DNAJC15

UniProt ID: Q9Y5T4
Organism: Homo sapiens
Review Status: COMPLETE
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Gene 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 Review

GO Term Evidence Action Reason
GO:0001405 PAM complex, Tim23 associated import motor
IBA
GO_REF:0000033 		ACCEPT
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.
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.
Supporting Evidence:
PMID:23263864
MCJ forms a stable subcomplex with a component of the mitochondrial import motor, MAGMAS
GO:0001671 ATPase activator activity
IBA
GO_REF:0000033 		ACCEPT
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.
Reason: Directly supported experimentally; stimulating mortalin/HSPA9 ATPase activity is the core molecular function of MCJ as a J-domain co-chaperone.
Supporting Evidence:
PMID:23263864
the recombinant soluble MCJ domain stimulates the ATPase activity of the human mtHsp70 chaperone, mortalin
GO:0030150 protein import into mitochondrial matrix
IBA
GO_REF:0000033 		ACCEPT
Summary: As a J co-chaperone of the TIM23 import motor, MCJ is required for efficient presequence-protein import into the mitochondrial matrix.
Reason: Pre-protein import into mitochondria is impaired in the absence of MCJ; a core biological process for this gene.
Supporting Evidence:
PMID:23263864
pre-protein import into mitochondria is impaired in the absence of MCJ
GO:0005743 mitochondrial inner membrane
IEA
GO_REF:0000120 		ACCEPT
Summary: Automated annotation of mitochondrial inner-membrane localization, consistent with the experimentally established single-pass inner-membrane topology of MCJ.
Reason: MCJ is anchored in the mitochondrial inner membrane (single-pass), its core site of action; corroborated by direct experimental evidence.
Supporting Evidence:
PMID:23263864
It is anchored in the mitochondrial inner membrane with the C-terminal J domain facing the matrix space.
GO:0005515 protein binding
IPI
PMID:23263864
Methylation-controlled J-protein MCJ acts in the import of p... 		KEEP AS NON CORE
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.
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.
Supporting Evidence:
PMID:23263864
MCJ forms a stable subcomplex with a component of the mitochondrial import motor, MAGMAS
GO:0005515 protein binding
IPI
PMID:25416956
A proteome-scale map of the human interactome network. 		KEEP AS NON CORE
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.
Reason: Uninformative GO:0005515 from a high-throughput Y2H screen with uncharacterized partners; not part of the established core function.
Supporting Evidence:
file:human/DNAJC15/DNAJC15-goa.tsv
GO:0005515 protein binding molecular_function ECO:0000353 IPI PMID:25416956 UniProtKB:Q8IUQ4
GO:0005515 protein binding
IPI
PMID:33961781
Dual proteome-scale networks reveal cell-specific remodeling... 		KEEP AS NON CORE
Summary: BioPlex affinity-purification interactome capturing the MCJ-PAM16/MAGMAS (Q9Y3D7) interaction. The bare protein binding term is uninformative.
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.
Supporting Evidence:
file:human/DNAJC15/DNAJC15-goa.tsv
GO:0005515 protein binding molecular_function ECO:0000353 IPI PMID:33961781 UniProtKB:Q9Y3D7
GO:0005739 mitochondrion
IEA
GO_REF:0000107 		KEEP AS NON CORE
Summary: Electronic (Ensembl orthology) annotation of mitochondrial localization, a generic parent of the specific inner-membrane localization.
Reason: Correct but generic; the specific mitochondrial inner-membrane localization is the informative, core annotation.
Supporting Evidence:
PMID:23263864
Our results demonstrate that MCJ is located in mitochondria.
GO:0005743 mitochondrial inner membrane
NAS
PMID:10339406
Genetic and structural characterization of the human mitocho... 		ACCEPT
Summary: Non-traceable author statement (ComplexPortal) of inner-membrane localization, redundant with the experimentally established inner-membrane topology.
Reason: Consistent with and corroborated by direct experimental evidence for inner-membrane anchoring; a core localization.
Supporting Evidence:
PMID:23263864
It is anchored in the mitochondrial inner membrane with the C-terminal J domain facing the matrix space.
GO:0005744 TIM23 mitochondrial import inner membrane translocase complex
NAS
PMID:10339406
Genetic and structural characterization of the human mitocho... 		ACCEPT
Summary: ComplexPortal annotation placing MCJ in the TIM23 translocase complex, supported by its interaction with the core TIM23 components and PAM16/MAGMAS.
Reason: MCJ interacts with the core TIM23 pre-protein translocase and functions as its J co-chaperone; membership is well supported.
Supporting Evidence:
PMID:23263864
MCJ and MAGMAS interact with the core components of the TIM23 pre-protein translocase.
GO:0006886 intracellular protein transport
NAS
PMID:10339406
Genetic and structural characterization of the human mitocho... 		KEEP AS NON CORE
Summary: ComplexPortal annotation of intracellular protein transport, a generic parent of MCJ's specific role in mitochondrial matrix protein import.
Reason: Correct but generic; the specific process (protein import into mitochondrial matrix) is the informative, core annotation.
Supporting Evidence:
PMID:23263864
pre-protein import into mitochondria is impaired in the absence of MCJ
GO:0005739 mitochondrion
HTP
PMID:34800366
Quantitative high-confidence human mitochondrial proteome an... 		KEEP AS NON CORE
Summary: High-throughput (FlyBase) annotation of mitochondrial localization, redundant with and consistent with the experimentally supported localization.
Reason: Correct but generic mitochondrial localization; superseded by the specific inner-membrane annotation.
Supporting Evidence:
PMID:23263864
Our results demonstrate that MCJ is located in mitochondria.

Core Functions

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:
ATPase activator activity
Cellular Locations:
mitochondrial inner membrane
In Complex:
TIM23 mitochondrial import inner membrane translocase complex
Supporting Evidence:
  • PMID:23263864
    the recombinant soluble MCJ domain stimulates the ATPase activity of the human mtHsp70 chaperone, mortalin
  • PMID:23263864
    pre-protein import into mitochondria is impaired in the absence of MCJ

Endogenous negative regulator of the mitochondrial respiratory chain that associates with complex I, impairs respiratory supercomplex assembly and restricts membrane potential and ATP production.

Directly Involved In:
negative regulation of mitochondrial electron transport, NADH to ubiquinone
Cellular Locations:
mitochondrial inner membrane
Supporting Evidence:
  • PMID:23530063
    We show that MCJ impairs the formation of supercomplexes and functions as a negative regulator of the respiratory chain.
  • PMID:23530063
    The loss of MCJ leads to increased complex I activity, mitochondrial membrane potential, and ATP production.

References

GO_REF:0000033
Annotation inferences using phylogenetic trees
GO_REF:0000107
Automatic transfer of experimentally verified manual GO annotation data to orthologs by Ensembl Compara
GO_REF:0000120
Combined Automated Annotation using Multiple IEA Methods
PMID:10339406
Genetic and structural characterization of the human mitochondrial inner membrane translocase.
PMID:23263864
Methylation-controlled J-protein MCJ acts in the import of proteins into human mitochondria.
  • 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.
PMID:23530063
MCJ/DnaJC15, an endogenous mitochondrial repressor of the respiratory chain that controls metabolic alterations.
  • 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.
PMID:25416956
A proteome-scale map of the human interactome network.
PMID:33961781
Dual proteome-scale networks reveal cell-specific remodeling of the human interactome.
PMID:34800366
Quantitative high-confidence human mitochondrial proteome and its dynamics in cellular context.
file:human/DNAJC15/DNAJC15-uniprot.txt
UniProt entry Q9Y5T4 (DJC15_HUMAN), DnaJ homolog subfamily C member 15 / MCJ
  • 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.

Suggested Questions for Experts

Q: 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?

Q: Does MCJ promoter hypermethylation and silencing causally drive chemoresistance through altered mitochondrial metabolism, or through reduced protein import capacity?

Suggested Experiments

Experiment: 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.

Experiment: 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.

📚 Additional Documentation

Notes

(DNAJC15-notes.md)

DNAJC15 (MCJ) research notes

Identity

  • UniProt Q9Y5T4, HGNC:20325, 150 aa. Small single-pass mitochondrial inner-membrane DnaJ/HSP40
    subfamily C protein. AltNames: Methylation-controlled J protein (MCJ); Cell growth-inhibiting
    gene 22 protein (GIG22). Synonym DNAJD1.
  • Topology: N-terminal segment in intermembrane space (1-35), single TM helix (36-58), C-terminal
    J domain (96-150) facing the mitochondrial matrix. [file:human/DNAJC15/DNAJC15-uniprot.txt]

Dual function: TIM23 import co-chaperone AND complex I repressor

(1) J co-chaperone of TIM23 import motor (PRESEQUENCE translocase)

  • PMID:23263864 (Schusdziarra 2013): "MCJ functions as J co-chaperone of the human TIM23 pre-protein
    translocase". "It is anchored in the mitochondrial inner membrane with the C-terminal J domain
    facing the matrix space." "MCJ forms a stable subcomplex with a component of the mitochondrial
    import motor, MAGMAS" (=PAM16). "the recombinant soluble MCJ domain stimulates the ATPase activity
    of the human mtHsp70 chaperone, mortalin" (=HSPA9). "This stimulation is counteracted by MAGMAS."
    "pre-protein import into mitochondria is impaired in the absence of MCJ." "MCJ is able to take over
    the function of Tim14" (=DNAJC19/yeast Pam18). PMID:23263864
  • UniProt FUNCTION: "Acts as an import component of the TIM23 translocase complex. Stimulates the
    ATPase activity of HSPA9." SUBUNIT: "Directly interacts with PAM16/MAGMAS; this interaction
    counteracts DNAJC15-dependent stimulation of HSPA9 ATPase activity." [file:human/DNAJC15/DNAJC15-uniprot.txt]

(2) Negative regulator of respiratory chain complex I

  • PMID:23530063 (Hatle 2013): "MCJ/DnaJC15 ... localizes at the mitochondrial inner membrane, where
    it interacts preferentially with complex I of the electron transfer chain. We show that MCJ impairs
    the formation of supercomplexes and functions as a negative regulator of the respiratory chain. The
    loss of MCJ leads to increased complex I activity, mitochondrial membrane potential, and ATP
    production." MCJ deficiency prevents pathological lipid accumulation in liver. PMID:23530063
  • UniProt FUNCTION: "Negative regulator of the mitochondrial respiratory chain. Prevents
    mitochondrial hyperpolarization state and restricts mitochondrial generation of ATP." "Associates
    with complex I ... this interaction may interfere with the formation of supercomplexes."
    [file:human/DNAJC15/DNAJC15-uniprot.txt]

Disease / cancer

  • Methylation-silenced in ovarian cancer; loss correlates with cisplatin chemoresistance
    (PMID:11358853). Highest expression in heart, then liver, kidney. [file:human/DNAJC15/DNAJC15-uniprot.txt]

GOA decisions

  • GO:0001671 ATPase activator activity (IBA): SUPPORTED experimentally (stimulates HSPA9/mortalin
    ATPase). Core MF. ACCEPT.
  • GO:0001405 PAM complex / GO:0005744 TIM23 translocase / GO:0030150 protein import into matrix /
    GO:0006886 intracellular protein transport: SUPPORTED (TIM23 import co-chaperone). ACCEPT.
  • GO:0005743 mitochondrial inner membrane / GO:0005739 mitochondrion: SUPPORTED. ACCEPT (mito generic
    is non-core relative to inner membrane).
  • complex I repressor / negative regulation of respiratory chain: these Ensembl-IEA BP terms
    (GO:0006120, GO:1902957, GO:0031333, GO:0065003, GO:0009267, GO:0019216) are NOT in the seeded
    ai-review list (they're in the UniProt DR block but the GOA tsv only lists a subset). Only review
    what's in the seeded file + goa.tsv.
  • IPI protein binding: WITH Q9Y3D7 = PAM16/MAGMAS (PMID:23263864, PMID:33961781) - functionally
    central (counteracts ATPase stimulation). KEEP_AS_NON_CORE (real, but bare term uninformative).
    PMID:25416956 WITH Q8IUQ4, Q8IZU0 (Y2H) - less characterized, KEEP_AS_NON_CORE.
  • PMID:10339406 NAS (ComplexPortal) and PMID:34800366 HTP (FlyBase mito) - localization support.

Core functions

  1. ATPase activator activity (GO:0001671) - J co-chaperone stimulating HSPA9/mortalin in TIM23 motor.
  2. Negative regulation of mitochondrial respiratory chain via complex I binding. The GOA-seeded list
    does NOT include a respiratory-chain MF/BP term, but it IS a documented core function; capture in
    core_functions with the negative-regulation BP term (GO:1902957 negative regulation of
    mitochondrial electron transport, NADH to ubiquinone), supported by PMID:23530063.

Pn Notes

(DNAJC15-pn-notes.md)

DNAJC15 PN Consistency Notes

  • Generated: 2026-06-18
  • Project: PROTEOSTASIS
  • Scope: PN consistency rereview against local AIGR review and available deep-research artifacts
  • UniProt: Q9Y5T4
  • AIGR review status: COMPLETE
  • Review batch: proteostasis-batch-2026-06-07b
  • Batch change status: added

Source Files Checked

Deep Research Files

  • No *-deep-research*.md file found in this gene directory.

AIGR Review Snapshot

  • 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/core annotation action counts: ACCEPT: 6; KEEP_AS_NON_CORE: 6

PN Consistency Summary

  • Consistency: Strong agreement. Deep-research notes, review YAML and PN node all converge on a TIM23/PAM J-domain co-chaperone that stimulates matrix HSP70 (mortalin/HSPA9). No contradictions. The review additionally documents a second, mitochondrial-import-independent role (negative regulation of respiratory chain/complex I, PMID:23530063) that the PN single-row mapping does not represent, but this is a coverage gap, not a contradiction.
  • PN story / NEW pressure: PN asserts the generic co-chaperone "Hsp70 protein binding". The review captures the function more precisely as GO:0001671 ATPase activator activity (experimentally demonstrated mortalin stimulation, PMID:23263864). GO:0030544 (verified real via OLS; child of GO:0031072/GO:0051087) is biologically true for MCJ but is NOT a parent of GO:0001671 — it is a different (binding vs activator) MF axis, and is broader/less informative than what the review already records. Not an ADD: the binding is real but the activator-activity annotation already exists and is superior.
  • Evidence alignment: Excellent overlap. Both rest on PMID:23263864 (Schusdziarra 2013, import co-chaperone) plus PMID:23530063 (Hatle 2013, respiratory repressor) in the review. PN reference titles match the import-cochaperone framing.
  • Verdict: Consistent; PN projection (Hsp70 binding) is true but already captured more informatively (ATPase activator activity). No edits required.

Full Consistency Review

  • UniProt: Q9Y5T4 (MCJ) · batch: proteostasis-batch-2026-06-07b · review status: COMPLETE
  • PN placement: Mitochondrial proteostasis | Chaperone | HSP70 system | J-domain containing HSP70 cochaperone (branch MI) ; PN-node mapping: type=mapped, scope=ok_for_propagation_to_go, GO:0030544 Hsp70 protein binding (goa_status=more_specific_than_existing_goa)
  • Consistency: Strong agreement. Deep-research notes, review YAML and PN node all converge on a TIM23/PAM J-domain co-chaperone that stimulates matrix HSP70 (mortalin/HSPA9). No contradictions. The review additionally documents a second, mitochondrial-import-independent role (negative regulation of respiratory chain/complex I, PMID:23530063) that the PN single-row mapping does not represent, but this is a coverage gap, not a contradiction.
  • PN story / NEW pressure: PN asserts the generic co-chaperone "Hsp70 protein binding". The review captures the function more precisely as GO:0001671 ATPase activator activity (experimentally demonstrated mortalin stimulation, PMID:23263864). GO:0030544 (verified real via OLS; child of GO:0031072/GO:0051087) is biologically true for MCJ but is NOT a parent of GO:0001671 — it is a different (binding vs activator) MF axis, and is broader/less informative than what the review already records. Not an ADD: the binding is real but the activator-activity annotation already exists and is superior.
  • Mapping strategy: No change to the node warranted from this gene. The "more_specific_than_existing_goa" tag is inaccurate here — GO:0030544 is not more specific than the existing GO:0001671 ATPase activator activity; it is an orthogonal/broader label. The respiratory-chain repressor role is genuinely outside the HSP70-cochaperone node and should not be forced into it.
  • Evidence alignment: Excellent overlap. Both rest on PMID:23263864 (Schusdziarra 2013, import co-chaperone) plus PMID:23530063 (Hatle 2013, respiratory repressor) in the review. PN reference titles match the import-cochaperone framing.
  • Verdict: Consistent; PN projection (Hsp70 binding) is true but already captured more informatively (ATPase activator activity). No edits required.

PN Dossier Context

  • review_batch: proteostasis-batch-2026-06-07b
  • review_yaml: genes/human/DNAJC15/DNAJC15-ai-review.yaml
  • PN workbook rows: 1

PN row 1: Mitochondrial proteostasis | Chaperone | HSP70 system | J-domain containing HSP70 cochaperone

  • UniProt: Q9Y5T4
  • In branches: MI
  • PN-node mapping records (path + ancestors):
    • [type] Mitochondrial proteostasis|Chaperone|HSP70 system|J-domain containing HSP70 cochaperone
      status=mapped scope=ok_for_propagation_to_go GO=[GO:0030544 Hsp70 protein binding]
      rationale: In the PN hierarchy, this type denotes J-domain cochaperones assigned to the HSP70 system. Their shared mechanistic role is direct interaction with HSP70-family chaperones, making Hsp70 protein binding the most defensible GO target in the current cache.
    • [group] Mitochondrial proteostasis|Chaperone|HSP70 system
      status=no_mapping scope= GO=[]
      rationale: Reviewed as a broad PN category rather than a specific GO class. The member genes span multiple activities, complexes, or contexts, so propagation from this node would overstate the shared biology; use narrower child or gene-level curations.
    • [class] Mitochondrial proteostasis|Chaperone
      status=no_mapping scope= GO=[]
      rationale: This PN class is too heterogeneous for a single safe GO mapping. In the workbook it mixes HSP70, HSP60, and HSP90 systems, small intermembrane-space chaperones, membrane-protein chaperones, and other mitochondrial-specific factors.
    • [branch] Mitochondrial proteostasis
      status=no_mapping scope= GO=[]
      rationale: Reviewed as a top-level PN branch. This is a systems/taxonomy umbrella, not a direct GO assertion; narrower child curations carry any propagating GO mappings.

Projected GO annotations (1)

  • GO:0030544 Hsp70 protein binding | scope=ok_for_propagation_to_go | goa_status=more_specific_than_existing_goa | from=Mitochondrial proteostasis|Chaperone|HSP70 system|J-domain containing HSP70 cochaperone

Note

This file is generated from the current PROTEOSTASIS phase-1 dossier and local gene-review artifacts. Edit the source review, PN mapping, or dossier rather than this generated note when correcting the underlying curation.

📄 View Raw YAML

 
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.