id: P0DJ07
gene_symbol: PET100
product_type: PROTEIN
status: INITIALIZED
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: >-
  PET100 is a small (73 aa) single-pass mitochondrial inner-membrane protein that
  functions as a Complex IV (cytochrome c oxidase, COX)-specific assembly chaperone.
  It is the human ortholog of yeast Pet100p and belongs to the PET100 family. PET100
  is non-catalytic; it promotes incorporation of the early nuclear-encoded COX
  subunits (the COX7/COX8 group, exemplified by its conserved interaction with COX
  subunit VIIa, COX7A2) into an early COX assembly intermediate, forming a ~300 kDa
  subcomplex with Complex IV subunits in the mitochondrial inner membrane. Loss of
  PET100 function causes isolated mitochondrial complex IV deficiency (mitochondrial
  complex IV deficiency nuclear type 12; Leigh syndrome), with reduced COX levels and
  activity.
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) assignment of PET100 to the mitochondrial inner membrane,
      consistent with its yeast ortholog Pet100p and with direct experimental
      evidence in human. This is the correct, specific subcellular location and a core
      aspect of PET100 biology.
    action: ACCEPT
    reason: >-
      PET100 is experimentally localized to the mitochondrial inner membrane, where it
      acts as a COX assembly chaperone. The IBA is fully concordant with the human
      experimental data.
    supported_by:
    - reference_id: PMID:24462369
      supporting_text: located in the mitochondrial inner membrane and forms a
    - reference_id: PMID:22356826
      supporting_text: >-
        corroborating the conserved interaction of fungal Pet100p-subunit VIIa that
        takes place in the inner mitochondrial membrane of yeast
- term:
    id: GO:0044183
    label: protein folding chaperone
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: enables
  review:
    summary: >-
      IBA molecular-function annotation as a "protein folding chaperone". PET100 is a
      COX-specific assembly/scaffolding chaperone that promotes incorporation of early
      COX subunits, but there is no evidence that it catalyzes or assists protein
      folding per se. This over-interprets its assembly role as a folding activity.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      PET100 has no demonstrated protein-folding-catalysis function; its documented
      role is binding COX subunits (e.g. COX7A2) and promoting their incorporation into
      the assembling complex. Notably the UniProt-listed PAN-GO molecular function is
      the binding term GO:0051082 (unfolded protein binding), not folding activity. The
      IBA is not overtly wrong (PET100 is chaperone-like) so it is retained as an
      over-annotation rather than removed, per curation policy for phylogenetically
      reviewed annotations.
    propagation_review:
      root_cause: TERM_SCOPING_PROBLEM
      failure_modes:
      - ROLE_CONFLATION
      source_entities:
      - source_id: SGD:S000002486
        source_label: PET100 (S. cerevisiae Pet100p)
        comment: >-
          Yeast Pet100p is a COX-specific assembly chaperone; the phylogenetic MF
          transfer over-labels this assembly/scaffolding role as protein-folding
          activity.
    supported_by:
    - reference_id: PMID:22356826
      supporting_text: >-
        The subunit VIIa of COX (encoded by the COX7A2 gene) was specifically
        co-purified with PET100
- term:
    id: GO:0051131
    label: chaperone-mediated protein complex assembly
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: >-
      IBA biological-process annotation describing PET100's chaperone-mediated role in
      assembling a protein complex. This accurately captures the mechanism by which
      PET100 promotes incorporation of COX subunits into Complex IV and complements the
      more specific GO:0033617.
    action: ACCEPT
    reason: >-
      PET100 acts as a chaperone that mediates assembly of the cytochrome c oxidase
      complex, interacting with COX7A2 and forming an early ~300 kDa COX subcomplex.
      This is a valid, mechanism-oriented characterization consistent with the
      literature.
    supported_by:
    - reference_id: PMID:24462369
      supporting_text: located in the mitochondrial inner membrane and forms a
    - reference_id: PMID:22356826
      supporting_text: >-
        The subunit VIIa of COX (encoded by the COX7A2 gene) was specifically
        co-purified with PET100
- term:
    id: GO:0033617
    label: mitochondrial respiratory chain complex IV assembly
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: >-
      IBA annotation to Complex IV assembly. This is the core biological process of
      PET100: it is a COX-specific assembly factor essential for Complex IV maturation
      and assembly, and its loss causes isolated Complex IV deficiency.
    action: ACCEPT
    reason: >-
      Strongly supported by experimental data in human (PET100 mutations cause isolated
      complex IV deficiency; PET100 forms an early COX subcomplex) and by orthology to
      yeast Pet100p, a COX assembly factor. This is the central function of the gene.
    supported_by:
    - reference_id: PMID:24462369
      supporting_text: located in the mitochondrial inner membrane and forms a
    - reference_id: PMID:22356826
      supporting_text: >-
        The subunit VIIa of COX (encoded by the COX7A2 gene) was specifically
        co-purified with PET100
- term:
    id: GO:0005739
    label: mitochondrion
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: located_in
  review:
    summary: >-
      Electronic annotation to mitochondrion (from InterPro/UniProt SubCell mapping).
      Correct but general; the specific location is the mitochondrial inner membrane.
    action: ACCEPT
    reason: >-
      PET100 is a mitochondrial protein; this parent term is accurate. It is retained
      as a correct, if less specific, location annotation alongside the inner-membrane
      term.
    supported_by:
    - reference_id: PMID:24462369
      supporting_text: located in the mitochondrial inner membrane and forms a
- term:
    id: GO:0005743
    label: mitochondrial inner membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: >-
      Electronic (SubCell mapping) annotation to the mitochondrial inner membrane. This
      is the correct specific location, independently supported experimentally.
    action: ACCEPT
    reason: >-
      Concordant with the experimental EXP and IBA inner-membrane annotations; PET100 is
      a single-pass inner-membrane protein.
    supported_by:
    - reference_id: file:human/PET100/PET100-uniprot.txt
      supporting_text: Mitochondrion inner membrane
- term:
    id: GO:0006457
    label: protein folding
  evidence_type: IEA
  original_reference_id: GO_REF:0000108
  qualifier: involved_in
  review:
    summary: >-
      Electronic annotation to "protein folding", derived by inter-ontology logical
      inference from the "protein folding chaperone" MF (GO:0044183). It inherits the
      over-interpretation of PET100's assembly role as a folding process.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      This BP is an automatic consequence of the over-annotated GO:0044183 MF (see the
      with/from GO:0044183). PET100 promotes assembly/incorporation of COX subunits but
      is not documented to participate in protein folding. Marked as over-annotated
      rather than removed because the underlying chaperone characterization is not
      overtly wrong.
    supported_by:
    - reference_id: PMID:24462369
      supporting_text: located in the mitochondrial inner membrane and forms a
- term:
    id: GO:0016020
    label: membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: >-
      Electronic annotation to the root "membrane" term (from the SubCell "single-pass
      membrane protein" mapping). Uninformative given the specific mitochondrial
      inner-membrane annotation.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      "membrane" is an unspecific location that adds no information beyond the more
      precise GO:0005743 (mitochondrial inner membrane). It reflects the generic
      single-pass-membrane-protein SubCell keyword rather than a distinct localization.
    supported_by:
    - reference_id: file:human/PET100/PET100-uniprot.txt
      supporting_text: Single-pass membrane protein
- term:
    id: GO:0033617
    label: mitochondrial respiratory chain complex IV assembly
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: involved_in
  review:
    summary: >-
      InterPro2GO electronic annotation to Complex IV assembly, based on the Pet100
      domain (IPR018625). Concordant with the IBA and experimental evidence for the
      core function.
    action: ACCEPT
    reason: >-
      The InterPro Pet100 signature is a reliable predictor of Complex IV assembly
      function; this duplicate of the core BP is correct.
    supported_by:
    - reference_id: PMID:24462369
      supporting_text: located in the mitochondrial inner membrane and forms a
- term:
    id: GO:0005739
    label: mitochondrion
  evidence_type: HTP
  original_reference_id: PMID:34800366
  qualifier: located_in
  review:
    summary: >-
      High-throughput proteomics (mitochondrial proteome) localization to mitochondrion.
      Correct but general; consistent with the specific inner-membrane location.
    action: ACCEPT
    reason: >-
      Independent HTP proteomic support for PET100's mitochondrial localization. Retained
      as a correct parent-level location.
    supported_by:
    - reference_id: PMID:24462369
      supporting_text: located in the mitochondrial inner membrane and forms a
- term:
    id: GO:0005743
    label: mitochondrial inner membrane
  evidence_type: EXP
  original_reference_id: PMID:24462369
  qualifier: located_in
  review:
    summary: >-
      Experimental (EXP) localization of PET100 to the mitochondrial inner membrane,
      where it forms a ~300 kDa subcomplex with Complex IV subunits. This is the
      definitive, experimentally established core location.
    action: ACCEPT
    reason: >-
      Directly demonstrated in the disease study establishing PET100's function; the
      strongest evidence for the inner-membrane location and the anchor for the other
      inner-membrane annotations.
    supported_by:
    - reference_id: PMID:24462369
      supporting_text: located in the mitochondrial inner membrane and forms a
core_functions:
- description: >-
    Non-catalytic Complex IV (cytochrome c oxidase)-specific assembly chaperone in the
    mitochondrial inner membrane. As the human ortholog of yeast Pet100p, PET100 binds
    early nuclear-encoded COX subunits (exemplified by the conserved interaction with
    COX subunit VIIa, COX7A2) and promotes their incorporation into an early COX
    assembly intermediate, forming a ~300 kDa subcomplex with Complex IV subunits.
    PET100 is essential for Complex IV maturation and assembly; its loss causes isolated
    Complex IV deficiency. No molecular-function term is asserted because PET100 has no
    catalytic activity and only binding/scaffolding-type molecular functions (the
    GOA "protein folding chaperone" term over-interprets this assembly role).
  directly_involved_in:
  - id: GO:0033617
    label: mitochondrial respiratory chain complex IV assembly
  locations:
  - id: GO:0005743
    label: mitochondrial inner membrane
  supported_by:
  - reference_id: PMID:24462369
    supporting_text: located in the mitochondrial inner membrane and forms a
  - reference_id: PMID:22356826
    supporting_text: >-
      The subunit VIIa of COX (encoded by the COX7A2 gene) was specifically co-purified
      with PET100
  - reference_id: file:human/PET100/PET100-uniprot.txt
    supporting_text: Plays an essential role in mitochondrial complex IV
proposed_new_terms: []
suggested_questions:
- question: >-
    Which specific early COX subunits (COX7A2/COX7B/COX8A and orthologs) does human
    PET100 directly engage, and does it act sequentially or as a scaffold that couples
    their incorporation into the assembling Complex IV?
- question: >-
    Does PET100 have any binding-type molecular function that could be captured by a
    more informative GO term than "protein folding chaperone", and if so what is its
    structural basis given the single transmembrane helix?
suggested_experiments:
- description: >-
    Perform complexome profiling / BN-PAGE with quantitative mass spectrometry in
    PET100-null versus wild-type cells to define which COX assembly intermediate stalls
    in the absence of PET100 and which subunits fail to be incorporated.
- description: >-
    Use crosslinking mass spectrometry or co-immunoprecipitation of tagged PET100 to map
    its direct interaction partners among COX subunits and other assembly factors, and
    to test the proposed role in incorporating the early COX7/COX8 subunit group.
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:0000108
  title: Automatic assignment of GO terms using logical inference, based on on inter-ontology
    links
  findings: []
- id: GO_REF:0000120
  title: Combined Automated Annotation using Multiple IEA Methods
  findings: []
- id: PMID:24462369
  title: A founder mutation in PET100 causes isolated complex IV deficiency in Lebanese
    individuals with Leigh syndrome.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Establishes PET100 (C19orf79) as the causal gene for isolated complex IV
      deficiency / Leigh syndrome via a founder c.3G>C (p.Met1?) mutation, confirmed by
      lentiviral phenotypic correction. Shows PET100 is located in the mitochondrial
      inner membrane and forms a ~300 kDa subcomplex with complex IV subunits. Cached
      abstract is abstract-only (full_text_available: false) but PMID/title verified and
      the quoted localization statement is verbatim in the cached record.
- id: PMID:22356826
  title: Iterative orthology prediction uncovers new mitochondrial proteins and identifies
    C12orf62 as the human ortholog of COX14, a protein involved in the assembly of cytochrome
    c oxidase.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Ortho-Profile study predicting PET100 (LOC100131801) as the human ortholog of
      yeast Pet100p (COX assembly factor) and experimentally co-purifying COX subunit
      VIIa (COX7A2) specifically with PET100, corroborating the conserved Pet100p-VIIa
      interaction in the inner mitochondrial membrane. Full text available and verified.
- 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-confidence human mitochondrial proteome (MitoCoP); source of independent
      HTP support for PET100's mitochondrial localization.
- id: file:human/PET100/PET100-uniprot.txt
  title: UniProtKB entry P0DJ07 (PT100_HUMAN)
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      UniProt record for PET100; FUNCTION ("essential role in mitochondrial complex IV
      maturation and assembly"), SUBUNIT (interacts with COX7A2), inner-membrane
      SUBCELLULAR LOCATION, single-pass membrane topology, and MC4DN12 disease
      association used as supporting evidence.