      supporting_text: >-
        cytochrome b is absent from a high-molecular-weight complex III
- term:
    id: GO:0034551
    label: mitochondrial respiratory chain complex III assembly
  evidence_type: IMP
  original_reference_id: PMID:25605331
  qualifier: involved_in
  review:
    summary: >-
      Mutant/knockdown-phenotype evidence that UQCC3 is required for Complex III
      assembly: it is specifically associated with the bc1 complex and stabilizes the
      bc1 core complex during the early stages of assembly.
    action: ACCEPT
    reason: >-
      Direct experimental (IMP) support for the core function. Depletion of UQCC3
      impairs bc1 assembly, and UQCC3 stabilizes the early bc1 core intermediate. This
      is the primary, core biological process of the gene.
    supported_by:
    - reference_id: PMID:25605331
      supporting_text: >-
        specifically associated with the bc1 complex of the electron
    - reference_id: PMID:25605331
      supporting_text: >-
        involved in the early stages of its assembly by stabilizing the bc1 core
        complex
- term:
    id: GO:0042407
    label: cristae formation
  evidence_type: IMP
  original_reference_id: PMID:25605331
  qualifier: involved_in
  review:
    summary: >-
      Depletion of UQCC3 (C11orf83) in HeLa cells causes abnormal crista morphology,
      linking UQCC3 to cristae organization. This is a downstream phenotypic consequence
      of its roles in Complex III/supercomplex assembly and cardiolipin homeostasis
      rather than a direct structural role in cristae biogenesis.
    action: KEEP_AS_NON_CORE
    reason: >-
      The mutant phenotype is real (abnormal crista morphology on depletion), but it is a
      secondary consequence of impaired supercomplex organization and altered cardiolipin
      composition, not a distinct core molecular activity of UQCC3. Retained as a non-core
      process annotation.
    supported_by:
    - reference_id: PMID:25605331
      supporting_text: >-
        C11orf83 depletion in HeLa cells caused abnormal crista morphology
- term:
    id: GO:0070300
    label: phosphatidic acid binding
  evidence_type: IDA
  original_reference_id: PMID:25605331
  qualifier: enables
  review:
    summary: >-
      Direct-assay lipid-binding annotation. UQCC3 has an intermembrane-space-facing
      lipid-binding region and binds anionic phospholipids; the physiologically salient
      ligand demonstrated in this study is cardiolipin, with phosphatidic acid binding
      reported in the full-text lipid-binding assays.
    action: KEEP_AS_NON_CORE
    reason: >-
      Experimental IDA from the same study; per curation policy an experimental lipid-binding
      annotation should not be removed. The cached abstract documents cardiolipin binding
      explicitly (see GO:1901612), and UniProt records a dedicated lipid-binding region;
      phosphatidic acid binding is a genuine but secondary lipid-binding activity, so kept as
      non-core while cardiolipin binding is treated as the core molecular function.
    supported_by:
    - reference_id: file:human/UQCC3/UQCC3-uniprot.txt
      supporting_text: Mediates lipid-binding
- term:
    id: GO:1901612
    label: cardiolipin binding
  evidence_type: IDA
  original_reference_id: PMID:25605331
  qualifier: enables
  review:
    summary: >-
      Direct-assay evidence that UQCC3 (C11orf83) binds cardiolipin through its α-helices
      2 and 3, correlating with effects on mitochondrial cardiolipin composition and
      supercomplex stability. This is the one informative molecular function of this
      otherwise non-catalytic assembly factor.
    action: ACCEPT
    reason: >-
      Well-supported experimental (IDA) molecular function; cardiolipin is the
      physiologically relevant lipid ligand and this binding underpins UQCC3's role in
      supercomplex/cristae stabilization. Core molecular function.
    supported_by:
    - reference_id: PMID:25605331
      supporting_text: >-
        We showed that C11orf83 binds
        to cardiolipin by its α-helices 2 and 3
- term:
    id: GO:0005743
    label: mitochondrial inner membrane
  evidence_type: IDA
  original_reference_id: PMID:25008109
  qualifier: located_in
  review:
    summary: >-
      Direct localization of UQCC3 to the mitochondrial inner membrane, the compartment
      where Complex III assembly occurs. UQCC3 is a single-pass inner-membrane protein.
    action: ACCEPT
    reason: >-
      Direct experimental support for the core cellular component. Consistent with the
      second primary study and UniProt.
    supported_by:
    - reference_id: file:human/UQCC3/UQCC3-uniprot.txt
      supporting_text: Mitochondrion inner membrane
- term:
    id: GO:0005743
    label: mitochondrial inner membrane
  evidence_type: IDA
  original_reference_id: PMID:25605331
  qualifier: located_in
  review:
    summary: >-
      Direct localization showing UQCC3 (C11orf83) is a mitochondrial inner membrane
      protein facing the intermembrane space. Core cellular component.
    action: ACCEPT
    reason: >-
      Direct experimental support; the topology (matrix N-terminus, single TM helix,
      IMS-facing C-terminus) places UQCC3 firmly in the inner membrane. Core CC.
    supported_by:
    - reference_id: PMID:25605331
      supporting_text: >-
        is a mitochondrial inner membrane protein facing the intermembrane space
core_functions:
- description: >-
    Non-catalytic Complex III (cytochrome bc1) assembly factor that binds cardiolipin
    and stabilizes the early cytochrome-b-containing bc1 core assembly intermediate in
    the mitochondrial inner membrane, acting downstream of UQCC1/UQCC2 and contributing
    to respiratory supercomplex organization.
  molecular_function:
    id: GO:1901612
    label: cardiolipin binding
  directly_involved_in:
  - id: GO:0034551
    label: mitochondrial respiratory chain complex III assembly
  locations:
  - id: GO:0005743
    label: mitochondrial inner membrane
  supported_by:
  - reference_id: PMID:25605331
    supporting_text: >-
      involved in the early stages of its assembly by stabilizing the bc1 core
      complex
  - reference_id: PMID:25605331
    supporting_text: >-
      We showed that C11orf83 binds
      to cardiolipin by its α-helices 2 and 3
  - reference_id: PMID:25008109
    supporting_text: >-
      UQCC3 functions in the complex III assembly pathway downstream of UQCC1 and
      UQCC2
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:0000052
  title: Gene Ontology annotation based on curation of immunofluorescence data
  findings: []
- id: PMID:25008109
  title: A mutation in the human CBP4 ortholog UQCC3 impairs complex III assembly,
    activity and cytochrome b stability.
  findings:
  - statement: >-
      A homozygous UQCC3 loss-of-function variant causes isolated Complex III
      deficiency; patient fibroblasts have reduced Complex III activity and
      holocomplex levels, and cytochrome b is destabilized, placing UQCC3 in the
      Complex III assembly pathway downstream of UQCC1 and UQCC2.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      PubMed-verified primary study establishing UQCC3 as the human CBP4 ortholog and
      a Complex III assembly factor; source of the MC3DN9 disease association. Cached
      entry is abstract-only.
- id: PMID:25605331
  title: C11orf83, a mitochondrial cardiolipin-binding protein involved in bc1 complex
    assembly and supercomplex stabilization.
  findings:
  - statement: >-
      C11orf83/UQCC3 is an inner-membrane protein facing the intermembrane space that
      stabilizes the early bc1 core complex, binds cardiolipin via α-helices 2 and 3,
      influences cardiolipin composition and cristae morphology, stabilizes bc1
      supercomplexes (III2/IV), and is cleaved by OMA1 upon depolarization.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      PubMed-verified primary study; source of the cardiolipin-binding, supercomplex,
      cristae, and OMA1-cleavage findings. Cached entry is abstract-only (phosphatidic
      acid binding is reported in the full-text lipid-binding assays).
- id: PMID:34800366
  title: Quantitative high-confidence human mitochondrial proteome and its dynamics
    in cellular context.
  findings:
  - statement: >-
      High-throughput mitochondrial proteomics detects UQCC3 as a mitochondrial protein.
    reference_section_type: RESULTS
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: >-
      High-throughput proteomic dataset supporting mitochondrial localization; corroborates
      the direct localization annotations.
- id: file:human/UQCC3/UQCC3-uniprot.txt
  title: UniProtKB Q6UW78 (UQCC3_HUMAN)
  findings:
  - statement: >-
      UniProt curates UQCC3 as required for Complex III (cytochrome b-c1) assembly via
      cytochrome b recruitment/stabilization, a cardiolipin-binding single-pass inner
      mitochondrial membrane protein with a lipid-binding region (residues 23-80), cleaved
      by OMA1 under stress, and causal for MC3DN9.
    reference_section_type: OTHER
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Swiss-Prot manually reviewed entry summarizing function, subcellular location,
      topology, lipid binding, PTM, and disease.