id: Q96DA6
gene_symbol: DNAJC19
product_type: PROTEIN
status: COMPLETE
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: DNAJC19 (TIM14/TIMM14; DnaJ homolog subfamily C member 19) is a J-domain co-chaperone of the mitochondrial inner membrane. It is a single-pass inner-membrane protein with a short intermembrane-space N-terminus, one transmembrane helix, and a matrix-facing J-domain. As the J-protein of the presequence translocase-associated import motor (PAM), it stimulates the ATPase activity of matrix mitochondrial HSP70 (mortalin/HSPA9) to drive ATP-dependent translocation of presequence-bearing precursor proteins from the TIM23 channel into the matrix. It forms a regulatory heterodimeric subcomplex with PAM16/Magmas (TIMM16), which restrains its HSP70-stimulating activity, and is tethered to the TIM23 translocase. DNAJC19 also associates with the prohibitin complex via PHB2 and has been implicated in cardiolipin remodeling. Biallelic loss-of-function variants cause dilated cardiomyopathy with ataxia (DCMA) syndrome / 3-methylglutaconic aciduria type 5.
alternative_products:
- name: '1'
  id: Q96DA6-1
- name: '2'
  id: Q96DA6-2
  sequence_note: VSP_047119
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: DNAJC19 is the J-protein component of the presequence translocase-associated import motor (PAM), the matrix-side motor of the TIM23 complex. Well supported for the human protein by co-immunoprecipitation with translocon components.
    action: ACCEPT
    reason: The PAM complex is the defining functional context of DNAJC19; human DNAJC19 co-precipitates with Magmas, hTim44 and hTim23 as part of the human translocon, and the orthology-based IBA is corroborated by direct experimental evidence.
    supported_by:
    - reference_id: PMID:20053669
      supporting_text: Pull down of Magmas along with other translocon components such as hTim44, hTim23, DnaJC19 provides direct evidence for the association of Magmas with the human translocon
- term:
    id: GO:0001671
    label: ATPase activator activity
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: enables
  review:
    summary: As a J-domain protein, DNAJC19 stimulates the ATPase activity of mitochondrial HSP70 (mortalin), the core molecular function that powers presequence import. Directly demonstrated for the human protein.
    action: ACCEPT
    reason: Human DNAJC19 directly stimulates human Mortalin (mtHSP70) ATPase activity via its J-domain; this is the central molecular function of the gene and is experimentally supported, not merely inferred.
    supported_by:
    - reference_id: PMID:20053669
      supporting_text: we have observed upto 70% reduction in ATPase stimulating activity of human Mortalin by Magmas:DnaJC19 complex
    - reference_id: PMID:19564938
      supporting_text: 'J-domain containing proteins, DnaJs, usually enhance the ATPase activity of Hsp70 chaperones'
- term:
    id: GO:0030150
    label: protein import into mitochondrial matrix
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: DNAJC19 participates in ATP-dependent import of precursor proteins across the inner membrane into the matrix, as the J-protein driving the import motor. The core biological process for the gene.
    action: ACCEPT
    reason: The motor activity of the PAM complex that DNAJC19 enables drives matrix protein import; this BP is the direct outcome of its ATPase-activator function and is supported by orthology and human experimental work.
    supported_by:
    - reference_id: PMID:19564938
      supporting_text: 'The latter role is played by the membrane-bound J-domain-containing protein named Tim14/Pam18'
- term:
    id: GO:0005743
    label: mitochondrial inner membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: located_in
  review:
    summary: Electronic annotation of inner-membrane localization, consistent with the experimentally supported single-pass inner-membrane topology of DNAJC19.
    action: ACCEPT
    reason: Correct compartment; agrees with UniProt subcellular location and the IDA inner-membrane annotation.
    supported_by:
    - reference_id: file:human/DNAJC19/DNAJC19-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Mitochondrion inner membrane'
- term:
    id: GO:0098800
    label: inner mitochondrial membrane protein complex
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: part_of
  review:
    summary: DNAJC19 is part of inner-membrane protein complexes (TIM23/PAM). This generic complex term is correct but less informative than the specific PAM/TIM23 complex annotations.
    action: KEEP_AS_NON_CORE
    reason: Correct but generic; the specific PAM complex and TIM23 translocase complex annotations capture the same information more precisely.
    supported_by:
    - reference_id: file:human/DNAJC19/DNAJC19-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Mitochondrion inner membrane'
- term:
    id: GO:0099617
    label: matrix side of mitochondrial inner membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: located_in
  review:
    summary: The J-domain of DNAJC19 faces the matrix side of the inner membrane, consistent with its topology and its role stimulating matrix mtHSP70.
    action: ACCEPT
    reason: Accurate sub-membrane localization matching the protein's topology, where the catalytic J-domain projects into the matrix to engage mtHSP70.
    supported_by:
    - reference_id: file:human/DNAJC19/DNAJC19-uniprot.txt
      supporting_text: Matrix side
- term:
    id: GO:1900208
    label: regulation of cardiolipin metabolic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: DNAJC19 has been implicated in cardiolipin remodeling through its association with the prohibitin complex (via PHB2). By-similarity/inferred; relevant to the DCMA disease phenotype but secondary to the import-motor function.
    action: KEEP_AS_NON_CORE
    reason: The cardiolipin-remodeling role is supported only by similarity and the prohibitin interaction; it is disease-relevant but not the core, experimentally established molecular function of DNAJC19.
    supported_by:
    - reference_id: file:human/DNAJC19/DNAJC19-uniprot.txt
      supporting_text: forms a complex with prohibitins to regulate cardiolipin remodeling
- term:
    id: GO:0005743
    label: mitochondrial inner membrane
  evidence_type: NAS
  original_reference_id: PMID:10339406
  qualifier: located_in
  review:
    summary: Inner-membrane localization asserted from the structural/genetic characterization of the human inner-membrane translocase. Consistent with all other evidence.
    action: ACCEPT
    reason: Correct localization, redundant with the IEA and IDA inner-membrane annotations for the same compartment.
    supported_by:
    - reference_id: file:human/DNAJC19/DNAJC19-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Mitochondrion inner membrane'
- 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: DNAJC19 is part of the TIM23 inner-membrane presequence translocase, tethered via its subcomplex with PAM16/Magmas. Supported by human translocon co-immunoprecipitation.
    action: ACCEPT
    reason: Human DNAJC19 co-precipitates with TIM23 translocon components (hTim23, hTim44, Magmas); membership in the TIM23 translocase complex is well established.
    supported_by:
    - reference_id: PMID:20053669
      supporting_text: Pull down of Magmas along with other translocon components such as hTim44, hTim23, DnaJC19 provides direct evidence for the association of Magmas with the human translocon
- term:
    id: GO:0006886
    label: intracellular protein transport
  evidence_type: NAS
  original_reference_id: PMID:10339406
  qualifier: involved_in
  review:
    summary: Generic protein-transport process term. DNAJC19's specific role is import of precursors into the mitochondrial matrix, captured more precisely by GO:0030150.
    action: KEEP_AS_NON_CORE
    reason: Correct but a high-level parent of the specific 'protein import into mitochondrial matrix' process; non-core because a more precise term applies.
    supported_by:
    - reference_id: PMID:19564938
      supporting_text: 'The latter role is played by the membrane-bound J-domain-containing protein named Tim14/Pam18'
- term:
    id: GO:0030150
    label: protein import into mitochondrial matrix
  evidence_type: NAS
  original_reference_id: PMID:16055927
  qualifier: involved_in
  review:
    summary: The same core import process as the IBA annotation, asserted in the DCMA disease report describing DNAJC19 as an inner-membrane import co-chaperone.
    action: ACCEPT
    reason: Matrix protein import is the core biological process of DNAJC19, consistent across orthology, biochemistry and the disease description.
    supported_by:
    - reference_id: file:human/DNAJC19/DNAJC19-uniprot.txt
      supporting_text: required for the translocation of transit peptide-containing proteins from the inner membrane into the mitochondrial matrix
- term:
    id: GO:0005739
    label: mitochondrion
  evidence_type: HTP
  original_reference_id: PMID:34800366
  qualifier: located_in
  review:
    summary: High-throughput proteomic detection of DNAJC19 in mitochondria. Correct but less specific than the inner-membrane annotations.
    action: KEEP_AS_NON_CORE
    reason: Accurate but generic organelle localization; the inner-membrane / matrix-side annotations are more informative.
    supported_by:
    - reference_id: file:human/DNAJC19/DNAJC19-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Mitochondrion inner membrane'
- term:
    id: GO:0098800
    label: inner mitochondrial membrane protein complex
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: part_of
  review:
    summary: By-similarity assertion of inner-membrane complex membership, duplicating the IEA annotation of the same term. Correct but generic.
    action: KEEP_AS_NON_CORE
    reason: Correct but generic complex term; more precise PAM/TIM23 complex annotations supersede it.
    supported_by:
    - reference_id: file:human/DNAJC19/DNAJC19-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Mitochondrion inner membrane'
- term:
    id: GO:0099617
    label: matrix side of mitochondrial inner membrane
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: located_in
  review:
    summary: By-similarity assertion of matrix-side localization, duplicating the IEA annotation. Matches the protein's topology.
    action: ACCEPT
    reason: Accurate sub-membrane localization consistent with the matrix-facing J-domain topology.
    supported_by:
    - reference_id: file:human/DNAJC19/DNAJC19-uniprot.txt
      supporting_text: Matrix side
- term:
    id: GO:1900208
    label: regulation of cardiolipin metabolic process
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: involved_in
  review:
    summary: By-similarity cardiolipin-remodeling annotation, duplicating the IEA version. Implicated through the prohibitin complex; disease-relevant but secondary.
    action: KEEP_AS_NON_CORE
    reason: Supported only by similarity and the prohibitin interaction; not the core experimentally established function.
    supported_by:
    - reference_id: file:human/DNAJC19/DNAJC19-uniprot.txt
      supporting_text: forms a complex with prohibitins to regulate cardiolipin remodeling
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:19564938
  qualifier: enables
  review:
    summary: IPI interaction with PAM16/Magmas (Q9Y3D7). DNAJC19 forms a heterodimeric J/J-like subcomplex with PAM16; the bare 'protein binding' term is uninformative, but the interaction is real and central to its regulation.
    action: KEEP_AS_NON_CORE
    reason: Per curation guidelines bare protein binding is uninformative and not elevated to core, but the documented DNAJC19-PAM16 interaction (the regulatory module of the import motor) is genuine; the IPI partner Q9Y3D7 is TIMM16/PAM16/Magmas.
    supported_by:
    - reference_id: file:human/DNAJC19/DNAJC19-uniprot.txt
      supporting_text: Interacts with TIMM16/PAM16
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:20053669
  qualifier: enables
  review:
    summary: IPI interaction with PAM16/Magmas (Q9Y3D7) demonstrated in human mitochondria by reciprocal co-immunoprecipitation. The bare term is uninformative but the interaction is genuine and functionally important.
    action: KEEP_AS_NON_CORE
    reason: Bare protein binding is uninformative; the underlying DNAJC19-Magmas subcomplex interaction is real (it regulates DNAJC19's ATPase-stimulating activity) and is retained as non-core.
    supported_by:
    - reference_id: PMID:20053669
      supporting_text: we have observed upto 70% reduction in ATPase stimulating activity of human Mortalin by Magmas:DnaJC19 complex
- term:
    id: GO:0005743
    label: mitochondrial inner membrane
  evidence_type: IDA
  original_reference_id: PMID:20053669
  qualifier: located_in
  review:
    summary: Direct experimental evidence localizing DNAJC19 to the mitochondrial inner membrane as part of the human translocon. The strongest localization annotation.
    action: ACCEPT
    reason: IDA-supported inner-membrane localization, fully consistent with the protein's single-pass inner-membrane topology and translocon membership.
    supported_by:
    - reference_id: file:human/DNAJC19/DNAJC19-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Mitochondrion inner membrane'
- term:
    id: GO:0032991
    label: protein-containing complex
  evidence_type: IDA
  original_reference_id: PMID:19564938
  qualifier: part_of
  review:
    summary: Generic complex-membership annotation reflecting the DNAJC19-PAM16 heterodimer. Correct but uninformative relative to the specific PAM/TIM23 complex terms.
    action: KEEP_AS_NON_CORE
    reason: Accurate but generic; subsumed by the specific PAM complex and TIM23 translocase annotations.
    supported_by:
    - reference_id: PMID:19564938
      supporting_text: heterodimeric complexes and that these complexes interact with yeast mtHsp
- term:
    id: GO:0032991
    label: protein-containing complex
  evidence_type: IDA
  original_reference_id: PMID:20053669
  qualifier: part_of
  review:
    summary: Generic complex-membership annotation from the human translocon co-IP. Correct but uninformative relative to the specific complex terms.
    action: KEEP_AS_NON_CORE
    reason: Accurate but generic; the specific PAM/TIM23 complex annotations are more informative.
    supported_by:
    - reference_id: PMID:20053669
      supporting_text: Pull down of Magmas along with other translocon components such as hTim44, hTim23, DnaJC19 provides direct evidence for the association of Magmas with the human translocon
- term:
    id: GO:0005739
    label: mitochondrion
  evidence_type: IDA
  original_reference_id: PMID:12592411
  qualifier: located_in
  review:
    summary: Direct detection of DNAJC19 in the human heart mitochondrial proteome. Correct but less specific than the inner-membrane annotations.
    action: KEEP_AS_NON_CORE
    reason: Accurate but generic organelle localization; the inner-membrane / matrix-side annotations are more precise.
    supported_by:
    - reference_id: file:human/DNAJC19/DNAJC19-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Mitochondrion inner membrane'
- term:
    id: GO:0016020
    label: membrane
  evidence_type: NAS
  original_reference_id: PMID:16055927
  qualifier: located_in
  review:
    summary: High-level membrane localization asserted in the DCMA disease report. Correct but very generic relative to the inner-membrane annotations.
    action: KEEP_AS_NON_CORE
    reason: Correct but a generic parent term; superseded by the specific inner-membrane localization.
    supported_by:
    - reference_id: file:human/DNAJC19/DNAJC19-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Mitochondrion inner membrane'
references:
- id: GO_REF:0000024
  title: Manual transfer of experimentally-verified manual GO annotation data to orthologs using Ensembl Compara
  findings: []
- 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 using 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:
  - statement: Characterized the human TIM23/TIM17/TIM44 inner-membrane translocase that drives presequence import in cooperation with mtHSP70.
    reference_section_type: RESULTS
- id: PMID:12592411
  title: Characterization of the human heart mitochondrial proteome.
  findings:
  - statement: Detected DNAJC19/TIM14 in the human heart mitochondrial proteome by mass spectrometry.
    reference_section_type: RESULTS
- id: PMID:16055927
  title: Mutation of DNAJC19, a human homologue of yeast inner mitochondrial membrane co-chaperones, causes DCMA syndrome, a novel autosomal recessive Barth syndrome-like condition.
  reference_review:
    relevance: HIGH
    correctness: UNVERIFIED
    review_notes: "Publication not cached in publications/; the title (the original DCMA-syndrome gene-discovery paper linking DNAJC19 to disease) is plausible and directly relevant to the gene's biology, but cannot be confirmed against a checkable source here, so left UNVERIFIED rather than asserting VERIFIED from the title alone."
  findings:
  - statement: Biallelic DNAJC19 variants cause dilated cardiomyopathy with ataxia (DCMA) / 3-methylglutaconic aciduria type 5, identifying DNAJC19 as a human inner-membrane import co-chaperone.
    reference_section_type: RESULTS
- id: PMID:19564938
  title: 'The mitochondrial protein translocation motor: structural conservation between the human and yeast Tim14/Pam18-Tim16/Pam16 co-chaperones.'
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: "Cached publication title matches the YAML title; the text explicitly describes the J-domain protein human Tim14/Pam18 (DNAJC19) enhancing mtHsp70 ATPase activity and forming heterodimers with Tim16/Pam16, supporting the ATPase-activator core MF. Cited in core_functions.supported_by."
  findings:
  - statement: J-domain proteins such as Tim14/Pam18 enhance the ATPase activity of Hsp70 chaperones to promote tight substrate binding during import; human Tim14/Pam18 and Tim16/Pam16 form heterodimeric complexes that interact with mtHSP70.
    reference_section_type: RESULTS
- id: PMID:20053669
  title: Role of Magmas in protein transport and human mitochondria biogenesis.
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: "Cached publication title matches the YAML title; Results show human DNAJC19 stimulates Mortalin (mtHSP70) ATPase activity (reduced ~70% by the Magmas:DnaJC19 complex) and co-precipitates with the human TIM23 translocon, directly supporting both the ATPase-activator MF and the matrix-import process. Cited in core_functions.supported_by."
  findings:
  - statement: Human DNAJC19 stimulates Mortalin (mtHSP70) ATPase activity, which is inhibited by the Magmas:DnaJC19 complex; DNAJC19 co-precipitates with the human TIM23 translocon (hTim44, hTim23, Magmas).
    reference_section_type: RESULTS
- id: PMID:34800366
  title: Quantitative high-confidence human mitochondrial proteome and its dynamics in cellular context.
  findings: []
- id: file:human/DNAJC19/DNAJC19-uniprot.txt
  title: UniProt entry Q96DA6 (TIM14_HUMAN), Mitochondrial import inner membrane translocase subunit TIM14
  findings:
  - statement: Mitochondrial co-chaperone of the PAM complex; single-pass inner-membrane protein with matrix-side J-domain; stimulates ATP-dependent import; interacts with PHB2 (prohibitin complex) and TIMM16/PAM16; cause of DCMA syndrome.
    reference_section_type: OTHER
core_functions:
- description: J-domain co-chaperone that stimulates the ATPase activity of matrix mitochondrial HSP70 (mortalin/HSPA9), the molecular function that powers the presequence translocase-associated import motor (PAM).
  molecular_function:
    id: GO:0001671
    label: ATPase activator activity
  locations:
  - id: GO:0005743
    label: mitochondrial inner membrane
  - id: GO:0099617
    label: matrix side of mitochondrial inner membrane
  supported_by:
  - reference_id: PMID:20053669
    supporting_text: we have observed upto 70% reduction in ATPase stimulating activity of human Mortalin by Magmas:DnaJC19 complex
  - reference_id: PMID:19564938
    supporting_text: 'J-domain containing proteins, DnaJs, usually enhance the ATPase activity of Hsp70 chaperones'
- description: As the J-protein of the TIM23-associated import motor, DNAJC19 drives ATP-dependent translocation of presequence-bearing precursor proteins from the inner membrane into the mitochondrial matrix.
  molecular_function:
    id: GO:0001671
    label: ATPase activator activity
  in_complex:
    id: GO:0001405
    label: PAM complex, Tim23 associated import motor
  supported_by:
  - reference_id: PMID:20053669
    supporting_text: Pull down of Magmas along with other translocon components such as hTim44, hTim23, DnaJC19 provides direct evidence for the association of Magmas with the human translocon
  directly_involved_in:
  - id: GO:0030150
    label: protein import into mitochondrial matrix
proposed_new_terms: []
suggested_questions:
- question: Does DNAJC19's prohibitin/cardiolipin-remodeling role represent a function separable from its import-motor activity, and which one underlies the DCMA cardiomyopathy?
- question: How does the DNAJC19-PAM16 (Magmas) heterodimer dynamically regulate mtHSP70 ATPase stimulation during active import versus resting states?
suggested_experiments:
- description: Reconstitute the human import motor in vitro with purified DNAJC19, PAM16, mtHSP70 and GRPEL to measure DNAJC19-dependent ATPase stimulation and precursor translocation, including disease-variant proteins.
- description: Conditional DNAJC19 depletion in cardiomyocytes followed by mitochondrial import assays and cardiolipin profiling to dissect import-motor versus cardiolipin-remodeling contributions to the DCMA phenotype.
- description: Cryo-EM of the human TIM23-PAM holo-translocase to define how the DNAJC19 J-domain engages mtHSP70 at the matrix exit of the channel.