DNAJC30

UniProt ID: Q96LL9
Organism: Homo sapiens
Review Status: COMPLETE
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Gene Description

DNAJC30 (WBSCR18) is a mitochondrial inner-membrane DnaJ/HSP40 (J-domain) protein encoded in the 7q11.23 Williams-Beuren syndrome critical region. Imported via an N-terminal transit peptide and anchored by a single transmembrane helix, it has two intertwined roles in oxidative phosphorylation. It is an auxiliary component of the ATP synthase machinery, interacting directly with MT-ATP6 and ATP5MC2 and facilitating ATP synthesis. It also acts as a chaperone in a mitochondrial complex I (NADH:ubiquinone oxidoreductase) repair mechanism, promoting the efficient exchange/turnover of N-module subunits damaged by reactive oxygen species and thereby maintaining complex I efficiency. DNAJC30 is highly expressed in brain (pyramidal neurons). Biallelic loss-of-function variants cause autosomal-recessive Leber hereditary optic neuropathy (LHONAR1), and hemizygous loss contributes to the mitochondrial dysfunction underlying neurodevelopmental features of Williams-Beuren syndrome.

Existing Annotations Review

GO Term Evidence Action Reason
GO:0005743 mitochondrial inner membrane
IEA
GO_REF:0000044 		ACCEPT
Summary: Electronic (UniProt SubCell) localization to the mitochondrial inner membrane, corroborated by direct experimental evidence (PMID:30318146).
Reason: Correct and well-supported core localization; DNAJC30 is an inner-membrane single-pass protein.
Supporting Evidence:
file:human/DNAJC30/DNAJC30-uniprot.txt
SUBCELLULAR LOCATION: Mitochondrion inner membrane
GO:0005515 protein binding
IPI
PMID:32296183
A reference map of the human binary protein interactome. 		KEEP AS NON CORE
Summary: A large set of binary HuRI yeast two-hybrid interactions, predominantly with membrane proteins (AQP6, BEST2, EBP, MGST2, MRM1 and others) unrelated to DNAJC30's OXPHOS function. Bare protein binding is uninformative.
Reason: High-throughput binary interactions, many likely membrane-protein Y2H artifacts; bare protein binding is not elevated to core and the partners do not inform the ATP-synthase/complex-I function.
Supporting Evidence:
file:human/DNAJC30/DNAJC30-uniprot.txt
Q96LL9; Q13520: AQP6; NbExp=3; IntAct=EBI-8639143, EBI-13059134
GO:0007420 brain development
IEA
GO_REF:0000107 		KEEP AS NON CORE
Summary: DNAJC30 is highly expressed in brain and its loss in mice diminishes neocortical pyramidal-neuron morphology and produces Williams-syndrome-like phenotypes, via mitochondrial dysfunction. This is a downstream, organ-level consequence of its mitochondrial molecular role.
Reason: Brain development is a pleiotropic downstream outcome of DNAJC30's mitochondrial OXPHOS function rather than its direct molecular activity; retained as non-core.
Supporting Evidence:
PMID:30318146
a novel role for mitochondria in normal human brain development and WS
GO:1905706 regulation of mitochondrial ATP synthesis coupled proton transport
IEA
GO_REF:0000107 		ACCEPT
Summary: DNAJC30 associates with the ATP synthase complex and facilitates ATP synthesis; loss decreases the integrity of OXPHOS supercomplexes and ATP-synthase dimers. This supports a role in regulating mitochondrial ATP synthesis.
Reason: Supported by direct ATP-synthase interaction (MT-ATP6, ATP5MC2) and the functional role as an auxiliary component of ATP-synthase machinery.
Supporting Evidence:
PMID:30318146
DNAJC30 is highly enriched in neurons and is a novel auxiliary protein of the mitochondrial ATP synthase complex
GO:0005739 mitochondrion
HTP
PMID:34800366
Quantitative high-confidence human mitochondrial proteome an... 		ACCEPT
Summary: High-throughput proteomic localization to mitochondrion, consistent with and less specific than the experimentally established inner-membrane localization.
Reason: Correct compartment, though broader than the inner-membrane annotation.
Supporting Evidence:
file:human/DNAJC30/DNAJC30-uniprot.txt
SUBCELLULAR LOCATION: Mitochondrion inner membrane
GO:0005515 protein binding
IPI
PMID:30318146
The 7q11.23 protein DNAJC30 interacts with ATP synthase and ... 		MODIFY
Summary: Direct interaction with the ATP synthase subunits MT-ATP6 (P00846) and ATP5MC2 (Q06055), establishing DNAJC30 as an auxiliary component of ATP synthase. The bare protein binding term understates this; the biologically meaningful function is binding to the ATP synthase complex.
Reason: Bare protein binding is uninformative; the documented partners are ATP synthase subunits, so enzyme binding better captures the molecular interaction with the ATP synthase complex.
Proposed replacements: enzyme binding
Supporting Evidence:
file:human/DNAJC30/DNAJC30-uniprot.txt
Interacts with MT-ATP6; interaction is direct (PubMed:30318146).
GO:0005743 mitochondrial inner membrane
IDA
PMID:30318146
The 7q11.23 protein DNAJC30 interacts with ATP synthase and ... 		ACCEPT
Summary: Direct experimental demonstration of DNAJC30 at the mitochondrial inner membrane.
Reason: Strongest-evidence localization; this is the core compartment of DNAJC30.
Supporting Evidence:
file:human/DNAJC30/DNAJC30-uniprot.txt
Mitochondrion inner membrane
GO:0007420 brain development
ISS
GO_REF:0000024 		KEEP AS NON CORE
Summary: Sequence/orthology-based brain-development annotation (from mouse P59041), same downstream-phenotype caveat as the IEA brain-development term.
Reason: Downstream pleiotropic consequence of mitochondrial function rather than DNAJC30's direct molecular activity.
Supporting Evidence:
PMID:30318146
a novel role for mitochondria in normal human brain development and WS
GO:1905706 regulation of mitochondrial ATP synthesis coupled proton transport
ISS
GO_REF:0000024 		ACCEPT
Summary: Orthology-based annotation (from mouse P59041) for regulation of mitochondrial ATP synthesis, consistent with the experimental ATP-synthase association.
Reason: Supported by the direct ATP-synthase interaction and the role as an auxiliary ATP-synthase component.
Supporting Evidence:
file:human/DNAJC30/DNAJC30-uniprot.txt
Associates with the ATP synthase complex (PubMed:30318146).

Core Functions

Chaperone in the mitochondrial complex I repair pathway that promotes efficient exchange/turnover of complex I (NADH:ubiquinone oxidoreductase) N-module subunits damaged by reactive oxygen species, maintaining complex I functional efficiency.

Molecular Function:
unfolded protein binding
Cellular Locations:
mitochondrial inner membrane
Supporting Evidence:
  • PMID:33465056
    DNAJC30 is a chaperone protein needed for the efficient exchange of complex I subunits exposed to reactive oxygen species and integral to a mitochondrial complex I repair mechanism

Auxiliary component of the mitochondrial ATP synthase machinery that interacts directly with MT-ATP6 and ATP5MC2 and facilitates ATP synthesis and OXPHOS supercomplex/ATP-synthase-dimer integrity.

Molecular Function:
enzyme binding
Cellular Locations:
mitochondrial inner membrane
Supporting Evidence:
  • PMID:30318146
    DNAJC30 is highly enriched in neurons and is a novel auxiliary protein of the mitochondrial ATP synthase complex
  • file:human/DNAJC30/DNAJC30-uniprot.txt
    Interacts with MT-ATP6; interaction is direct (PubMed:30318146).

References

GO_REF:0000024
Manual transfer of experimentally-verified manual GO annotation data to orthologs by curator judgment of sequence similarity
GO_REF:0000044
Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location vocabulary mapping, accompanied by conservation of the subcellular location
GO_REF:0000107
Automatic transfer of experimentally verified manual GO annotation data to orthologs using Ensembl Compara
PMID:30318146
The 7q11.23 protein DNAJC30 interacts with ATP synthase and links mitochondria to brain development.
  • DNAJC30 is an inner-membrane mitochondrial protein that interacts directly with ATP synthase subunits (MT-ATP6, ATP5MC2) and is an auxiliary component of the ATP-synthase machinery; its loss causes mitochondrial hypofunction and Williams-syndrome-like neurodevelopmental phenotypes.
PMID:32296183
A reference map of the human binary protein interactome.
PMID:33465056
Impaired complex I repair causes recessive Leber's hereditary optic neuropathy.
  • Biallelic DNAJC30 mutations cause autosomal-recessive Leber hereditary optic neuropathy; DNAJC30 is a chaperone needed for efficient exchange of complex I N-module subunits exposed to reactive oxygen species, integral to a mitochondrial complex I repair mechanism.
PMID:34800366
Quantitative high-confidence human mitochondrial proteome and its dynamics in cellular context.
file:human/DNAJC30/DNAJC30-uniprot.txt
UniProt entry Q96LL9 (DJC30_HUMAN), DnaJ homolog subfamily C member 30, mitochondrial
  • Mitochondrial inner-membrane J-domain protein; associates with the ATP synthase complex and facilitates ATP synthesis; chaperone involved in turnover of complex I N-module subunits damaged by oxidative stress; causes autosomal-recessive LHON.

Suggested Questions for Experts

Q: Does DNAJC30 act mechanistically as a canonical J-domain co-chaperone (stimulating a mitochondrial HSP70 such as mortalin/HSPA9) during complex I subunit exchange, or by a non-canonical holdase/extraction mechanism?

Q: Are the ATP-synthase auxiliary role and the complex I repair role mediated by the same activity, and which is primarily disrupted by the LHONAR1 variants?

Suggested Experiments

Experiment: Reconstitute complex I subunit exchange in vitro or in DNAJC30-knockout cells with wild-type vs LHONAR1 variants to quantify turnover of specific N-module subunits and complex I activity.

Experiment: Test DNAJC30 J-domain function (HPD-motif mutagenesis, mitochondrial HSP70 ATPase-stimulation assay) to determine whether it is a bona fide co-chaperone.

Experiment: Cross-linking/structural analysis of DNAJC30 within the ATP synthase complex to define how it contributes to ATP-synthase dimer and supercomplex integrity.

📚 Additional Documentation

Notes

(DNAJC30-notes.md)

DNAJC30 (WBSCR18) research notes

Identity

  • UniProt Q96LL9 (DJC30_HUMAN), 226 aa precursor. HGNC:16410. Synonym WBSCR18 (Williams-Beuren syndrome chromosomal region 18 protein). Located in 7q11.23 WBS critical region.
  • Mitochondrial J-domain (HSP40/DnaJ subfamily C) protein. N-terminal mitochondrial transit peptide (1-38); J domain 49-114; single-pass transmembrane helix 208-225. Inner mitochondrial membrane.

Function (well-supported)

  • Mitochondrial inner-membrane protein; auxiliary component of the ATP synthase machinery; facilitates ATP synthesis.
    [PMID:30318146 "we identify DNAJC30 as an auxiliary component of ATP-synthase machinery"; "the 7q11.23 protein DNAJC30, which interacts with mitochondrial ATP-synthase machinery."]
    [UniProt FUNCTION "Associates with the ATP synthase complex and facilitates ATP synthesis (By similarity)."]
  • Chaperone in complex I (NADH:ubiquinone oxidoreductase) "repair": facilitates the efficient exchange/turnover of complex I N-module subunits damaged by reactive oxygen species, integral to a complex I repair mechanism; contributes to complex I functional efficiency.
    PMID:33465056
    [UniProt FUNCTION "May be a chaperone protein involved in the turnover of the subunits of mitochondrial complex I N-module. It facilitates the degradation of N-module subunits damaged by oxidative stress, and contributes to complex I functional efficiency (PubMed:33465056)."]

Interactions

  • Direct interaction with MT-ATP6 (P00846) and ATP5MC2 (Q06055); associates with ATP synthase complex (PMID:30318146).
  • Large set of binary HuRI interactions (PMID:32296183) with mostly membrane proteins (AQP6, BEST2, EBP, MGST2, MRM1, etc.) — likely membrane-protein Y2H artifacts, uninformative bare protein binding.

Localization

  • Mitochondrion inner membrane (IDA, PMID:30318146); single-pass membrane protein.
  • HTP mitochondrion (PMID:34800366, FlyBase high-throughput).
  • Highly expressed in brain; enriched in pyramidal neurons.

Disease

  • Autosomal-recessive Leber hereditary optic neuropathy (LHONAR1/arLHON, MIM:619382): biallelic DNAJC30 mutations (e.g. Y51C, P78S, L101Q) recapitulate all hallmarks of mtDNA LHON (incomplete penetrance, male predominance, idebenone responsivity). Variants reduce turnover of complex I N-module subunits and impair complex I function.
    PMID:33465056
  • DNAJC30 deletion contributes to mitochondrial dysfunction in Williams-Beuren syndrome neurodevelopmental phenotypes (PMID:30318146).

GO annotation review reasoning

  • mitochondrial inner membrane (IDA, IEA) — ACCEPT (core localization, experimentally demonstrated).
  • mitochondrion (HTP) — ACCEPT (consistent, less specific).
  • regulation of mitochondrial ATP synthesis coupled proton transport (ISS/IEA from mouse P59041) — ACCEPT; supported by ATP synthase association and facilitation of ATP synthesis.
  • brain development (ISS/IEA) — KEEP_AS_NON_CORE; reflects neurodevelopmental phenotype/high brain expression but is a downstream pleiotropic outcome, not the molecular core.
  • protein binding (IPI) — the MT-ATP6/ATP5MC2 interactions (PMID:30318146) are biologically meaningful (ATP synthase) — could MODIFY toward a specific term; the HuRI set (PMID:32296183) is uninformative -> KEEP_AS_NON_CORE.
  • Core MF: chaperone/co-chaperone activity in complex I subunit exchange + ATP synthase auxiliary subunit. Best MF terms: protein-folding chaperone binding / unfolded protein binding not directly shown; the gene acts as a holdase/chaperone facilitating subunit exchange. The clearest experimentally-grounded MF for the ATP-synthase role is enzyme/structural association; for complex I it's chaperone activity. Use GO:0051082 unfolded protein binding? Not demonstrated. Better core: biological processes (complex I repair / ATP synthesis regulation). For MF, GO:0140662? (ATP-dependent protein folding chaperone) is not apt (it's not ATP-dependent foldase). Will use a chaperone-binding/holdase framing carefully.

Pn Notes

(DNAJC30-pn-notes.md)

DNAJC30 PN Consistency Notes

  • Generated: 2026-06-18
  • Project: PROTEOSTASIS
  • Scope: PN consistency rereview against local AIGR review and available deep-research artifacts
  • UniProt: Q96LL9
  • 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: DNAJC30 (WBSCR18) is a mitochondrial inner-membrane DnaJ/HSP40 (J-domain) protein encoded in the 7q11.23 Williams-Beuren syndrome critical region. Imported via an N-terminal transit peptide and anchored by a single transmembrane helix, it has two intertwined roles in oxidative phosphorylation. It is an auxiliary component of the ATP synthase machinery, interacting directly with MT-ATP6 and ATP5MC2 and facilitating ATP synthesis. It also acts as a chaperone in a mitochondrial complex I (NADH:ubiquinone oxidoreductase) repair mechanism, promoting the efficient exchange/turnover of N-module subunits damaged by reactive oxygen species and thereby maintaining complex I efficiency. DNAJC30 is highly expressed in brain (pyramidal neurons). Biallelic loss-of-function variants cause autosomal-recessive Leber hereditary optic neuropathy (LHONAR1), and hemizygous loss contributes to the mitochondrial dysfunction underlying neurodevelopmental features of Williams-Beuren syndrome.
  • Existing/core annotation action counts: ACCEPT: 5; KEEP_AS_NON_CORE: 3; MODIFY: 1

PN Consistency Summary

  • Consistency: SUBSTANTIVE TENSION. Deep research and review YAML establish DNAJC30 as a mitochondrial inner-membrane factor with two well-supported, NON-canonical-chaperone roles: (1) auxiliary component of ATP synthase (direct MT-ATP6/ATP5MC2 binding, PMID:30318146; core MF GO:0019899 enzyme binding); (2) chaperone in complex I N-module repair/subunit exchange (PMID:33465056; core MF GO:0051082 unfolded protein binding; causes recessive LHON). The review explicitly does NOT establish any HSP70 interaction. The PN "J-domain HSP70 cochaperone" placement is an over-broad family inference: DNAJC30 is a complex-I assembly/repair factor, not a characterized HSP70 cochaperone.
  • PN story / NEW pressure: PN asserts GO:0030544 Hsp70 protein binding (verified real) — but this is contradicted in emphasis by the review, which found no HSP70 partner (the J-domain's canonical cochaperone activity is itself flagged as an open question in suggested_questions). GOA has no chaperone-binding term, so "more_specific_than_existing_goa" is wrong; at most new_to_goa, and even as new it OVER-REACHES given the characterized complex-I/ATP-synthase biology. Mirrors the TOMM20/HSPA8/RAB7A "rejected as broader/family-inferred" precedent.
  • Evidence alignment: PN row no titles; review cites PMID:30318146 (ATP synthase/brain dev) and PMID:33465056 (complex I repair / recessive LHON) — both VERIFIED, full-text cached. No paper supports HSP70 binding.
  • Verdict: Over-reach. GO:0030544 projection is unsupported for DNAJC30 (a complex-I repair / ATP-synthase auxiliary factor). Recommended edits: [MAP] do not propagate GO:0030544 to DNAJC30 (family-level over-inference; gene-level GO:0051082 + GO:0019899 already capture its biology); [MAP] if retained, downgrade goa_status to new_to_goa and mark as IBA/family-inferred only.

Full Consistency Review

  • UniProt: Q96LL9 (WBSCR18) · batch: proteostasis-batch-2026-06-07b · review status: COMPLETE
  • PN placement: Mitochondrial proteostasis|Chaperone|HSP70 system|J-domain containing HSP70 cochaperone ; PN-node mapping: type=mapped, scope=ok_for_propagation_to_go, GO:0030544 Hsp70 protein binding (projected more_specific_than_existing_goa); group/class/branch=no_mapping (class explicitly "too heterogeneous").
  • Consistency: SUBSTANTIVE TENSION. Deep research and review YAML establish DNAJC30 as a mitochondrial inner-membrane factor with two well-supported, NON-canonical-chaperone roles: (1) auxiliary component of ATP synthase (direct MT-ATP6/ATP5MC2 binding, PMID:30318146; core MF GO:0019899 enzyme binding); (2) chaperone in complex I N-module repair/subunit exchange (PMID:33465056; core MF GO:0051082 unfolded protein binding; causes recessive LHON). The review explicitly does NOT establish any HSP70 interaction. The PN "J-domain HSP70 cochaperone" placement is an over-broad family inference: DNAJC30 is a complex-I assembly/repair factor, not a characterized HSP70 cochaperone.
  • PN story / NEW pressure: PN asserts GO:0030544 Hsp70 protein binding (verified real) — but this is contradicted in emphasis by the review, which found no HSP70 partner (the J-domain's canonical cochaperone activity is itself flagged as an open question in suggested_questions). GOA has no chaperone-binding term, so "more_specific_than_existing_goa" is wrong; at most new_to_goa, and even as new it OVER-REACHES given the characterized complex-I/ATP-synthase biology. Mirrors the TOMM20/HSPA8/RAB7A "rejected as broader/family-inferred" precedent.
  • Mapping strategy: This gene argues AGAINST propagating GO:0030544 from the type node to DNAJC30. The review's evidence-backed MFs (GO:0051082, GO:0019899) are the right calls; the family-projected GO:0030544 is broader/unsupported for this member.
  • Evidence alignment: PN row no titles; review cites PMID:30318146 (ATP synthase/brain dev) and PMID:33465056 (complex I repair / recessive LHON) — both VERIFIED, full-text cached. No paper supports HSP70 binding.
  • Verdict: Over-reach. GO:0030544 projection is unsupported for DNAJC30 (a complex-I repair / ATP-synthase auxiliary factor). Recommended edits: [MAP] do not propagate GO:0030544 to DNAJC30 (family-level over-inference; gene-level GO:0051082 + GO:0019899 already capture its biology); [MAP] if retained, downgrade goa_status to new_to_goa and mark as IBA/family-inferred only.

PN Dossier Context

  • review_batch: proteostasis-batch-2026-06-07b
  • review_yaml: genes/human/DNAJC30/DNAJC30-ai-review.yaml
  • PN workbook rows: 1

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

  • UniProt: Q96LL9
  • 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: Q96LL9
gene_symbol: DNAJC30
product_type: PROTEIN
status: COMPLETE
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: DNAJC30 (WBSCR18) is a mitochondrial inner-membrane DnaJ/HSP40 (J-domain) protein encoded in the 7q11.23 Williams-Beuren syndrome critical region. Imported via an N-terminal transit peptide and anchored by a single transmembrane helix, it has two intertwined roles in oxidative phosphorylation. It is an auxiliary component of the ATP synthase machinery, interacting directly with MT-ATP6 and ATP5MC2 and facilitating ATP synthesis. It also acts as a chaperone in a mitochondrial complex I (NADH:ubiquinone oxidoreductase) repair mechanism, promoting the efficient exchange/turnover of N-module subunits damaged by reactive oxygen species and thereby maintaining complex I efficiency. DNAJC30 is highly expressed in brain (pyramidal neurons). Biallelic loss-of-function variants cause autosomal-recessive Leber hereditary optic neuropathy (LHONAR1), and hemizygous loss contributes to the mitochondrial dysfunction underlying neurodevelopmental features of Williams-Beuren syndrome.
existing_annotations:
- 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) localization to the mitochondrial inner membrane, corroborated by direct experimental evidence (PMID:30318146).
    action: ACCEPT
    reason: Correct and well-supported core localization; DNAJC30 is an inner-membrane single-pass protein.
    supported_by:
    - reference_id: file:human/DNAJC30/DNAJC30-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Mitochondrion inner membrane'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:32296183
  qualifier: enables
  review:
    summary: A large set of binary HuRI yeast two-hybrid interactions, predominantly with membrane proteins (AQP6, BEST2, EBP, MGST2, MRM1 and others) unrelated to DNAJC30's OXPHOS function. Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: High-throughput binary interactions, many likely membrane-protein Y2H artifacts; bare protein binding is not elevated to core and the partners do not inform the ATP-synthase/complex-I function.
    supported_by:
    - reference_id: file:human/DNAJC30/DNAJC30-uniprot.txt
      supporting_text: 'Q96LL9; Q13520: AQP6; NbExp=3; IntAct=EBI-8639143, EBI-13059134'
- term:
    id: GO:0007420
    label: brain development
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: DNAJC30 is highly expressed in brain and its loss in mice diminishes neocortical pyramidal-neuron morphology and produces Williams-syndrome-like phenotypes, via mitochondrial dysfunction. This is a downstream, organ-level consequence of its mitochondrial molecular role.
    action: KEEP_AS_NON_CORE
    reason: Brain development is a pleiotropic downstream outcome of DNAJC30's mitochondrial OXPHOS function rather than its direct molecular activity; retained as non-core.
    supported_by:
    - reference_id: PMID:30318146
      supporting_text: a novel role for mitochondria in normal human brain development and WS
- term:
    id: GO:1905706
    label: regulation of mitochondrial ATP synthesis coupled proton transport
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: DNAJC30 associates with the ATP synthase complex and facilitates ATP synthesis; loss decreases the integrity of OXPHOS supercomplexes and ATP-synthase dimers. This supports a role in regulating mitochondrial ATP synthesis.
    action: ACCEPT
    reason: Supported by direct ATP-synthase interaction (MT-ATP6, ATP5MC2) and the functional role as an auxiliary component of ATP-synthase machinery.
    supported_by:
    - reference_id: PMID:30318146
      supporting_text: DNAJC30 is highly enriched in neurons and is a novel auxiliary protein of the mitochondrial ATP synthase complex
- term:
    id: GO:0005739
    label: mitochondrion
  evidence_type: HTP
  original_reference_id: PMID:34800366
  qualifier: located_in
  review:
    summary: High-throughput proteomic localization to mitochondrion, consistent with and less specific than the experimentally established inner-membrane localization.
    action: ACCEPT
    reason: Correct compartment, though broader than the inner-membrane annotation.
    supported_by:
    - reference_id: file:human/DNAJC30/DNAJC30-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Mitochondrion inner membrane'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:30318146
  qualifier: enables
  review:
    summary: Direct interaction with the ATP synthase subunits MT-ATP6 (P00846) and ATP5MC2 (Q06055), establishing DNAJC30 as an auxiliary component of ATP synthase. The bare protein binding term understates this; the biologically meaningful function is binding to the ATP synthase complex.
    action: MODIFY
    reason: Bare protein binding is uninformative; the documented partners are ATP synthase subunits, so enzyme binding better captures the molecular interaction with the ATP synthase complex.
    proposed_replacement_terms:
    - id: GO:0019899
      label: enzyme binding
    supported_by:
    - reference_id: file:human/DNAJC30/DNAJC30-uniprot.txt
      supporting_text: Interacts with MT-ATP6; interaction is direct (PubMed:30318146).
- term:
    id: GO:0005743
    label: mitochondrial inner membrane
  evidence_type: IDA
  original_reference_id: PMID:30318146
  qualifier: located_in
  review:
    summary: Direct experimental demonstration of DNAJC30 at the mitochondrial inner membrane.
    action: ACCEPT
    reason: Strongest-evidence localization; this is the core compartment of DNAJC30.
    supported_by:
    - reference_id: file:human/DNAJC30/DNAJC30-uniprot.txt
      supporting_text: Mitochondrion inner membrane
- term:
    id: GO:0007420
    label: brain development
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: involved_in
  review:
    summary: Sequence/orthology-based brain-development annotation (from mouse P59041), same downstream-phenotype caveat as the IEA brain-development term.
    action: KEEP_AS_NON_CORE
    reason: Downstream pleiotropic consequence of mitochondrial function rather than DNAJC30's direct molecular activity.
    supported_by:
    - reference_id: PMID:30318146
      supporting_text: a novel role for mitochondria in normal human brain development and WS
- term:
    id: GO:1905706
    label: regulation of mitochondrial ATP synthesis coupled proton transport
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: involved_in
  review:
    summary: Orthology-based annotation (from mouse P59041) for regulation of mitochondrial ATP synthesis, consistent with the experimental ATP-synthase association.
    action: ACCEPT
    reason: Supported by the direct ATP-synthase interaction and the role as an auxiliary ATP-synthase component.
    supported_by:
    - reference_id: file:human/DNAJC30/DNAJC30-uniprot.txt
      supporting_text: Associates with the ATP synthase complex (PubMed:30318146).
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:0000044
  title: Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location vocabulary mapping, accompanied by conservation of the subcellular location
  findings: []
- id: GO_REF:0000107
  title: Automatic transfer of experimentally verified manual GO annotation data to orthologs using Ensembl Compara
  findings: []
- id: PMID:30318146
  title: The 7q11.23 protein DNAJC30 interacts with ATP synthase and links mitochondria to brain development.
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: "Cached publication (publications/PMID_30318146.md, full text available) title matches and establishes DNAJC30 as a mitochondrial inner-membrane protein that interacts with ATP synthase, supporting the enzyme binding core function and its role in the ATP-synthase machinery."
  findings:
  - statement: DNAJC30 is an inner-membrane mitochondrial protein that interacts directly with ATP synthase subunits (MT-ATP6, ATP5MC2) and is an auxiliary component of the ATP-synthase machinery; its loss causes mitochondrial hypofunction and Williams-syndrome-like neurodevelopmental phenotypes.
    reference_section_type: ABSTRACT
- id: PMID:32296183
  title: A reference map of the human binary protein interactome.
  findings: []
- id: PMID:33465056
  title: Impaired complex I repair causes recessive Leber's hereditary optic neuropathy.
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: "Cached publication (publications/PMID_33465056.md, full text available) title matches and establishes DNAJC30 as a chaperone required for complex I N-module subunit repair, with biallelic mutations causing recessive LHON, supporting the unfolded protein binding / chaperone core function."
  findings:
  - statement: Biallelic DNAJC30 mutations cause autosomal-recessive Leber hereditary optic neuropathy; DNAJC30 is a chaperone needed for efficient exchange of complex I N-module subunits exposed to reactive oxygen species, integral to a mitochondrial complex I repair mechanism.
    reference_section_type: ABSTRACT
- id: PMID:34800366
  title: Quantitative high-confidence human mitochondrial proteome and its dynamics in cellular context.
  findings: []
- id: file:human/DNAJC30/DNAJC30-uniprot.txt
  title: UniProt entry Q96LL9 (DJC30_HUMAN), DnaJ homolog subfamily C member 30, mitochondrial
  findings:
  - statement: Mitochondrial inner-membrane J-domain protein; associates with the ATP synthase complex and facilitates ATP synthesis; chaperone involved in turnover of complex I N-module subunits damaged by oxidative stress; causes autosomal-recessive LHON.
    reference_section_type: OTHER
core_functions:
- description: Chaperone in the mitochondrial complex I repair pathway that promotes efficient exchange/turnover of complex I (NADH:ubiquinone oxidoreductase) N-module subunits damaged by reactive oxygen species, maintaining complex I functional efficiency.
  molecular_function:
    id: GO:0051082
    label: unfolded protein binding
  locations:
  - id: GO:0005743
    label: mitochondrial inner membrane
  supported_by:
  - reference_id: PMID:33465056
    supporting_text: DNAJC30 is a chaperone protein needed for the efficient exchange of complex I subunits exposed to reactive oxygen species and integral to a mitochondrial complex I repair mechanism
- description: Auxiliary component of the mitochondrial ATP synthase machinery that interacts directly with MT-ATP6 and ATP5MC2 and facilitates ATP synthesis and OXPHOS supercomplex/ATP-synthase-dimer integrity.
  molecular_function:
    id: GO:0019899
    label: enzyme binding
  locations:
  - id: GO:0005743
    label: mitochondrial inner membrane
  supported_by:
  - reference_id: PMID:30318146
    supporting_text: DNAJC30 is highly enriched in neurons and is a novel auxiliary protein of the mitochondrial ATP synthase complex
  - reference_id: file:human/DNAJC30/DNAJC30-uniprot.txt
    supporting_text: Interacts with MT-ATP6; interaction is direct (PubMed:30318146).
proposed_new_terms: []
suggested_questions:
- question: Does DNAJC30 act mechanistically as a canonical J-domain co-chaperone (stimulating a mitochondrial HSP70 such as mortalin/HSPA9) during complex I subunit exchange, or by a non-canonical holdase/extraction mechanism?
- question: Are the ATP-synthase auxiliary role and the complex I repair role mediated by the same activity, and which is primarily disrupted by the LHONAR1 variants?
suggested_experiments:
- description: Reconstitute complex I subunit exchange in vitro or in DNAJC30-knockout cells with wild-type vs LHONAR1 variants to quantify turnover of specific N-module subunits and complex I activity.
- description: Test DNAJC30 J-domain function (HPD-motif mutagenesis, mitochondrial HSP70 ATPase-stimulation assay) to determine whether it is a bona fide co-chaperone.
- description: Cross-linking/structural analysis of DNAJC30 within the ATP synthase complex to define how it contributes to ATP-synthase dimer and supercomplex integrity.