id: Q9Y5T4
gene_symbol: DNAJC15
product_type: PROTEIN
status: COMPLETE
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: DNAJC15 (MCJ, "methylation-controlled J protein") is a small (150 aa) single-pass mitochondrial inner-membrane protein of the DnaJ/HSP40 subfamily C, anchored by a single transmembrane helix with its C-terminal J domain facing the matrix. It has two intertwined activities. As a J co-chaperone of the TIM23 presequence translocase import motor, it stimulates the ATPase activity of the matrix HSP70 chaperone mortalin (HSPA9) to drive presequence-protein import into the matrix; it forms a stable subcomplex with PAM16/MAGMAS, which counteracts this ATPase stimulation. Independently, MCJ associates with respiratory-chain complex I, impairs supercomplex assembly and acts as an endogenous negative regulator of the respiratory chain, restricting mitochondrial membrane potential and ATP production. DNAJC15 is highly expressed in heart, liver and kidney; its promoter is hypermethylated and silenced in many cancers, where loss of expression is associated with chemoresistance.
existing_annotations:
- term:
    id: GO:0001405
    label: PAM complex, Tim23 associated import motor
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: part_of
  review:
    summary: Phylogenetic (IBA) annotation placing MCJ in the PAM (presequence translocase-associated motor) of the TIM23 complex. Experimentally supported by its interaction with PAM16/MAGMAS and the core TIM23 components and its J co-chaperone activity in import.
    action: ACCEPT
    reason: MCJ forms a subcomplex with the import motor component MAGMAS and interacts with the core TIM23 translocase; it is a genuine PAM-associated J co-chaperone.
    supported_by:
    - reference_id: PMID:23263864
      supporting_text: MCJ forms a stable subcomplex with a component of the mitochondrial import motor, MAGMAS
- term:
    id: GO:0001671
    label: ATPase activator activity
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: enables
  review:
    summary: MCJ stimulates the ATPase activity of the matrix HSP70 chaperone mortalin (HSPA9), the defining molecular function of a TIM23-motor J co-chaperone. Experimentally demonstrated for the recombinant soluble MCJ J domain.
    action: ACCEPT
    reason: Directly supported experimentally; stimulating mortalin/HSPA9 ATPase activity is the core molecular function of MCJ as a J-domain co-chaperone.
    supported_by:
    - reference_id: PMID:23263864
      supporting_text: the recombinant soluble MCJ domain stimulates the ATPase activity of the human mtHsp70 chaperone, mortalin
- term:
    id: GO:0030150
    label: protein import into mitochondrial matrix
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: As a J co-chaperone of the TIM23 import motor, MCJ is required for efficient presequence-protein import into the mitochondrial matrix.
    action: ACCEPT
    reason: Pre-protein import into mitochondria is impaired in the absence of MCJ; a core biological process for this gene.
    supported_by:
    - reference_id: PMID:23263864
      supporting_text: pre-protein import into mitochondria is impaired in the absence of MCJ
- term:
    id: GO:0005743
    label: mitochondrial inner membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: located_in
  review:
    summary: Automated annotation of mitochondrial inner-membrane localization, consistent with the experimentally established single-pass inner-membrane topology of MCJ.
    action: ACCEPT
    reason: MCJ is anchored in the mitochondrial inner membrane (single-pass), its core site of action; corroborated by direct experimental evidence.
    supported_by:
    - reference_id: PMID:23263864
      supporting_text: It is anchored in the mitochondrial inner membrane with the C-terminal J domain facing the matrix space.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:23263864
  qualifier: enables
  review:
    summary: Curated interaction with PAM16/MAGMAS (Q9Y3D7), the import-motor partner that forms a stable subcomplex with MCJ and antagonizes its HSPA9 ATPase-stimulating activity. The bare protein binding term is uninformative, but the interaction is functionally central.
    action: KEEP_AS_NON_CORE
    reason: Records a real, functionally important interaction (PAM16/MAGMAS), but GO:0005515 is uninformative; the functional consequence (J co-chaperone regulation) is captured by the ATPase activator activity and import annotations.
    supported_by:
    - reference_id: PMID:23263864
      supporting_text: MCJ forms a stable subcomplex with a component of the mitochondrial import motor, MAGMAS
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:25416956
  qualifier: enables
  review:
    summary: Yeast two-hybrid human interactome screen capturing MCJ interactions with Q8IUQ4 and Q8IZU0. The bare protein binding term is uninformative and these high-throughput partners are not characterized in the context of MCJ function.
    action: KEEP_AS_NON_CORE
    reason: Uninformative GO:0005515 from a high-throughput Y2H screen with uncharacterized partners; not part of the established core function.
    supported_by:
    - reference_id: file:human/DNAJC15/DNAJC15-goa.tsv
      supporting_text: GO:0005515 protein binding molecular_function ECO:0000353 IPI PMID:25416956 UniProtKB:Q8IUQ4
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:33961781
  qualifier: enables
  review:
    summary: BioPlex affinity-purification interactome capturing the MCJ-PAM16/MAGMAS (Q9Y3D7) interaction. The bare protein binding term is uninformative.
    action: KEEP_AS_NON_CORE
    reason: Records the real PAM16/MAGMAS interaction but GO:0005515 itself is uninformative; the functional meaning is captured elsewhere and it is not elevated to core.
    supported_by:
    - reference_id: file:human/DNAJC15/DNAJC15-goa.tsv
      supporting_text: GO:0005515 protein binding molecular_function ECO:0000353 IPI PMID:33961781 UniProtKB:Q9Y3D7
- term:
    id: GO:0005739
    label: mitochondrion
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: located_in
  review:
    summary: Electronic (Ensembl orthology) annotation of mitochondrial localization, a generic parent of the specific inner-membrane localization.
    action: KEEP_AS_NON_CORE
    reason: Correct but generic; the specific mitochondrial inner-membrane localization is the informative, core annotation.
    supported_by:
    - reference_id: PMID:23263864
      supporting_text: Our results demonstrate that MCJ is located in mitochondria.
- term:
    id: GO:0005743
    label: mitochondrial inner membrane
  evidence_type: NAS
  original_reference_id: PMID:10339406
  qualifier: located_in
  review:
    summary: Non-traceable author statement (ComplexPortal) of inner-membrane localization, redundant with the experimentally established inner-membrane topology.
    action: ACCEPT
    reason: Consistent with and corroborated by direct experimental evidence for inner-membrane anchoring; a core localization.
    supported_by:
    - reference_id: PMID:23263864
      supporting_text: It is anchored in the mitochondrial inner membrane with the C-terminal J domain facing the matrix space.
- term:
    id: GO:0005744
    label: TIM23 mitochondrial import inner membrane translocase complex
  evidence_type: NAS
  original_reference_id: PMID:10339406
  qualifier: part_of
  review:
    summary: ComplexPortal annotation placing MCJ in the TIM23 translocase complex, supported by its interaction with the core TIM23 components and PAM16/MAGMAS.
    action: ACCEPT
    reason: MCJ interacts with the core TIM23 pre-protein translocase and functions as its J co-chaperone; membership is well supported.
    supported_by:
    - reference_id: PMID:23263864
      supporting_text: MCJ and MAGMAS interact with the core components of the TIM23 pre-protein translocase.
- term:
    id: GO:0006886
    label: intracellular protein transport
  evidence_type: NAS
  original_reference_id: PMID:10339406
  qualifier: involved_in
  review:
    summary: ComplexPortal annotation of intracellular protein transport, a generic parent of MCJ's specific role in mitochondrial matrix protein import.
    action: KEEP_AS_NON_CORE
    reason: Correct but generic; the specific process (protein import into mitochondrial matrix) is the informative, core annotation.
    supported_by:
    - reference_id: PMID:23263864
      supporting_text: pre-protein import into mitochondria is impaired in the absence of MCJ
- term:
    id: GO:0005739
    label: mitochondrion
  evidence_type: HTP
  original_reference_id: PMID:34800366
  qualifier: located_in
  review:
    summary: High-throughput (FlyBase) annotation of mitochondrial localization, redundant with and consistent with the experimentally supported localization.
    action: KEEP_AS_NON_CORE
    reason: Correct but generic mitochondrial localization; superseded by the specific inner-membrane annotation.
    supported_by:
    - reference_id: PMID:23263864
      supporting_text: Our results demonstrate that MCJ is located in mitochondria.
references:
- id: GO_REF:0000033
  title: Annotation inferences using phylogenetic trees
  findings: []
- id: GO_REF:0000107
  title: Automatic transfer of experimentally verified manual GO annotation data to orthologs by Ensembl Compara
  findings: []
- id: GO_REF:0000120
  title: Combined Automated Annotation using Multiple IEA Methods
  findings: []
- id: PMID:10339406
  title: 'Genetic and structural characterization of the human mitochondrial inner membrane translocase.'
  findings: []
- id: PMID:23263864
  title: Methylation-controlled J-protein MCJ acts in the import of proteins into human mitochondria.
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: "Cached publication title matches the YAML title; Results confirm MCJ is an inner-membrane J-protein whose soluble J domain 'stimulates the ATPase activity of the human mtHsp70 chaperone, mortalin' and that interacts with the TIM23 translocase, supporting the import co-chaperone core function. Anchors the GOA IPI annotation (PMID:23263864)."
  findings:
  - statement: MCJ is anchored in the mitochondrial inner membrane with its C-terminal J domain facing the matrix; it forms a subcomplex with MAGMAS/PAM16, interacts with the core TIM23 translocase, and its soluble J domain stimulates the ATPase activity of mortalin (HSPA9), an activity counteracted by MAGMAS; MCJ loss impairs pre-protein import.
    reference_section_type: RESULTS
- id: PMID:23530063
  title: MCJ/DnaJC15, an endogenous mitochondrial repressor of the respiratory chain that controls metabolic alterations.
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: "Cached publication title matches the YAML title; Results repeatedly establish MCJ as a 'respiratory chain' repressor that impairs supercomplex formation and negatively regulates complex I, supporting the negative-regulator-of-respiratory-chain core function (this PMID is cited in core_functions.supported_by)."
  findings:
  - statement: MCJ impairs the formation of respiratory supercomplexes and functions as a negative regulator of the respiratory chain; MCJ loss increases complex I activity, mitochondrial membrane potential, and ATP production.
    reference_section_type: RESULTS
- id: PMID:25416956
  title: A proteome-scale map of the human interactome network.
  findings: []
- id: PMID:33961781
  title: Dual proteome-scale networks reveal cell-specific remodeling of the human interactome.
  findings: []
- id: PMID:34800366
  title: Quantitative high-confidence human mitochondrial proteome and its dynamics in cellular context.
  findings: []
- id: file:human/DNAJC15/DNAJC15-uniprot.txt
  title: UniProt entry Q9Y5T4 (DJC15_HUMAN), DnaJ homolog subfamily C member 15 / MCJ
  findings:
  - statement: Single-pass mitochondrial inner-membrane J-protein; import component of the TIM23 translocase that stimulates HSPA9 ATPase (counteracted by PAM16/MAGMAS); negative regulator of the respiratory chain that associates with complex I and impairs supercomplex formation.
    reference_section_type: OTHER
core_functions:
- description: J-domain co-chaperone of the TIM23 presequence-translocase import motor that stimulates the ATPase activity of matrix HSP70 (mortalin/HSPA9) to drive protein import into the mitochondrial matrix; regulated by its partner PAM16/MAGMAS.
  molecular_function:
    id: GO:0001671
    label: ATPase activator activity
  locations:
  - id: GO:0005743
    label: mitochondrial inner membrane
  in_complex:
    id: GO:0005744
    label: TIM23 mitochondrial import inner membrane translocase complex
  supported_by:
  - reference_id: PMID:23263864
    supporting_text: the recombinant soluble MCJ domain stimulates the ATPase activity of the human mtHsp70 chaperone, mortalin
  - reference_id: PMID:23263864
    supporting_text: pre-protein import into mitochondria is impaired in the absence of MCJ
- description: Endogenous negative regulator of the mitochondrial respiratory chain that associates with complex I, impairs respiratory supercomplex assembly and restricts membrane potential and ATP production.
  locations:
  - id: GO:0005743
    label: mitochondrial inner membrane
  supported_by:
  - reference_id: PMID:23530063
    supporting_text: We show that MCJ impairs the formation of supercomplexes and functions as a negative regulator of the respiratory chain.
  - reference_id: PMID:23530063
    supporting_text: The loss of MCJ leads to increased complex I activity, mitochondrial membrane potential, and ATP production.
  directly_involved_in:
  - id: GO:1902957
    label: negative regulation of mitochondrial electron transport, NADH to ubiquinone
proposed_new_terms: []
suggested_questions:
- question: How is the balance between MCJ's two roles (TIM23 import co-chaperone versus complex I repressor) regulated, and do they occur in the same or distinct inner-membrane pools?
- question: Does MCJ promoter hypermethylation and silencing causally drive chemoresistance through altered mitochondrial metabolism, or through reduced protein import capacity?
suggested_experiments:
- description: Structure-function analysis of the MCJ J domain (HPD-motif mutants) testing separately its mortalin/HSPA9 ATPase-stimulating import activity and its complex I/supercomplex regulatory activity, to determine whether the two functions are separable.
- description: Blue-native PAGE and respirometry in MCJ-knockout versus reconstituted cells to quantify supercomplex assembly, complex I activity and ATP output, paired with import assays for TIM23 substrates.