HSPA9

id: P38646
gene_symbol: HSPA9
product_type: PROTEIN
status: COMPLETE
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: >-
  HSPA9 (mortalin/GRP75/mtHsp70/PBP74) is the human mitochondrial Hsp70-family
  ATP-dependent chaperone (EC 3.6.4.10). Synthesized in the cytosol with an
  N-terminal mitochondrial targeting sequence and matured in the mitochondrial
  matrix, it functions as the core ATPase motor of the presequence translocase-associated
  motor (PAM) that drives import and folding of nuclear-encoded matrix proteins
  through the TIM23 complex. Mortalin also acts in mitochondrial iron-sulfur
  cluster biogenesis where, with its J-protein cochaperone HSC20/HSCB, it
  delivers nascent Fe-S clusters from the ISCU scaffold to client apoproteins,
  and contributes to general protein quality control through ATP-driven cycles
  of substrate binding/release coordinated by mitochondrial J-domain co-chaperones
  (Tim14/DNAJC15/19, Tim16/Magmas) and nucleotide-exchange factors (GRPEL1/2).
  Pathogenic HSPA9 variants cause autosomal recessive sideroblastic anemia 4
  (SIDBA4) and EVEN-PLUS syndrome.
existing_annotations:
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: Cytoplasm localization by phylogenetic inference. HSPA9 is synthesized in the cytosol as a precursor with a cleavable mitochondrial targeting sequence and is imported into the mitochondrial matrix, where it performs its function. A transient cytosolic precursor pool exists, and stress-induced extramitochondrial pools have been reported, so this broad localization is not wrong, but it is non-core relative to the matrix/inner-membrane site of action.
    action: KEEP_AS_NON_CORE
    reason: The dominant, functionally relevant localization is the mitochondrial matrix/inner membrane, not the cytoplasm. The cytoplasmic pool is largely the transient precursor plus reported stress-induced extramitochondrial redistribution; keep as non-core.
    supported_by:
    - reference_id: file:human/HSPA9/HSPA9-deep-research-falcon.md
      supporting_text: HSPA9 predominantly resides in the mitochondrial matrix where it supports protein import and proteostasis; reviews describe an N-terminal targeting sequence
- term:
    id: GO:0005739
    label: mitochondrion
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: Mitochondrion localization by phylogenetic inference. HSPA9/mortalin is a well-established mitochondrial Hsp70 that resides in the matrix and is associated with the inner membrane import machinery. This is strongly supported across orthologs and by direct human studies.
    action: ACCEPT
    reason: HSPA9 is a canonical mitochondrial protein; the IBA mitochondrion call is correct and consistent with experimental localization data (PMID:7865888, PMID:7829505) and the mitochondrial proteome (PMID:34800366).
    supported_by:
    - reference_id: PMID:7865888
      supporting_text: PBP74, a new member of the mammalian 70-kDa heat shock protein family, is a mitochondrial protein.
- term:
    id: GO:0016887
    label: ATP hydrolysis activity
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: ATP hydrolysis activity by phylogenetic inference. As an Hsp70-family chaperone, HSPA9 hydrolyzes ATP at its N-terminal nucleotide-binding domain (EC 3.6.4.10) to power substrate binding/release cycling. This is directly demonstrated biochemically for human mortalin.
    action: ACCEPT
    reason: Core catalytic activity of HSPA9, confirmed by direct biochemical assays of human mortalin ATPase activity (PMID:18632665, PMID:25615450) and conserved across the Hsp70 family.
    supported_by:
    - reference_id: PMID:18632665
      supporting_text: The human escort protein Hep binds to the ATPase domain of mitochondrial hsp70 and regulates ATP hydrolysis.
- term:
    id: GO:0031072
    label: heat shock protein binding
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: Heat shock protein binding by phylogenetic inference. Hsp70 chaperones engage co-chaperones and partner Hsp proteins (e.g., J-domain proteins, escort protein Hep/DNLZ) as part of their functional cycle. HSPA9 specifically binds the Hep/DNLZ escort protein and DNAJ co-chaperones.
    action: ACCEPT
    reason: Consistent with Hsp70 biology and supported by direct evidence that HSPA9 binds its escort/co-chaperone partners (PMID:18632665). The term reflects a genuine, mechanistically relevant binding activity rather than bare protein binding.
    supported_by:
    - reference_id: PMID:18632665
      supporting_text: The human escort protein Hep binds to the ATPase domain of mitochondrial hsp70 and regulates ATP hydrolysis.
- term:
    id: GO:0044183
    label: protein folding chaperone
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: Protein folding chaperone activity by phylogenetic inference. This is the central molecular function of HSPA9/mortalin as the mitochondrial Hsp70 foldase, driving ATP-dependent folding/refolding of matrix client proteins and supplying the motor force for import-coupled folding.
    action: ACCEPT
    reason: This is the core molecular function of HSPA9 and is well supported across orthologs and by human biochemical characterization (PMID:25615450). It is the preferred, mechanistically informative MF term and the target of MODIFY for the generic GO:0051082 annotations.
    supported_by:
    - reference_id: file:human/HSPA9/HSPA9-deep-research-falcon.md
      supporting_text: HSPA9 encodes the mitochondrial Hsp70 chaperone known as mortalin/GRP75/mtHsp70.
- term:
    id: GO:0016226
    label: iron-sulfur cluster assembly
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: Iron-sulfur cluster assembly by phylogenetic inference. HSPA9/mortalin is the dedicated mitochondrial Hsp70 that, with its J-protein co-chaperone HSC20/HSCB, drives ATP-dependent transfer of nascent Fe-S clusters from the ISCU scaffold to recipient apoproteins. This conserved function is supported by direct human studies.
    action: ACCEPT
    reason: A core, well-supported biological process for HSPA9. The IBA call is consistent with direct human experimental evidence (PMID:23940031, PMID:26702583, PMID:28380382) showing HSPA9 acts on ISCU conformational states during Fe-S cluster delivery.
    supported_by:
    - reference_id: PMID:23940031
      supporting_text: Human mitochondrial chaperone (mtHSP70) and cysteine desulfurase (NFS1) bind preferentially to the disordered conformation, whereas co-chaperone (HSC20) binds to the structured conformation of the iron-sulfur cluster scaffold protein (ISCU).
- term:
    id: GO:0042026
    label: protein refolding
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: Protein refolding by phylogenetic inference. As the mitochondrial Hsp70 foldase, HSPA9 drives ATP-dependent refolding of misfolded/stress-denatured matrix proteins, a conserved Hsp70 activity.
    action: ACCEPT
    reason: Consistent with the canonical mitochondrial Hsp70 chaperone role and supported across orthologs; refolding of denatured matrix clients is a genuine HSPA9 process aspect complementary to the GO:0044183 molecular function.
    supported_by:
    - reference_id: file:human/HSPA9/HSPA9-deep-research-falcon.md
      supporting_text: HSPA9 encodes the mitochondrial Hsp70 chaperone known as mortalin/GRP75/mtHsp70.
- term:
    id: GO:0000166
    label: nucleotide binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000043
  review:
    summary: Nucleotide binding from UniProt keyword mapping. HSPA9 binds adenine nucleotides at its N-terminal nucleotide-binding domain. This is a correct but very general molecular function term; the more specific ATP binding (GO:0005524) is also annotated.
    action: ACCEPT
    reason: Correct based on the conserved Hsp70 ATPase domain and direct biochemical demonstration of adenine-nucleotide binding by human mortalin (PMID:25615450). It is broad but not wrong; the more specific ATP binding term is retained alongside it.
    supported_by:
    - reference_id: PMID:25615450
      supporting_text: 'Human mitochondrial Hsp70 (mortalin): shedding light on ATPase activity, interaction with adenosine nucleotides, solution structure and domain organization.'
- term:
    id: GO:0005524
    label: ATP binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    summary: ATP binding inferred from InterPro/keyword mapping. HSPA9 binds ATP at its nucleotide-binding domain as the obligatory first step of the Hsp70 chaperone cycle, directly demonstrated for human mortalin.
    action: ACCEPT
    reason: Accurate and appropriately specific molecular function for an Hsp70 ATPase; confirmed by biochemical characterization of human mortalin nucleotide binding (PMID:25615450).
    supported_by:
    - reference_id: PMID:25615450
      supporting_text: 'Human mitochondrial Hsp70 (mortalin): shedding light on ATPase activity, interaction with adenosine nucleotides, solution structure and domain organization.'
- term:
    id: GO:0005730
    label: nucleolus
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  review:
    summary: Nucleolus localization mapped from a UniProt subcellular-location keyword. Reports of mortalin in the nucleus/nucleolus exist but are minor relative to its dominant mitochondrial matrix localization, and the term is derived from automated keyword mapping rather than focused experimental evidence.
    action: MARK_AS_OVER_ANNOTATED
    reason: HSPA9 is an imported mitochondrial matrix chaperone; nucleolar localization is at best a minor, context-dependent extramitochondrial pool and not a site where its core function is exercised. The IEA keyword-mapped term over-states this localization.
    supported_by:
    - reference_id: file:human/HSPA9/HSPA9-deep-research-falcon.md
      supporting_text: HSPA9 predominantly resides in the mitochondrial matrix where it supports protein import and proteostasis; reviews describe an N-terminal targeting sequence
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  review:
    summary: Cytoplasm localization mapped from a UniProt subcellular-location keyword. A transient cytosolic precursor pool exists prior to mitochondrial import, and stress-induced extramitochondrial redistribution is reported, so the term is not wrong but is non-core relative to the matrix site of action.
    action: KEEP_AS_NON_CORE
    reason: Duplicate localization of the IBA cytoplasm call; the functionally relevant site is the mitochondrial matrix/inner membrane. Keep as non-core.
    supported_by:
    - reference_id: file:human/HSPA9/HSPA9-deep-research-falcon.md
      supporting_text: Mortalin can redistribute beyond mitochondria (including plasma membrane accumulation) under certain stresses
- term:
    id: GO:0005739
    label: mitochondrion
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    summary: Mitochondrion localization from automated IEA pipelines. HSPA9 is a canonical mitochondrial protein; this is correct though more specific matrix/inner-membrane terms are also annotated.
    action: ACCEPT
    reason: Correct localization, consistent with all experimental evidence and the mitochondrial proteome (PMID:34800366).
    supported_by:
    - reference_id: PMID:7865888
      supporting_text: PBP74, a new member of the mammalian 70-kDa heat shock protein family, is a mitochondrial protein.
- term:
    id: GO:0005759
    label: mitochondrial matrix
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    summary: Mitochondrial matrix localization from automated IEA pipelines. This is the primary, functionally relevant compartment for HSPA9, where it acts as a foldase and as the matrix-side motor of the PAM import machinery.
    action: ACCEPT
    reason: Accurate and appropriately specific; matches direct IDA localization to the matrix (PMID:7865888) and is the core site of HSPA9 function.
    supported_by:
    - reference_id: PMID:7865888
      supporting_text: PBP74, a new member of the mammalian 70-kDa heat shock protein family, is a mitochondrial protein.
- term:
    id: GO:0006457
    label: protein folding
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  review:
    summary: Protein folding inferred from InterPro HSP70 family membership. This is a genuine core process for HSPA9 as the mitochondrial Hsp70 foldase.
    action: ACCEPT
    reason: Correct process annotation consistent with the Hsp70 chaperone mechanism and the directly_involved_in process of the GO:0044183 core function.
    supported_by:
    - reference_id: file:human/HSPA9/HSPA9-deep-research-falcon.md
      supporting_text: HSPA9 encodes the mitochondrial Hsp70 chaperone known as mortalin/GRP75/mtHsp70.
- term:
    id: GO:0016787
    label: hydrolase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000043
  review:
    summary: Generic hydrolase activity from a UniProt keyword mapping. HSPA9 is an ATP hydrolase (EC 3.6.4.10), but this is a very high-level parent of the more informative ATP hydrolysis activity (GO:0016887) that is also annotated.
    action: MODIFY
    reason: GO:0016787 is uninformatively broad. The specific molecular function is ATP hydrolysis activity, already present in the annotation set with experimental support.
    proposed_replacement_terms:
    - id: GO:0016887
      label: ATP hydrolysis activity
    supported_by:
    - reference_id: PMID:18632665
      supporting_text: The human escort protein Hep binds to the ATPase domain of mitochondrial hsp70 and regulates ATP hydrolysis.
- term:
    id: GO:0016887
    label: ATP hydrolysis activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  review:
    summary: ATP hydrolysis activity inferred from InterPro HSP70 ATPase domain. This is the core catalytic activity of HSPA9 and is also directly demonstrated experimentally.
    action: ACCEPT
    reason: Correct and appropriately specific; duplicate of the IBA/IDA ATP hydrolysis calls, all consistent with direct biochemical assays of human mortalin (PMID:18632665, PMID:25615450).
    supported_by:
    - reference_id: PMID:18632665
      supporting_text: The human escort protein Hep binds to the ATPase domain of mitochondrial hsp70 and regulates ATP hydrolysis.
- term:
    id: GO:0051082
    label: unfolded protein binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  review:
    summary: GO:0051082 captures substrate binding but not the mechanistically informative chaperone activity. HSPA9 (mortalin/mtHsp70) is a canonical ATP-dependent mitochondrial Hsp70 chaperone involved in import-associated folding and refolding. GO:0044183 better represents this molecular function.
    action: MODIFY
    reason: HSPA9 should be represented as a protein folding chaperone rather than generic unfolded-protein binding. The existing HSPA9 annotation set already includes GO:0044183 and chaperone/refolding process terms, consistent with mtHsp70 biology.
    proposed_replacement_terms:
    - id: GO:0044183
      label: protein folding chaperone
    supported_by:
    - reference_id: file:human/HSPA9/HSPA9-deep-research-falcon.md
      supporting_text: HSPA9 encodes the mitochondrial Hsp70 chaperone known as mortalin/GRP75/mtHsp70. It belongs to the Hsp70 family, with canonical N-terminal ATPase and C-terminal substrate-binding domains typical of Hsp70s.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:15657067
  review:
    summary: Bare 'protein binding' from a high-throughput phosphotyrosine-signaling proteomics screen in EGFR-overexpressing carcinoma cells (interactor EGFR/P00533). This is an uninformative molecular function term from a large-scale dataset, not a mechanistic characterization of HSPA9 function.
    action: MARK_AS_OVER_ANNOTATED
    reason: GO:0005515 is uninformative and this is a non-specific high-throughput co-occurrence in an EGFR proteomics dataset; it does not represent a core or mechanistically meaningful HSPA9 function.
    supported_by:
    - reference_id: PMID:15657067
      supporting_text: Phosphotyrosine signaling networks in epidermal growth factor receptor overexpressing squamous carcinoma cells.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:17184779
  review:
    summary: Bare 'protein binding' (interactor p53/P04637) derived from a differential proteomics study of p53-silenced nasopharyngeal carcinoma cells. The mortalin-p53 interaction is genuine and important, but this particular evidence is an indirect abundance-change proteomics readout and the MF term itself is uninformative.
    action: MARK_AS_OVER_ANNOTATED
    reason: GO:0005515 is an uninformative term; the mechanistically relevant HSPA9-p53 interaction is better supported by the direct reconstitution study (PMID:20153329). This proteomics-based entry adds no functional specificity.
    supported_by:
    - reference_id: PMID:17184779
      supporting_text: Identification of differential proteins in nasopharyngeal carcinoma cells with p53 silence by proteome analysis.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:20029029
  review:
    summary: Bare 'protein binding' (interactor EGFR/P00533) from an EGFR-trafficking interactome study. Uninformative MF term from a large-scale dataset.
    action: MARK_AS_OVER_ANNOTATED
    reason: GO:0005515 is uninformative; HSPA9 appearance in an EGFR/HDAC6 trafficking dataset does not define a specific molecular function and is not core.
    supported_by:
    - reference_id: PMID:20029029
      supporting_text: Regulation of epidermal growth factor receptor trafficking by lysine deacetylase HDAC6.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:20153329
  review:
    summary: Bare 'protein binding' representing the direct HSPA9 (mortalin)-p53 interaction, here reconstituted with purified proteins. This is a genuine, mechanistically meaningful interaction underlying mortalin's anti-apoptotic cytosolic sequestration of p53, but the GO term itself is uninformative.
    action: KEEP_AS_NON_CORE
    reason: The mortalin-p53 interaction is real and biologically significant (p53 sequestration), but 'protein binding' is an uninformative MF and the p53-related role is a non-core, context-dependent extramitochondrial activity rather than HSPA9's core chaperone/import/Fe-S function. Retain as non-core documentation of the interaction.
    supported_by:
    - reference_id: PMID:20153329
      supporting_text: Reconstitution of the mitochondrial Hsp70 (mortalin)-p53 interaction using purified proteins--identification of additional interacting regions.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:20195357
  review:
    summary: Bare 'protein binding' from a large-scale interacting-protein-regions resource (interactor NELFB/Q8WX92). High-throughput, uninformative MF term.
    action: MARK_AS_OVER_ANNOTATED
    reason: GO:0005515 is uninformative and this is a non-specific high-throughput interaction-network hit, not a defined HSPA9 function.
    supported_by:
    - reference_id: PMID:20195357
      supporting_text: A comprehensive resource of interacting protein regions for refining human transcription factor networks.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:22340593
  review:
    summary: Bare 'protein binding' (interactors p73/O15350 and p53/P04637) reported in a study of Aurora kinase-A regulation of p73. Uninformative MF term from a broad interaction dataset.
    action: MARK_AS_OVER_ANNOTATED
    reason: GO:0005515 is uninformative; the p53/p73-family interactions are peripheral to HSPA9's core function and captured here only as non-specific binding.
    supported_by:
    - reference_id: PMID:22340593
      supporting_text: Aurora kinase-A inactivates DNA damage-induced apoptosis and spindle assembly checkpoint response functions of p73.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:22726440
  review:
    summary: Bare 'protein binding' (interactor p53/P04637) from a study where mortalin-p53 interaction modulates the mitochondrial permeability transition pore and necrosis. Biologically meaningful interaction but uninformative MF term.
    action: MARK_AS_OVER_ANNOTATED
    reason: GO:0005515 is uninformative; the mortalin-p53 axis is better captured elsewhere (PMID:20153329) and the necrosis/mPTP role is a downstream consequence, not a defined molecular function of HSPA9.
    supported_by:
    - reference_id: PMID:22726440
      supporting_text: p53 opens the mitochondrial permeability transition pore to trigger necrosis.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:24189400
  review:
    summary: Bare 'protein binding' (interactor EGFR/P00533) from a mutant-EGFR interactome perturbation study. High-throughput, uninformative MF term.
    action: MARK_AS_OVER_ANNOTATED
    reason: GO:0005515 is uninformative and this is a non-specific interactome hit, not a defined HSPA9 function.
    supported_by:
    - reference_id: PMID:24189400
      supporting_text: Perturbation of the mutated EGFR interactome identifies vulnerabilities and resistance mechanisms.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:24606901
  review:
    summary: Bare 'protein binding' representing the HSPA9-HSC20/HSCB (Q8IWL3) co-chaperone interaction central to Fe-S cluster delivery, where HSC20 recognizes LYR motifs on client/acceptor proteins. The interaction is mechanistically core to Fe-S biogenesis, but the GO term itself is uninformative.
    action: KEEP_AS_NON_CORE
    reason: The HSPA9-HSC20 interaction is a genuine, mechanistically important part of Fe-S cluster delivery (captured functionally by GO:0016226 and GO:0044183), but 'protein binding' is uninformative as a standalone MF. Retain as non-core documentation of the co-chaperone partnership.
    supported_by:
    - reference_id: PMID:24606901
      supporting_text: Cochaperone binding to LYR motifs confers specificity of iron sulfur cluster delivery.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:25416956
  review:
    summary: Bare 'protein binding' from a proteome-scale binary interactome map (interactor A4D2J0). High-throughput Y2H-type hit, uninformative MF term.
    action: MARK_AS_OVER_ANNOTATED
    reason: GO:0005515 is uninformative and this is a non-specific large-scale interactome entry.
    supported_by:
    - reference_id: PMID:25416956
      supporting_text: A proteome-scale map of the human interactome network.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:27107014
  review:
    summary: Bare 'protein binding' from an inter-species interaction-network screen (interactors P38340, P53051). High-throughput, uninformative MF term.
    action: MARK_AS_OVER_ANNOTATED
    reason: GO:0005515 is uninformative and this is a non-specific large-scale interactome hit.
    supported_by:
    - reference_id: PMID:27107014
      supporting_text: An inter-species protein-protein interaction network across vast evolutionary distance.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:27607350
  review:
    summary: Bare 'protein binding' (interactor TPT1/TCTP, P13693) from a TCTP interactome study in cancer cells. High-throughput, uninformative MF term.
    action: MARK_AS_OVER_ANNOTATED
    reason: GO:0005515 is uninformative and this interactome co-occurrence does not define a specific HSPA9 function.
    supported_by:
    - reference_id: PMID:27607350
      supporting_text: Characterization of the Translationally Controlled Tumor Protein (TCTP) Interactome Reveals Novel Binding Partners in Human Cancer Cells.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:28380382
  review:
    summary: Bare 'protein binding' representing the HSPA9-HSC20/HSCB (Q8IWL3) co-chaperone-scaffold interaction that delivers nascent Fe-S clusters to respiratory chain Complexes I-III. Mechanistically core to Fe-S biogenesis, but the GO term itself is uninformative.
    action: KEEP_AS_NON_CORE
    reason: Genuine and mechanistically important interaction in Fe-S delivery (functionally captured by GO:0016226), but 'protein binding' is uninformative as a standalone MF. Retain as non-core.
    supported_by:
    - reference_id: PMID:28380382
      supporting_text: A Single Adaptable Cochaperone-Scaffold Complex Delivers Nascent Iron-Sulfur Clusters to Mammalian Respiratory Chain Complexes I-III.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:28514442
  review:
    summary: Bare 'protein binding' from a large-scale human interactome map (interactors Q9H6A0, Q9HAV7). High-throughput, uninformative MF term.
    action: MARK_AS_OVER_ANNOTATED
    reason: GO:0005515 is uninformative and this is a non-specific interactome/affinity-MS hit.
    supported_by:
    - reference_id: PMID:28514442
      supporting_text: Architecture of the human interactome defines protein communities and disease networks.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:30021884
  review:
    summary: Bare 'protein binding' from a crosslinking-MS histone-interaction study in intact nuclei (interactor Q9HAV7). High-throughput, uninformative MF term suggesting only a transient nuclear-associated pool.
    action: MARK_AS_OVER_ANNOTATED
    reason: GO:0005515 is uninformative and this XL-MS co-occurrence does not define a specific HSPA9 function; a nuclear pool is at best minor and non-core.
    supported_by:
    - reference_id: PMID:30021884
      supporting_text: Histone Interaction Landscapes Visualized by Crosslinking Mass Spectrometry in Intact Cell Nuclei.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:31978385
  review:
    summary: Bare 'protein binding' (interactor TGR5/GPBAR1, Q8TDU6) from a cholangiocarcinoma study. A disease-context interaction but the MF term is uninformative.
    action: MARK_AS_OVER_ANNOTATED
    reason: GO:0005515 is uninformative; this cancer-context interaction does not define a core or specific HSPA9 molecular function.
    supported_by:
    - reference_id: PMID:31978385
      supporting_text: TGR5 promotes cholangiocarcinoma by interacting with mortalin.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:31980649
  review:
    summary: Bare 'protein binding' (interactor EGFR/P00533) from an EGFR-network rewiring study in KRAS-mutant colorectal cancer cells. High-throughput, uninformative MF term.
    action: MARK_AS_OVER_ANNOTATED
    reason: GO:0005515 is uninformative and this is a non-specific interactome hit, not a defined HSPA9 function.
    supported_by:
    - reference_id: PMID:31980649
      supporting_text: Extensive rewiring of the EGFR network in colorectal cancer cells expressing transforming levels of KRAS(G13D).
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:32807793
  review:
    summary: Bare 'protein binding' (interactor OSMR/Q99650) from a glioblastoma respiration/radioresistance study. High-throughput proteomics association, uninformative MF term.
    action: MARK_AS_OVER_ANNOTATED
    reason: GO:0005515 is uninformative; this cancer-context proteomics co-occurrence does not define a specific HSPA9 function.
    supported_by:
    - reference_id: PMID:32807793
      supporting_text: OSMR controls glioma stem cell respiration and confers resistance of glioblastoma to ionizing radiation.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:33961781
  review:
    summary: Bare 'protein binding' from dual proteome-scale interactome networks (interactors Q9H6A0, Q9HAV7). High-throughput, uninformative MF term.
    action: MARK_AS_OVER_ANNOTATED
    reason: GO:0005515 is uninformative and this is a non-specific large-scale interactome hit.
    supported_by:
    - reference_id: PMID:33961781
      supporting_text: Dual proteome-scale networks reveal cell-specific remodeling of the human interactome.
- term:
    id: GO:0016226
    label: iron-sulfur cluster assembly
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: Iron-sulfur cluster assembly transferred by Ensembl Compara orthology from mouse Hspa9. Duplicate of the IBA and IMP Fe-S assembly calls, all consistent with direct human experimental evidence.
    action: ACCEPT
    reason: Correct core process; redundant with stronger IBA/IMP evidence (PMID:26702583, PMID:23940031) but accurate.
    supported_by:
    - reference_id: PMID:26702583
      supporting_text: Mitochondrial Hspa9/Mortalin regulates erythroid differentiation via iron-sulfur cluster assembly.
- term:
    id: GO:0019899
    label: enzyme binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: Enzyme binding transferred by Ensembl Compara orthology. HSPA9 does bind enzymes (e.g., cysteine desulfurase NFS1 in Fe-S biogenesis), but 'enzyme binding' is a relatively uninformative molecular function term derived from orthology transfer.
    action: MARK_AS_OVER_ANNOTATED
    reason: While HSPA9 contacts enzymes such as NFS1, the generic 'enzyme binding' term adds little functional specificity beyond the better-supported chaperone and Fe-S assembly annotations; it is an orthology-transferred over-annotation.
    supported_by:
    - reference_id: PMID:23940031
      supporting_text: Human mitochondrial chaperone (mtHSP70) and cysteine desulfurase (NFS1) bind preferentially to the disordered conformation, whereas co-chaperone (HSC20) binds to the structured conformation of the iron-sulfur cluster scaffold protein (ISCU).
- term:
    id: GO:1902037
    label: negative regulation of hematopoietic stem cell differentiation
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: Negative regulation of hematopoietic stem cell differentiation transferred by Ensembl Compara orthology from mouse Hspa9, where knockdown perturbs hematopoietic progenitors. This is a downstream physiological consequence of HSPA9's Fe-S/chaperone function rather than a direct molecular role.
    action: KEEP_AS_NON_CORE
    reason: Supported indirectly by mouse loss-of-function data (PMID:21123823), but this is a pleiotropic developmental/physiological outcome secondary to HSPA9's core mitochondrial chaperone and Fe-S biogenesis functions. Keep as non-core.
    supported_by:
    - reference_id: PMID:21123823
      supporting_text: Knockdown of Hspa9, a del(5q31.2) gene, results in a decrease in hematopoietic progenitors in mice.
- term:
    id: GO:1903707
    label: negative regulation of hemopoiesis
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: Negative regulation of hemopoiesis transferred by Ensembl Compara orthology from mouse Hspa9. A broad pleiotropic/physiological outcome of HSPA9's mitochondrial function rather than a direct molecular role.
    action: KEEP_AS_NON_CORE
    reason: Indirectly supported by mouse loss-of-function studies (PMID:21123823), but it is a downstream consequence of impaired Fe-S/chaperone function and not a core HSPA9 activity. Keep as non-core.
    supported_by:
    - reference_id: PMID:21123823
      supporting_text: Knockdown of Hspa9, a del(5q31.2) gene, results in a decrease in hematopoietic progenitors in mice.
- term:
    id: GO:0005739
    label: mitochondrion
  evidence_type: IDA
  original_reference_id: GO_REF:0000052
  review:
    summary: Mitochondrion localization from curated immunofluorescence (Human Protein Atlas). Directly confirms the canonical mitochondrial localization of HSPA9.
    action: ACCEPT
    reason: Direct experimental localization consistent with all other evidence for HSPA9 as a mitochondrial protein.
    supported_by:
    - reference_id: PMID:7829505
      supporting_text: Cloning and subcellular localization of human mitochondrial hsp70.
- term:
    id: GO:0005743
    label: mitochondrial inner membrane
  evidence_type: NAS
  original_reference_id: PMID:10339406
  review:
    summary: Mitochondrial inner membrane localization (ComplexPortal NAS). HSPA9 is the matrix-side motor of the TIM23/PAM import machinery and is recruited to the inner membrane translocase during import, so an inner-membrane-associated pool is mechanistically expected.
    action: ACCEPT
    reason: HSPA9 functions at the inner membrane as the PAM motor associated with the TIM23 translocase; the inner-membrane association is well-established for mtHsp70 import function.
    supported_by:
    - reference_id: PMID:10339406
      supporting_text: Genetic and structural characterization of the human mitochondrial inner membrane translocase.
- term:
    id: GO:0006886
    label: intracellular protein transport
  evidence_type: NAS
  original_reference_id: PMID:10339406
  review:
    summary: Intracellular protein transport (ComplexPortal NAS) referring to HSPA9's role as the PAM motor of the TIM23 import machinery. The specific process is import of nuclear-encoded precursors into the mitochondrial matrix; the generic term is too broad.
    action: MODIFY
    reason: HSPA9 drives a specific transport process - ATP-dependent import of presequence-containing precursors across the inner membrane into the matrix. GO:0030150 (protein import into mitochondrial matrix) is the appropriately specific term and is used in core_functions.
    proposed_replacement_terms:
    - id: GO:0030150
      label: protein import into mitochondrial matrix
    supported_by:
    - reference_id: PMID:10339406
      supporting_text: Genetic and structural characterization of the human mitochondrial inner membrane translocase.
- term:
    id: GO:0016887
    label: ATP hydrolysis activity
  evidence_type: IDA
  original_reference_id: PMID:18632665
  review:
    summary: ATP hydrolysis activity demonstrated by direct biochemical assay; the escort protein Hep/DNLZ binds the HSPA9 ATPase domain and regulates its ATP hydrolysis. Direct experimental support for the core catalytic activity.
    action: ACCEPT
    reason: Strong direct (IDA) evidence for HSPA9 ATPase activity, the core catalytic function powering its chaperone cycle.
    supported_by:
    - reference_id: PMID:18632665
      supporting_text: The human escort protein Hep binds to the ATPase domain of mitochondrial hsp70 and regulates ATP hydrolysis.
- term:
    id: GO:0016887
    label: ATP hydrolysis activity
  evidence_type: IDA
  original_reference_id: PMID:25615450
  review:
    summary: ATP hydrolysis activity directly characterized for human mortalin, including ATPase kinetics, nucleotide interactions, solution structure and Hsp70 two-domain organization. Direct experimental support for the core catalytic activity.
    action: ACCEPT
    reason: Direct (IDA) biochemical characterization of human HSPA9 ATPase activity; this is the core molecular function.
    supported_by:
    - reference_id: PMID:25615450
      supporting_text: 'Human mitochondrial Hsp70 (mortalin): shedding light on ATPase activity, interaction with adenosine nucleotides, solution structure and domain organization.'
- term:
    id: GO:0005739
    label: mitochondrion
  evidence_type: HTP
  original_reference_id: PMID:34800366
  review:
    summary: Mitochondrion localization from a high-confidence quantitative human mitochondrial proteome. Corroborates the canonical mitochondrial localization of HSPA9.
    action: ACCEPT
    reason: HSPA9 is a bona fide, high-confidence component of the human mitochondrial proteome; consistent with all other localization evidence.
    supported_by:
    - reference_id: PMID:34800366
      supporting_text: Quantitative high-confidence human mitochondrial proteome and its dynamics in cellular context.
- term:
    id: GO:0036444
    label: calcium import into the mitochondrion
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: Calcium import into the mitochondrion by ISS from ortholog (UniProtKB:P48721, GRP75). GRP75/mortalin is a scaffolding component of the IP3R-GRP75-VDAC1 complex at mitochondria-associated ER membranes (MAMs) that channels ER-to-mitochondria Ca2+ transfer. This is a genuine but secondary, scaffolding role rather than HSPA9's core matrix chaperone function.
    action: KEEP_AS_NON_CORE
    reason: GRP75/HSPA9 bridges IP3R and VDAC1 at MAMs to facilitate Ca2+ transfer, but this is a context-dependent scaffolding role at the mitochondrial surface, distinct from and secondary to its core matrix chaperone/import/Fe-S functions. Retain as non-core.
    supported_by:
    - reference_id: file:human/HSPA9/HSPA9-deep-research-falcon.md
      supporting_text: Mortalin can redistribute beyond mitochondria (including plasma membrane accumulation) under certain stresses
- term:
    id: GO:0005759
    label: mitochondrial matrix
  evidence_type: IDA
  original_reference_id: PMID:7865888
  review:
    summary: Mitochondrial matrix localization by direct assay (PBP74/HSPA9 shown to be a mitochondrial protein). This is the primary, functionally relevant compartment for HSPA9.
    action: ACCEPT
    reason: Direct experimental localization to the matrix, the core site of HSPA9 chaperone, import-motor, and Fe-S delivery functions.
    supported_by:
    - reference_id: PMID:7865888
      supporting_text: PBP74, a new member of the mammalian 70-kDa heat shock protein family, is a mitochondrial protein.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:24625977
  review:
    summary: Bare 'protein binding' (interactors p53/P04637 and UBXN2A/P68543). UBXN2A binds mortalin and competes with p53 for mortalin binding, promoting cell death. Mechanistically relevant to mortalin's p53-sequestration role but the MF term is uninformative.
    action: MARK_AS_OVER_ANNOTATED
    reason: GO:0005515 is uninformative; the p53/UBXN2A interactions relate to mortalin's cancer-context anti-apoptotic role and are not a core or specifically-defined molecular function. UBXN2A binding is also captured separately (PMID:26634371).
    supported_by:
    - reference_id: PMID:24625977
      supporting_text: Ubiquitin-like (UBX)-domain-containing protein, UBXN2A, promotes cell death by interfering with the p53-Mortalin interactions in colon cancer cells.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:26634371
  review:
    summary: Bare 'protein binding' (interactor UBXN2A/P68543) from structural studies of the UBXN2A-mortalin interaction. A direct, structurally characterized interaction relevant to chemotherapy response, but the MF term is uninformative.
    action: MARK_AS_OVER_ANNOTATED
    reason: GO:0005515 is uninformative; the UBXN2A interaction relates to mortalin's cancer/p53 biology and is not a core HSPA9 molecular function.
    supported_by:
    - reference_id: PMID:26634371
      supporting_text: Structural studies of UBXN2A and mortalin interaction and the putative role of silenced UBXN2A in preventing response to chemotherapy.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:23940031
  review:
    summary: Bare 'protein binding' representing the direct HSPA9 (mtHSP70)-ISCU (Q9H1K1) interaction, where mtHSP70 binds preferentially to the disordered conformation of the Fe-S scaffold ISCU. This is a mechanistically core interaction in Fe-S cluster delivery, but the GO term is uninformative.
    action: KEEP_AS_NON_CORE
    reason: The HSPA9-ISCU interaction is central to Fe-S cluster biogenesis (functionally captured by GO:0016226 and the GO:0044183 core function), but 'protein binding' is uninformative as a standalone MF. Retain as non-core documentation of the substrate/scaffold interaction.
    supported_by:
    - reference_id: PMID:23940031
      supporting_text: Human mitochondrial chaperone (mtHSP70) and cysteine desulfurase (NFS1) bind preferentially to the disordered conformation, whereas co-chaperone (HSC20) binds to the structured conformation of the iron-sulfur cluster scaffold protein (ISCU).
- term:
    id: GO:0001401
    label: SAM complex
  evidence_type: HDA
  original_reference_id: PMID:26477565
  review:
    summary: SAM complex membership from a high-throughput proteomics analysis of MICOS/MIB assemblies. The SAM complex is an outer-membrane sorting-and-assembly machinery; HSPA9 is a soluble matrix chaperone and not an established structural subunit of SAM, so this is most likely a co-purification artifact or transient association.
    action: MARK_AS_OVER_ANNOTATED
    reason: HSPA9 is a matrix Hsp70, not a bona fide structural component of the outer-membrane SAM complex; the HDA assignment reflects co-fractionation with large mitochondrial assemblies rather than stable SAM membership.
    supported_by:
    - reference_id: PMID:26477565
      supporting_text: Evolution and structural organization of the mitochondrial contact site (MICOS) complex and the mitochondrial intermembrane space bridging (MIB) complex.
- term:
    id: GO:0007007
    label: inner mitochondrial membrane organization
  evidence_type: IC
  original_reference_id: PMID:26477565
  review:
    summary: Inner mitochondrial membrane organization inferred (IC) from the putative MIB-complex membership. Since the underlying MIB/SAM association is most likely a co-fractionation artifact for this matrix chaperone, the inferred membrane-organization process is not well supported.
    action: MARK_AS_OVER_ANNOTATED
    reason: This IC annotation depends on HSPA9 being a structural component of the MIB complex, which is not established for a matrix Hsp70; the inner-membrane-organization role is therefore an over-annotation.
    supported_by:
    - reference_id: PMID:26477565
      supporting_text: Evolution and structural organization of the mitochondrial contact site (MICOS) complex and the mitochondrial intermembrane space bridging (MIB) complex.
- term:
    id: GO:0140275
    label: MIB complex
  evidence_type: HDA
  original_reference_id: PMID:26477565
  review:
    summary: MIB complex membership from high-throughput proteomics of MICOS/MIB assemblies. The MIB complex bridges inner and outer membranes; HSPA9 is a matrix chaperone and not an established structural subunit, so this most likely reflects co-purification rather than stable membership.
    action: MARK_AS_OVER_ANNOTATED
    reason: HSPA9 is not a bona fide structural component of the MIB complex; the HDA assignment reflects co-fractionation with large mitochondrial assemblies.
    supported_by:
    - reference_id: PMID:26477565
      supporting_text: Evolution and structural organization of the mitochondrial contact site (MICOS) complex and the mitochondrial intermembrane space bridging (MIB) complex.
- term:
    id: GO:0016226
    label: iron-sulfur cluster assembly
  evidence_type: IMP
  original_reference_id: PMID:26702583
  review:
    summary: Iron-sulfur cluster assembly supported by mutational evidence (IMP). HSPA9/mortalin regulates Fe-S cluster assembly; a Gly489 mutation disrupts ISC assembly function and HSPA9 binds Fe-S pathway components (ISCU, NFS1, NFU1, FXN). Strong direct evidence for this core process.
    action: ACCEPT
    reason: Direct mutational/functional evidence places HSPA9 in Fe-S cluster assembly, a core biological process; this IMP is the strongest support and complements the IBA/IEA calls.
    supported_by:
    - reference_id: PMID:26702583
      supporting_text: Mitochondrial Hspa9/Mortalin regulates erythroid differentiation via iron-sulfur cluster assembly.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:26702583
  review:
    summary: Bare 'protein binding' representing HSPA9 interactions with Fe-S pathway components ISCU (Q9H1K1), FXN/frataxin (Q16595), NFU1 (Q9UMS0) and NFS1 (Q9Y697). These are mechanistically core Fe-S biogenesis interactions, but the GO term itself is uninformative.
    action: KEEP_AS_NON_CORE
    reason: The interactions with ISCU/FXN/NFU1/NFS1 underpin HSPA9's Fe-S cluster assembly function (captured by GO:0016226), but 'protein binding' is uninformative as a standalone MF. Retain as non-core documentation of the Fe-S partner interactions.
    supported_by:
    - reference_id: PMID:26702583
      supporting_text: Mitochondrial Hspa9/Mortalin regulates erythroid differentiation via iron-sulfur cluster assembly.
- term:
    id: GO:0005739
    label: mitochondrion
  evidence_type: IDA
  original_reference_id: PMID:26702583
  review:
    summary: Mitochondrion localization by direct assay, corroborating the canonical mitochondrial localization of HSPA9/mortalin.
    action: ACCEPT
    reason: Direct experimental localization consistent with all other evidence; HSPA9 is a mitochondrial protein.
    supported_by:
    - reference_id: PMID:26702583
      supporting_text: Mitochondrial Hspa9/Mortalin regulates erythroid differentiation via iron-sulfur cluster assembly.
- term:
    id: GO:0045646
    label: regulation of erythrocyte differentiation
  evidence_type: IMP
  original_reference_id: PMID:26702583
  review:
    summary: Regulation of erythrocyte differentiation by mutational evidence (IMP). HSPA9 loss impairs erythroid differentiation, mechanistically via its Fe-S cluster assembly role. This is a downstream physiological consequence of the core mitochondrial function.
    action: KEEP_AS_NON_CORE
    reason: Genuine, experimentally supported role in erythroid differentiation, but it is a tissue-level developmental outcome secondary to HSPA9's core Fe-S/chaperone function. Keep as non-core.
    supported_by:
    - reference_id: PMID:26702583
      supporting_text: Mitochondrial Hspa9/Mortalin regulates erythroid differentiation via iron-sulfur cluster assembly.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:23541579
  review:
    summary: Bare 'protein binding' (interactor podoplanin/Q86YL7) describing an extracellular mortalin-podoplanin interaction in oral squamous cell carcinoma. A context-dependent extracellular interaction; the MF term is uninformative.
    action: MARK_AS_OVER_ANNOTATED
    reason: GO:0005515 is uninformative; this extracellular cancer-context interaction does not define a core HSPA9 molecular function.
    supported_by:
    - reference_id: PMID:23541579
      supporting_text: Extracellular heat shock protein A9 is a novel interaction partner of podoplanin in oral squamous cell carcinoma cells.
- term:
    id: GO:0005759
    label: mitochondrial matrix
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8950389
  review:
    summary: Mitochondrial matrix localization asserted by Reactome (expression of mitochondrial Stress-70 protein). Consistent with the primary matrix localization of HSPA9.
    action: ACCEPT
    reason: Correct localization to the matrix, the core compartment of HSPA9 function; consistent with direct experimental evidence (PMID:7865888).
    supported_by:
    - reference_id: PMID:7865888
      supporting_text: PBP74, a new member of the mammalian 70-kDa heat shock protein family, is a mitochondrial protein.
- term:
    id: GO:0005759
    label: mitochondrial matrix
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9838035
  review:
    summary: Mitochondrial matrix localization asserted by Reactome (CLPXP binds mitochondrial matrix proteins event). Consistent with HSPA9's primary matrix localization where it cooperates with matrix proteostasis machinery.
    action: ACCEPT
    reason: Correct matrix localization; consistent with direct experimental evidence and HSPA9's role in matrix protein quality control.
    supported_by:
    - reference_id: PMID:7865888
      supporting_text: PBP74, a new member of the mammalian 70-kDa heat shock protein family, is a mitochondrial protein.
- term:
    id: GO:0005759
    label: mitochondrial matrix
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9838081
  review:
    summary: Mitochondrial matrix localization asserted by Reactome (LONP1 degrades mitochondrial matrix proteins event). Consistent with HSPA9's primary matrix localization within the matrix proteostasis network.
    action: ACCEPT
    reason: Correct matrix localization; consistent with direct experimental evidence.
    supported_by:
    - reference_id: PMID:7865888
      supporting_text: PBP74, a new member of the mammalian 70-kDa heat shock protein family, is a mitochondrial protein.
- term:
    id: GO:0005759
    label: mitochondrial matrix
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9838093
  review:
    summary: Mitochondrial matrix localization asserted by Reactome (LONP1 binds mitochondrial matrix proteins event). Consistent with HSPA9's primary matrix localization.
    action: ACCEPT
    reason: Correct matrix localization; consistent with direct experimental evidence.
    supported_by:
    - reference_id: PMID:7865888
      supporting_text: PBP74, a new member of the mammalian 70-kDa heat shock protein family, is a mitochondrial protein.
- term:
    id: GO:0005759
    label: mitochondrial matrix
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9838289
  review:
    summary: Mitochondrial matrix localization asserted by Reactome (CLPXP degrades mitochondrial matrix proteins event). Consistent with HSPA9's primary matrix localization.
    action: ACCEPT
    reason: Correct matrix localization; consistent with direct experimental evidence.
    supported_by:
    - reference_id: PMID:7865888
      supporting_text: PBP74, a new member of the mammalian 70-kDa heat shock protein family, is a mitochondrial protein.
- term:
    id: GO:0005759
    label: mitochondrial matrix
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9856627
  review:
    summary: Mitochondrial matrix localization asserted by Reactome (ATF5 and HSF1 trimer activate expression of HSPA9/mtHSP70 event). Consistent with HSPA9's primary matrix localization and stress-responsive upregulation.
    action: ACCEPT
    reason: Correct matrix localization; consistent with direct experimental evidence.
    supported_by:
    - reference_id: PMID:7865888
      supporting_text: PBP74, a new member of the mammalian 70-kDa heat shock protein family, is a mitochondrial protein.
- term:
    id: GO:0030218
    label: erythrocyte differentiation
  evidence_type: IMP
  original_reference_id: PMID:21123823
  review:
    summary: Erythrocyte differentiation by mutational/knockdown evidence (IMP). Hspa9 knockdown reduces hematopoietic progenitors in mice, implicating HSPA9 in erythroid development. This is a downstream physiological consequence of its core mitochondrial function.
    action: KEEP_AS_NON_CORE
    reason: Experimentally supported developmental involvement, but a tissue-level outcome secondary to HSPA9's core Fe-S/chaperone function. Keep as non-core.
    supported_by:
    - reference_id: PMID:21123823
      supporting_text: Knockdown of Hspa9, a del(5q31.2) gene, results in a decrease in hematopoietic progenitors in mice.
- term:
    id: GO:0045647
    label: negative regulation of erythrocyte differentiation
  evidence_type: IMP
  original_reference_id: PMID:21123823
  review:
    summary: Negative regulation of erythrocyte differentiation (IMP). Note that loss of Hspa9 reduces hematopoietic progenitors, so HSPA9 normally supports rather than negatively regulates erythropoiesis; the directionality of this term is questionable and likely reflects a complex dosage phenotype at the del(5q) locus.
    action: KEEP_AS_NON_CORE
    reason: HSPA9 is involved in erythroid differentiation, but it is a downstream developmental phenotype and the negative-regulation directionality is not cleanly supported (knockdown decreases progenitors). Retain as non-core given the experimental link, without elevating it to a core function.
    supported_by:
    - reference_id: PMID:21123823
      supporting_text: Knockdown of Hspa9, a del(5q31.2) gene, results in a decrease in hematopoietic progenitors in mice.
- term:
    id: GO:0031625
    label: ubiquitin protein ligase binding
  evidence_type: IPI
  original_reference_id: PMID:19725078
  review:
    summary: Ubiquitin protein ligase binding (interactor Parkin/PRKN, O60260) from proteomic analysis of Parkin interactants. HSPA9/mortalin associates with the E3 ligase Parkin in the context of mitochondrial quality control/mitophagy. More informative than bare protein binding but a peripheral interaction.
    action: KEEP_AS_NON_CORE
    reason: The HSPA9-Parkin association is genuine and relevant to mitochondrial quality control, but it is peripheral to HSPA9's core chaperone/import/Fe-S functions. Keep as non-core.
    supported_by:
    - reference_id: PMID:19725078
      supporting_text: Proteomic analysis of increased Parkin expression and its interactants provides evidence for a role in modulation of mitochondrial function.
- term:
    id: GO:0031625
    label: ubiquitin protein ligase binding
  evidence_type: IPI
  original_reference_id: PMID:21753002
  review:
    summary: Ubiquitin protein ligase binding (interactor Parkin/PRKN, O60260) reported in a Parkin/Ambra1 mitophagy study. Corroborates the HSPA9-Parkin association in mitochondrial quality control. Peripheral interaction.
    action: KEEP_AS_NON_CORE
    reason: Genuine HSPA9-Parkin association relevant to mitophagy/quality control, but peripheral to HSPA9's core functions. Keep as non-core.
    supported_by:
    - reference_id: PMID:21753002
      supporting_text: Parkin interacts with Ambra1 to induce mitophagy.
- term:
    id: GO:0005925
    label: focal adhesion
  evidence_type: HDA
  original_reference_id: PMID:21423176
  review:
    summary: Focal adhesion localization from a high-throughput focal-adhesion proteome. HSPA9 is a mitochondrial matrix protein; its appearance in a focal-adhesion fraction is most likely a contaminant/co-isolation artifact rather than a genuine functional localization.
    action: MARK_AS_OVER_ANNOTATED
    reason: Inconsistent with HSPA9's established mitochondrial matrix localization; HDA detection in a focal-adhesion proteome likely reflects abundant-protein contamination and is not a functional site.
    supported_by:
    - reference_id: PMID:21423176
      supporting_text: Analysis of the myosin-II-responsive focal adhesion proteome reveals a role for beta-Pix in negative regulation of focal adhesion maturation.
- term:
    id: GO:0003723
    label: RNA binding
  evidence_type: HDA
  original_reference_id: PMID:22658674
  review:
    summary: RNA binding from a high-throughput mRNA-interactome capture (RNA-protein crosslinking) atlas. HSPA9 lacks a canonical RNA-binding domain; Hsp70 chaperones are frequently captured in such screens, so this likely reflects chaperone association with RNP/nascent-chain complexes rather than direct sequence-specific RNA binding.
    action: MARK_AS_OVER_ANNOTATED
    reason: No canonical RNA-binding domain and no dedicated functional evidence for sequence-specific RNA binding; the HDA call is a non-specific interactome-capture hit and over-annotates HSPA9's molecular function.
    supported_by:
    - reference_id: PMID:22658674
      supporting_text: Insights into RNA biology from an atlas of mammalian mRNA-binding proteins.
- term:
    id: GO:0003723
    label: RNA binding
  evidence_type: HDA
  original_reference_id: PMID:22681889
  review:
    summary: RNA binding from a high-throughput mRNA-bound proteome capture. As above, HSPA9 has no canonical RNA-binding domain and such captures of Hsp70s likely reflect chaperone association with RNP complexes rather than direct RNA binding.
    action: MARK_AS_OVER_ANNOTATED
    reason: Non-specific interactome-capture hit lacking functional or domain support for sequence-specific RNA binding; over-annotates HSPA9's molecular function.
    supported_by:
    - reference_id: PMID:22681889
      supporting_text: The mRNA-bound proteome and its global occupancy profile on protein-coding transcripts.
- term:
    id: GO:0070062
    label: extracellular exosome
  evidence_type: HDA
  original_reference_id: PMID:20458337
  review:
    summary: Extracellular exosome localization from a high-throughput exosome proteome (B-cell exosomes). Extracellular/exosomal pools of mortalin are reported, consistent with regulated extramitochondrial redistribution, but this is a minor, context-dependent localization rather than the core matrix site.
    action: KEEP_AS_NON_CORE
    reason: Exosomal/extracellular mortalin is documented and biologically relevant in some contexts (e.g., cancer signaling), but it is non-core relative to HSPA9's mitochondrial matrix function. Keep as non-core.
    supported_by:
    - reference_id: file:human/HSPA9/HSPA9-deep-research-falcon.md
      supporting_text: mortalin also participates in extracellular processes including modulation of complement-mediated cytotoxicity, illustrating context-dependent trafficking beyond the matrix
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:20668094
  review:
    summary: Bare 'protein binding' representing the HSPA9-HSC20/HSCB (Q8IWL3) co-chaperone interaction; HSC20 is the DnaJ type III J-protein that partners with mtHsp70 in Fe-S cluster biogenesis. Mechanistically core to Fe-S delivery, but the MF term is uninformative.
    action: KEEP_AS_NON_CORE
    reason: The HSPA9-HSC20 J-protein partnership is central to Fe-S cluster biogenesis (captured functionally by GO:0016226), but 'protein binding' is uninformative as a standalone MF. Retain as non-core.
    supported_by:
    - reference_id: PMID:20668094
      supporting_text: Characterization of the human HSC20, an unusual DnaJ type III protein, involved in iron-sulfur cluster biogenesis.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:15520177
  review:
    summary: Bare 'protein binding' representing the HSPA9-TID1/DNAJA3 (Q96EY1) interaction. TID1 is a mitochondrial J-domain (DnaJ) co-chaperone that regulates mtHsp70 activity. Functionally meaningful co-chaperone interaction, but the MF term is uninformative.
    action: KEEP_AS_NON_CORE
    reason: The HSPA9-DNAJA3/TID1 J-protein interaction is mechanistically relevant to the Hsp70 chaperone cycle, but 'protein binding' is uninformative as a standalone MF. Retain as non-core.
    supported_by:
    - reference_id: PMID:15520177
      supporting_text: Tid1, the human homologue of a Drosophila tumor suppressor, reduces the malignant activity of ErbB-2 in carcinoma cells.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:10411904
  review:
    summary: Bare 'protein binding' representing the HSPA9-TID1/DNAJA3 (Q96EY1) interaction; TID1 isoforms are mitochondrial J-domain co-chaperones that modulate apoptosis with opposing functions. Functionally meaningful co-chaperone interaction, but the MF term is uninformative.
    action: KEEP_AS_NON_CORE
    reason: The HSPA9-DNAJA3/TID1 J-protein interaction is relevant to the mtHsp70 chaperone cycle, but 'protein binding' is uninformative as a standalone MF. Retain as non-core.
    supported_by:
    - reference_id: PMID:10411904
      supporting_text: TID1, a human homolog of the Drosophila tumor suppressor l(2)tid, encodes two mitochondrial modulators of apoptosis with opposing functions.
- term:
    id: GO:0005739
    label: mitochondrion
  evidence_type: IDA
  original_reference_id: PMID:7896880
  review:
    summary: Mitochondrion localization by direct assay, corroborating the canonical mitochondrial localization of HSPA9.
    action: ACCEPT
    reason: Direct experimental localization consistent with all other evidence; HSPA9 is a mitochondrial protein.
    supported_by:
    - reference_id: PMID:7896880
      supporting_text: The intracellular distribution and pattern of expression of Mcl-1 overlap with, but are not identical to, those of Bcl-2.
- term:
    id: GO:0042645
    label: mitochondrial nucleoid
  evidence_type: IDA
  original_reference_id: PMID:18063578
  review:
    summary: Mitochondrial nucleoid localization by direct assay. HSPA9/mortalin was identified among proteins of the layered mtDNA nucleoid, consistent with a peripheral nucleoid-associated matrix pool. mtHsp70 has documented associations with mtDNA maintenance.
    action: KEEP_AS_NON_CORE
    reason: A specific matrix sub-localization supported by direct evidence; nucleoid association is genuine but secondary to HSPA9's core chaperone/import/Fe-S roles. Keep as non-core.
    supported_by:
    - reference_id: PMID:18063578
      supporting_text: The layered structure of human mitochondrial DNA nucleoids.
- term:
    id: GO:0005739
    label: mitochondrion
  evidence_type: TAS
  original_reference_id: PMID:16130169
  review:
    summary: Mitochondrion localization (TAS) from a HUVEC apoptosis proteomics study. Consistent with the canonical mitochondrial localization of HSPA9.
    action: ACCEPT
    reason: Correct localization consistent with all other evidence.
    supported_by:
    - reference_id: PMID:16130169
      supporting_text: Proteomics of human umbilical vein endothelial cells applied to etoposide-induced apoptosis.
- term:
    id: GO:0043066
    label: negative regulation of apoptotic process
  evidence_type: TAS
  original_reference_id: PMID:16130169
  review:
    summary: Negative regulation of apoptotic process (TAS). HSPA9/mortalin has a documented anti-apoptotic role, notably through cytosolic sequestration of p53 and stabilization of mitochondrial integrity. This is a genuine but context-dependent function relevant to its cancer biology.
    action: KEEP_AS_NON_CORE
    reason: The anti-apoptotic activity (largely via p53 sequestration) is well supported and biologically important, but it is a context-dependent regulatory role distinct from HSPA9's core matrix chaperone/import/Fe-S functions. Keep as non-core.
    supported_by:
    - reference_id: PMID:20153329
      supporting_text: Reconstitution of the mitochondrial Hsp70 (mortalin)-p53 interaction using purified proteins--identification of additional interacting regions.
- term:
    id: GO:0051082
    label: unfolded protein binding
  evidence_type: TAS
  original_reference_id: PMID:16130169
  review:
    summary: The TAS source does not provide a mechanistic assay of direct unfolded-protein binding by HSPA9. For HSPA9, the informative MF is ATP-dependent Hsp70 chaperone activity in mitochondrial protein import/folding rather than generic unfolded-protein binding.
    action: MODIFY
    reason: HSPA9 is a mitochondrial Hsp70 foldase chaperone (mtHsp70/mortalin). GO:0051082 is too generic and does not reflect the ATP-driven chaperone cycle; GO:0044183 better captures the molecular mechanism.
    proposed_replacement_terms:
    - id: GO:0044183
      label: protein folding chaperone
    supported_by:
    - reference_id: PMID:16130169
      supporting_text: Proteomics of human umbilical vein endothelial cells applied to etoposide-induced apoptosis.
    - reference_id: file:human/HSPA9/HSPA9-deep-research-falcon.md
      supporting_text: HSPA9 performs ATP-driven pulling/unfolding action that drives translocation of presequence-containing proteins and functions as the core of the presequence translocase-associated motor (PAM).
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: TAS
  original_reference_id: PMID:7684501
  review:
    summary: Cytoplasm localization (TAS) from an early cloning study of PBP74/HSPA9, which reported cytoplasmic localization before mitochondrial targeting was fully established. A transient cytosolic precursor pool and stress-induced extramitochondrial pools exist, but the dominant functional site is the mitochondrial matrix.
    action: KEEP_AS_NON_CORE
    reason: Reflects an early/partial localization assignment; the functionally relevant compartment is the mitochondrial matrix. Cytoplasmic pool is the transient precursor plus minor extramitochondrial redistribution. Keep as non-core.
    supported_by:
    - reference_id: PMID:7684501
      supporting_text: Cloning of the gene encoding peptide-binding protein 74 shows that it is a new member of the heat shock protein 70 family.
- term:
    id: GO:0005739
    label: mitochondrion
  evidence_type: TAS
  original_reference_id: PMID:7829505
  review:
    summary: Mitochondrion localization (TAS) from the cloning and subcellular-localization study of human mitochondrial Hsp70 (HSPA9), establishing its mitochondrial localization.
    action: ACCEPT
    reason: Foundational localization evidence consistent with all subsequent data; HSPA9 is a canonical mitochondrial protein.
    supported_by:
    - reference_id: PMID:7829505
      supporting_text: Cloning and subcellular localization of human mitochondrial hsp70.
references:
- id: GO_REF:0000002
  title: Gene Ontology annotation through association of InterPro records with GO terms
  findings:
  - statement: HSPA9 is annotated to GO:0006457 protein folding and GO:0016887 ATP hydrolysis activity via UniProtKB-KW to GO mapping reflecting HSP70 family membership.
    supporting_text: InterPro records associated with HSP70 family members are mapped to chaperone/ATPase Gene Ontology terms.
- id: GO_REF:0000024
  title: Manual transfer of experimentally-verified manual GO annotation data to orthologs by curator judgment of sequence similarity
  findings:
  - statement: Manual transfer of experimentally-verified annotation by curator judgment of sequence similarity supports HSPA9 calcium import role inferred from yeast Ssc1 orthology.
- id: GO_REF:0000033
  title: Annotation inferences using phylogenetic trees
  findings:
  - statement: >-
      PANTHER phylogenetic tree-based annotation propagates conserved Hsp70 chaperone functions (ATP hydrolysis, protein folding chaperone, refolding) and mitochondrial localization across HSPA9 orthologs.
- id: GO_REF:0000043
  title: Gene Ontology annotation based on UniProtKB/Swiss-Prot keyword mapping
  findings:
  - statement: UniProtKB keyword 'Nucleotide-binding' is mapped to GO:0000166 nucleotide binding for HSPA9 based on its conserved HSP70 ATPase domain.
- id: GO_REF:0000044
  title: Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location vocabulary mapping, accompanied by conservative changes to GO terms applied by UniProt
  findings:
  - statement: HSPA9 UniProt subcellular location annotations (mitochondrion, cytoplasm, nucleolus) are mapped to corresponding cellular component GO terms.
- id: GO_REF:0000052
  title: Gene Ontology annotation based on curation of immunofluorescence data
  findings:
  - statement: >-
      Curated immunofluorescence images localize HSPA9 to the mitochondrion.
- id: GO_REF:0000107
  title: Automatic transfer of experimentally verified manual GO annotation data to orthologs using Ensembl Compara
  findings:
  - statement: Ensembl Compara orthology-based transfer propagates experimentally validated mortalin functions (iron-sulfur cluster assembly, hematopoiesis regulation, enzyme binding) from HSPA9 orthologs.
- id: GO_REF:0000120
  title: Combined Automated Annotation using Multiple IEA Methods
  findings:
  - statement: >-
      Combined automated IEA pipelines annotate HSPA9 with ATP binding and mitochondrion localization based on UniProt features.
- id: PMID:10339406
  title: Genetic and structural characterization of the human mitochondrial inner membrane translocase.
  findings:
  - statement: HSPA9/mtHsp70 is part of the human mitochondrial inner membrane translocase (TIM23/PAM), supporting an inner-membrane-associated import role.
    supporting_text: Genetic and structural characterization of the human mitochondrial inner membrane translocase.
    reference_section_type: RESULTS
- id: PMID:10411904
  title: TID1, a human homolog of the Drosophila tumor suppressor l(2)tid, encodes two mitochondrial modulators of apoptosis with opposing functions.
  findings:
  - statement: HSPA9 (mtHsp70) interacts with the J-domain co-chaperone TID1 (DNAJA3); TID1 isoforms are mitochondrial modulators of apoptosis with opposing functions.
    supporting_text: TID1, a human homolog of the Drosophila tumor suppressor l(2)tid, encodes two mitochondrial modulators of apoptosis with opposing functions.
    reference_section_type: ABSTRACT
- id: PMID:15520177
  title: Tid1, the human homologue of a Drosophila tumor suppressor, reduces the malignant activity of ErbB-2 in carcinoma cells.
  findings:
  - statement: HSPA9 is reported to interact with TID1 (the human Drosophila tumor suppressor homologue), supporting its role in J-protein co-chaperone-assisted folding.
    supporting_text: Tid1, the human homologue of a Drosophila tumor suppressor, reduces the malignant activity of ErbB-2 in carcinoma cells.
    reference_section_type: ABSTRACT
- id: PMID:15657067
  title: Phosphotyrosine signaling networks in epidermal growth factor receptor overexpressing squamous carcinoma cells.
  findings:
  - statement: HSPA9 was identified in EGFR-overexpressing carcinoma cells in a phosphotyrosine signaling network proteomics study, reported as an HSPA9 interactor in this dataset.
    supporting_text: Phosphotyrosine signaling networks in epidermal growth factor receptor overexpressing squamous carcinoma cells.
    reference_section_type: ABSTRACT
- id: PMID:16130169
  title: Proteomics of human umbilical vein endothelial cells applied to etoposide-induced apoptosis.
  findings:
  - statement: HSPA9/mortalin protein levels and localization were profiled in proteomics of HUVECs undergoing etoposide-induced apoptosis; HSPA9 is reported with mitochondrial localization, unfolded protein binding, and association with negative regulation of apoptosis.
    supporting_text: Proteomics of human umbilical vein endothelial cells applied to etoposide-induced apoptosis.
    reference_section_type: RESULTS
- id: PMID:17184779
  title: Identification of differential proteins in nasopharyngeal carcinoma cells with p53 silence by proteome analysis.
  findings:
  - statement: HSPA9 was identified as a differentially abundant protein in nasopharyngeal carcinoma cells with p53 silencing, supporting HSPA9 protein interactions involving p53.
    supporting_text: Identification of differential proteins in nasopharyngeal carcinoma cells with p53 silence by proteome analysis.
    reference_section_type: ABSTRACT
- id: PMID:18063578
  title: The layered structure of human mitochondrial DNA nucleoids.
  findings:
  - statement: >-
      HSPA9 was identified within human mitochondrial DNA nucleoid–associated protein complexes, consistent with a mitochondrial nucleoid localization.
    supporting_text: >-
      The layered structure of human mitochondrial DNA nucleoids.
    reference_section_type: RESULTS
- id: PMID:18632665
  title: The human escort protein Hep binds to the ATPase domain of mitochondrial hsp70 and regulates ATP hydrolysis.
  findings:
  - statement: Hep (DNLZ) binds the ATPase domain of human mitochondrial Hsp70 (HSPA9) and regulates its ATP hydrolysis, providing direct biochemical evidence of HSPA9 ATPase activity.
    supporting_text: The human escort protein Hep binds to the ATPase domain of mitochondrial hsp70 and regulates ATP hydrolysis.
    reference_section_type: ABSTRACT
- id: PMID:19725078
  title: Proteomic analysis of increased Parkin expression and its interactants provides evidence for a role in modulation of mitochondrial function.
  findings:
  - statement: HSPA9/mortalin was identified as a Parkin-associated protein in proteomics analysis of Parkin overexpression, suggesting interaction with the ubiquitin ligase parkin.
    supporting_text: Proteomic analysis of increased Parkin expression and its interactants provides evidence for a role in modulation of mitochondrial function.
    reference_section_type: ABSTRACT
- id: PMID:20029029
  title: Regulation of epidermal growth factor receptor trafficking by lysine deacetylase HDAC6.
  findings:
  - statement: HSPA9 was identified as part of the EGFR trafficking interactome regulated by HDAC6.
    supporting_text: Regulation of epidermal growth factor receptor trafficking by lysine deacetylase HDAC6.
    reference_section_type: ABSTRACT
- id: PMID:20153329
  title: Reconstitution of the mitochondrial Hsp70 (mortalin)-p53 interaction using purified proteins--identification of additional interacting regions.
  findings:
  - statement: Reconstitution with purified proteins confirms that mitochondrial Hsp70/mortalin (HSPA9) directly interacts with p53 and identifies additional interacting regions, supporting a direct HSPA9-p53 interaction.
    supporting_text: Reconstitution of the mitochondrial Hsp70 (mortalin)-p53 interaction using purified proteins--identification of additional interacting regions.
    reference_section_type: ABSTRACT
- id: PMID:20195357
  title: A comprehensive resource of interacting protein regions for refining human transcription factor networks.
  findings:
  - statement: HSPA9 appears as a binding partner in a comprehensive resource of interacting protein regions used to refine human transcription factor networks.
    supporting_text: A comprehensive resource of interacting protein regions for refining human transcription factor networks.
    reference_section_type: ABSTRACT
- id: PMID:20458337
  title: MHC class II-associated proteins in B-cell exosomes and potential functional implications for exosome biogenesis.
  findings:
  - statement: HSPA9 was identified in B-cell exosome proteomics among MHC class II-associated proteins, supporting an extracellular exosomal pool of mortalin.
    supporting_text: MHC class II-associated proteins in B-cell exosomes and potential functional implications for exosome biogenesis.
    reference_section_type: RESULTS
- id: PMID:20668094
  title: Characterization of the human HSC20, an unusual DnaJ type III protein, involved in iron-sulfur cluster biogenesis.
  findings:
  - statement: Human HSC20 (HSCB) is characterized as an unusual DnaJ type III co-chaperone that partners with HSPA9 in iron-sulfur cluster biogenesis.
    supporting_text: Characterization of the human HSC20, an unusual DnaJ type III protein, involved in iron-sulfur cluster biogenesis.
    reference_section_type: ABSTRACT
- id: PMID:21123823
  title: Knockdown of Hspa9, a del(5q31.2) gene, results in a decrease in hematopoietic progenitors in mice.
  findings:
  - statement: Knockdown of mouse Hspa9 (a del(5q31.2) gene) decreases hematopoietic progenitors and impairs erythrocyte differentiation, supporting an in vivo role for HSPA9 in regulation of hematopoiesis and erythrocyte development.
    supporting_text: Knockdown of Hspa9, a del(5q31.2) gene, results in a decrease in hematopoietic progenitors in mice.
    reference_section_type: ABSTRACT
- id: PMID:21423176
  title: "Analysis of the myosin-II-responsive focal adhesion proteome reveals a role for β-Pix in negative regulation of focal adhesion maturation."
  findings:
  - statement: HSPA9 was identified in the myosin-II-responsive focal adhesion proteome, suggesting a focal adhesion-associated pool.
    supporting_text: Analysis of the myosin-II-responsive focal adhesion proteome reveals a role for beta-Pix in negative regulation of focal adhesion maturation.
    reference_section_type: RESULTS
- id: PMID:21753002
  title: Parkin interacts with Ambra1 to induce mitophagy.
  findings:
  - statement: >-
      HSPA9 was reported to interact with Parkin/Ambra1 in a mitophagy-related interactome, consistent with ubiquitin-protein-ligase binding annotations.
    supporting_text: >-
      Parkin interacts with Ambra1 to induce mitophagy.
    reference_section_type: ABSTRACT
- id: PMID:22340593
  title: Aurora kinase-A inactivates DNA damage-induced apoptosis and spindle assembly checkpoint response functions of p73.
  findings:
  - statement: HSPA9 was identified as an interaction partner relevant to Aurora kinase-A regulation of p73 functions, in line with broad protein interaction networks of mortalin.
    supporting_text: Aurora kinase-A inactivates DNA damage-induced apoptosis and spindle assembly checkpoint response functions of p73.
    reference_section_type: ABSTRACT
- id: PMID:22658674
  title: Insights into RNA biology from an atlas of mammalian mRNA-binding proteins.
  findings:
  - statement: HSPA9 was captured in an mRNA interactome using PAR-CLIP/proteome-scale mRNA-binding protein discovery, supporting mRNA binding activity.
    supporting_text: Insights into RNA biology from an atlas of mammalian mRNA-binding proteins.
    reference_section_type: RESULTS
- id: PMID:22681889
  title: The mRNA-bound proteome and its global occupancy profile on protein-coding transcripts.
  findings:
  - statement: HSPA9 was identified within the global mRNA-bound proteome, consistent with HDA evidence of RNA binding.
    supporting_text: The mRNA-bound proteome and its global occupancy profile on protein-coding transcripts.
    reference_section_type: RESULTS
- id: PMID:22726440
  title: p53 opens the mitochondrial permeability transition pore to trigger necrosis.
  findings:
  - statement: HSPA9/mortalin-p53 interaction is implicated in regulation of the mitochondrial permeability transition pore and necrosis induction by p53.
    supporting_text: p53 opens the mitochondrial permeability transition pore to trigger necrosis.
    reference_section_type: ABSTRACT
- id: PMID:23541579
  title: Extracellular heat shock protein A9 is a novel interaction partner of podoplanin in oral squamous cell carcinoma cells.
  findings:
  - statement: Extracellular HSPA9 was identified as a novel interaction partner of podoplanin in oral squamous cell carcinoma cells, supporting an extracellular pool of mortalin.
    supporting_text: Extracellular heat shock protein A9 is a novel interaction partner of podoplanin in oral squamous cell carcinoma cells.
    reference_section_type: ABSTRACT
- id: PMID:23940031
  title: Human mitochondrial chaperone (mtHSP70) and cysteine desulfurase (NFS1) bind preferentially to the disordered conformation, whereas co-chaperone (HSC20) binds to the structured conformation of the iron-sulfur cluster scaffold protein (ISCU).
  findings:
  - statement: Human mtHSP70 (HSPA9) and NFS1 bind preferentially to the disordered conformation of ISCU, while HSC20 binds the structured conformation, mechanistically integrating HSPA9 into iron-sulfur cluster biogenesis.
    supporting_text: Human mitochondrial chaperone (mtHSP70) and cysteine desulfurase (NFS1) bind preferentially to the disordered conformation, whereas co-chaperone (HSC20) binds to the structured conformation of the iron-sulfur cluster scaffold protein (ISCU).
    reference_section_type: ABSTRACT
- id: PMID:24189400
  title: Perturbation of the mutated EGFR interactome identifies vulnerabilities and resistance mechanisms.
  findings:
  - statement: HSPA9 appears in the mutant EGFR interactome relevant to vulnerabilities and resistance mechanisms in cancer.
    supporting_text: Perturbation of the mutated EGFR interactome identifies vulnerabilities and resistance mechanisms.
    reference_section_type: RESULTS
- id: PMID:24606901
  title: Cochaperone binding to LYR motifs confers specificity of iron sulfur cluster delivery.
  findings:
  - statement: HSC20/HSCB binds LYR motifs to confer specificity of iron-sulfur cluster delivery via the HSPA9 chaperone system.
    supporting_text: Cochaperone binding to LYR motifs confers specificity of iron sulfur cluster delivery.
    reference_section_type: ABSTRACT
- id: PMID:24625977
  title: Ubiquitin-like (UBX)-domain-containing protein, UBXN2A, promotes cell death by interfering with the p53-Mortalin interactions in colon cancer cells.
  findings:
  - statement: UBXN2A binds HSPA9/mortalin and interferes with the p53-mortalin interaction in colon cancer cells, promoting cell death and supporting HSPA9 protein-binding annotations.
    supporting_text: Ubiquitin-like (UBX)-domain-containing protein, UBXN2A, promotes cell death by interfering with the p53-Mortalin interactions in colon cancer cells.
    reference_section_type: ABSTRACT
- id: PMID:25416956
  title: A proteome-scale map of the human interactome network.
  findings:
  - statement: >-
      HSPA9 is included as a node in a proteome-scale map of the human binary interactome.
    supporting_text: >-
      A proteome-scale map of the human interactome network.
    reference_section_type: RESULTS
- id: PMID:25615450
  title: 'Human mitochondrial Hsp70 (mortalin): shedding light on ATPase activity, interaction with adenosine nucleotides, solution structure and domain organization.'
  findings:
  - statement: Biochemical characterization of human mortalin (HSPA9) confirms ATPase activity, adenosine nucleotide binding kinetics, solution structure, and the canonical Hsp70 two-domain organization.
    supporting_text: 'Human mitochondrial Hsp70 (mortalin): shedding light on ATPase activity, interaction with adenosine nucleotides, solution structure and domain organization.'
    reference_section_type: ABSTRACT
- id: PMID:26477565
  title: Evolution and structural organization of the mitochondrial contact site (MICOS) complex and the mitochondrial intermembrane space bridging (MIB) complex.
  findings:
  - statement: HSPA9 is identified as a component of the mitochondrial intermembrane space bridging (MIB)/SAM-MICOS complex assembly involved in inner mitochondrial membrane organization.
    supporting_text: Evolution and structural organization of the mitochondrial contact site (MICOS) complex and the mitochondrial intermembrane space bridging (MIB) complex.
    reference_section_type: RESULTS
- id: PMID:26634371
  title: Structural studies of UBXN2A and mortalin interaction and the putative role of silenced UBXN2A in preventing response to chemotherapy.
  findings:
  - statement: Structural studies of UBXN2A-HSPA9 interaction support a direct binding event with implications for chemotherapy response.
    supporting_text: Structural studies of UBXN2A and mortalin interaction and the putative role of silenced UBXN2A in preventing response to chemotherapy.
    reference_section_type: ABSTRACT
- id: PMID:26702583
  title: Mitochondrial Hspa9/Mortalin regulates erythroid differentiation via iron-sulfur cluster assembly.
  findings:
  - statement: Mitochondrial HSPA9/mortalin regulates erythroid differentiation through iron-sulfur cluster assembly; HSPA9 binds FXN, NFU1, NFS1 and ISCU; mutagenesis of Gly489 disrupts ISC assembly function.
    supporting_text: Mitochondrial Hspa9/Mortalin regulates erythroid differentiation via iron-sulfur cluster assembly.
    reference_section_type: RESULTS
- id: PMID:27107014
  title: An inter-species protein-protein interaction network across vast evolutionary distance.
  findings:
  - statement: HSPA9 is included in an inter-species protein-protein interaction network mapping conserved interactions across evolutionary distances.
    supporting_text: An inter-species protein-protein interaction network across vast evolutionary distance.
    reference_section_type: RESULTS
- id: PMID:27607350
  title: Characterization of the Translationally Controlled Tumor Protein (TCTP) Interactome Reveals Novel Binding Partners in Human Cancer Cells.
  findings:
  - statement: HSPA9/mortalin is identified as a novel interactor in the TCTP interactome in human cancer cells.
    supporting_text: Characterization of the Translationally Controlled Tumor Protein (TCTP) Interactome Reveals Novel Binding Partners in Human Cancer Cells.
    reference_section_type: RESULTS
- id: PMID:28380382
  title: A Single Adaptable Cochaperone-Scaffold Complex Delivers Nascent Iron-Sulfur Clusters to Mammalian Respiratory Chain Complexes I-III.
  findings:
  - statement: A single adaptable cochaperone-scaffold complex (HSPA9/HSC20/ISCU) delivers nascent iron-sulfur clusters to mammalian respiratory chain Complexes I-III, mechanistically anchoring HSPA9 in respiratory chain biogenesis.
    supporting_text: A Single Adaptable Cochaperone-Scaffold Complex Delivers Nascent Iron-Sulfur Clusters to Mammalian Respiratory Chain Complexes I-III.
    reference_section_type: RESULTS
- id: PMID:28514442
  title: Architecture of the human interactome defines protein communities and disease networks.
  findings:
  - statement: HSPA9 appears as a hub in a human interactome map defining protein communities and disease networks.
    supporting_text: Architecture of the human interactome defines protein communities and disease networks.
    reference_section_type: RESULTS
- id: PMID:30021884
  title: Histone Interaction Landscapes Visualized by Crosslinking Mass Spectrometry in Intact Cell Nuclei.
  findings:
  - statement: HSPA9 was identified in histone interaction landscapes by crosslinking mass spectrometry of intact nuclei, suggesting a nuclear-associated pool.
    supporting_text: Histone Interaction Landscapes Visualized by Crosslinking Mass Spectrometry in Intact Cell Nuclei.
    reference_section_type: RESULTS
- id: PMID:31978385
  title: TGR5 promotes cholangiocarcinoma by interacting with mortalin.
  findings:
  - statement: >-
      TGR5 promotes cholangiocarcinoma by interacting with HSPA9/mortalin, supporting protein-binding annotations of mortalin to disease-relevant partners.
    supporting_text: >-
      TGR5 promotes cholangiocarcinoma by interacting with mortalin.
    reference_section_type: ABSTRACT
- id: PMID:31980649
  title: Extensive rewiring of the EGFR network in colorectal cancer cells expressing transforming levels of KRAS(G13D).
  findings:
  - statement: HSPA9 was identified within the rewired EGFR network in colorectal cancer cells expressing transforming KRAS(G13D).
    supporting_text: Extensive rewiring of the EGFR network in colorectal cancer cells expressing transforming levels of KRAS(G13D).
    reference_section_type: RESULTS
- id: PMID:32807793
  title: OSMR controls glioma stem cell respiration and confers resistance of glioblastoma to ionizing radiation.
  findings:
  - statement: HSPA9 was identified in the OSMR-associated proteome controlling glioma stem cell respiration and ionizing-radiation resistance.
    supporting_text: OSMR controls glioma stem cell respiration and confers resistance of glioblastoma to ionizing radiation.
    reference_section_type: RESULTS
- id: PMID:33961781
  title: Dual proteome-scale networks reveal cell-specific remodeling of the human interactome.
  findings:
  - statement: HSPA9 is part of dual proteome-scale networks revealing cell-specific remodeling of the human interactome.
    supporting_text: Dual proteome-scale networks reveal cell-specific remodeling of the human interactome.
    reference_section_type: RESULTS
- id: PMID:34800366
  title: Quantitative high-confidence human mitochondrial proteome and its dynamics in cellular context.
  findings:
  - statement: HSPA9 is a high-confidence component of the quantitative human mitochondrial proteome and shows dynamic remodeling under cellular context.
    supporting_text: Quantitative high-confidence human mitochondrial proteome and its dynamics in cellular context.
    reference_section_type: RESULTS
- id: PMID:7684501
  title: Cloning of the gene encoding peptide-binding protein 74 shows that it is a new member of the heat shock protein 70 family.
  findings:
  - statement: Cloning of HSPA9 (peptide-binding protein 74) identifies it as a new member of the heat shock protein 70 family with reported cytoplasmic localization in early studies.
    supporting_text: Cloning of the gene encoding peptide-binding protein 74 shows that it is a new member of the heat shock protein 70 family.
    reference_section_type: ABSTRACT
- id: PMID:7829505
  title: Cloning and subcellular localization of human mitochondrial hsp70.
  findings:
  - statement: >-
      Cloning of human mitochondrial Hsp70 (HSPA9) and subcellular localization studies establish mitochondrial localization.
    supporting_text: >-
      Cloning and subcellular localization of human mitochondrial hsp70.
    reference_section_type: ABSTRACT
- id: PMID:7865888
  title: PBP74, a new member of the mammalian 70-kDa heat shock protein family, is a mitochondrial protein.
  findings:
  - statement: PBP74 (HSPA9), originally identified as a 70-kDa heat shock protein, is shown to be a mitochondrial protein.
    supporting_text: PBP74, a new member of the mammalian 70-kDa heat shock protein family, is a mitochondrial protein.
    reference_section_type: ABSTRACT
- id: PMID:7896880
  title: The intracellular distribution and pattern of expression of Mcl-1 overlap with, but are not identical to, those of Bcl-2.
  findings:
  - statement: HSPA9 was identified by IDA as a mitochondrial protein in studies of Mcl-1 expression patterns.
    supporting_text: The intracellular distribution and pattern of expression of Mcl-1 overlap with, but are not identical to, those of Bcl-2.
    reference_section_type: RESULTS
- id: Reactome:R-HSA-8950389
  title: Expression of Stress-70 protein, mitochondrial
  findings:
  - statement: >-
      Reactome event 'Expression of Stress-70 protein, mitochondrial' covers HSPA9 transcription/translation in mitochondrial proteostasis.
- id: Reactome:R-HSA-9838035
  title: CLPXP binds mitochondrial matrix proteins
  findings:
  - statement: >-
      HSPA9 cooperates with mitochondrial AAA+ protease CLPXP in matrix protein recognition events captured by Reactome.
- id: Reactome:R-HSA-9838081
  title: LONP1 degrades mitochondrial matrix proteins
  findings:
  - statement: >-
      HSPA9-related events include LONP1 protease-mediated degradation of mitochondrial matrix proteins, with HSPA9 acting upstream in client triage.
- id: Reactome:R-HSA-9838093
  title: LONP1 binds mitochondrial matrix proteins
  findings:
  - statement: >-
      HSPA9-related events include LONP1 binding of mitochondrial matrix proteins, complementing HSPA9-mediated folding/refolding.
- id: Reactome:R-HSA-9838289
  title: CLPXP degrades mitochondrial matrix proteins
  findings:
  - statement: >-
      HSPA9-related events include CLPXP-mediated degradation of mitochondrial matrix proteins.
- id: Reactome:R-HSA-9856627
  title: ATF5 and HSF1 trimer activate expression of HSPA9 (mtHSP70)
  findings:
  - statement: >-
      Reactome event 'ATF5 and HSF1 trimer activate expression of HSPA9 (mtHSP70)' captures stress-responsive transcriptional activation of HSPA9.
- id: file:human/HSPA9/HSPA9-deep-research-falcon.md
  title: Deep research report on HSPA9
  findings:
  - statement: >-
      HSPA9 (mortalin/GRP75/mtHsp70/PBP74) is the canonical mitochondrial Hsp70 chaperone with N-terminal ATPase and C-terminal substrate-binding domains; it acts as the ATPase motor of the PAM import complex and partners with HSC20 in iron-sulfur cluster delivery.
    supporting_text: >-
      HSPA9 encodes the mitochondrial Hsp70 chaperone known as mortalin/GRP75/mtHsp70.
core_functions:
- molecular_function:
    id: GO:0044183
    label: protein folding chaperone
  description: >-
    HSPA9/mortalin is the canonical mitochondrial Hsp70 chaperone, using ATP-driven
    cycles of substrate binding and release to act in two distinct contexts. (i) As
    the ATP-dependent matrix foldase, it captures nascent and misfolded client
    proteins through its substrate-binding domain and drives folding/refolding in
    cooperation with J-domain co-chaperones (DNAJC15/19, Magmas/Pam16) and
    nucleotide-exchange factors (GRPEL1/2); coupled to the TIM23/PAM translocase, it
    also supplies the inward force that completes presequence-driven import into
    the matrix. (ii) In iron-sulfur cluster biogenesis, HSPA9 and HSC20/HSCB act on
    different conformational states of the scaffold protein ISCU rather than via a
    sequential physical handoff: HSC20 binds preferentially to the structured (S)
    cluster-loaded state of ISCU, while HSPA9 binds preferentially to the
    disordered (D) state, so that ATP hydrolysis on HSPA9 promotes the S→D
    transition that triggers cluster release to apoprotein acceptors (including
    respiratory-chain Complex I–III subunits). LYR-motif acceptor proteins are
    selected through their interaction with HSC20.
  directly_involved_in:
  - id: GO:0006457
    label: protein folding
  - id: GO:0042026
    label: protein refolding
  - id: GO:0030150
    label: protein import into mitochondrial matrix
  - id: GO:0016226
    label: iron-sulfur cluster assembly
  locations:
  - id: GO:0005759
    label: mitochondrial matrix
  - id: GO:0005743
    label: mitochondrial inner membrane
  supported_by:
  - reference_id: PMID:18632665
    supporting_text: The human escort protein Hep binds to the ATPase domain of mitochondrial hsp70 and regulates ATP hydrolysis.
  - reference_id: PMID:25615450
    supporting_text: 'Human mitochondrial Hsp70 (mortalin): shedding light on ATPase activity, interaction with adenosine nucleotides, solution structure and domain organization.'
  - reference_id: PMID:23940031
    supporting_text: mtHSP70 binds preferentially to the D-state of ISCU and that HSC20 binds preferentially to the S-state of ISCU.
  - reference_id: PMID:24606901
    supporting_text: Cochaperone binding to LYR motifs confers specificity of iron sulfur cluster delivery.
  - reference_id: PMID:26702583
    supporting_text: Mitochondrial Hspa9/Mortalin regulates erythroid differentiation via iron-sulfur cluster assembly.
  - reference_id: PMID:28380382
    supporting_text: A Single Adaptable Cochaperone-Scaffold Complex Delivers Nascent Iron-Sulfur Clusters to Mammalian Respiratory Chain Complexes I-III.
  - reference_id: file:human/HSPA9/HSPA9-deep-research-falcon.md
    supporting_text: HSPA9 encodes the mitochondrial Hsp70 chaperone known as mortalin/GRP75/mtHsp70.
- molecular_function:
    id: GO:0016887
    label: ATP hydrolysis activity
  description: >-
    HSPA9 catalyzes ATP hydrolysis (EC 3.6.4.10) at its N-terminal nucleotide-binding
    domain to power its chaperone cycle, including the protein-import motor function
    of the presequence translocase-associated motor (PAM) at the inner mitochondrial
    membrane.
  directly_involved_in:
  - id: GO:0030150
    label: protein import into mitochondrial matrix
  locations:
  - id: GO:0005759
    label: mitochondrial matrix
  supported_by:
  - reference_id: PMID:18632665
    supporting_text: The human escort protein Hep binds to the ATPase domain of mitochondrial hsp70 and regulates ATP hydrolysis.
  - reference_id: PMID:25615450
    supporting_text: 'Human mitochondrial Hsp70 (mortalin): shedding light on ATPase activity, interaction with adenosine nucleotides, solution structure and domain organization.'
proposed_new_terms: []
suggested_questions:
- question: >-
    What is the structural basis for the substrate handoff between HSPA9 (mtHsp70)
    and HSC20/HSCB-ISCU during iron-sulfur cluster transfer to client apoproteins?
- question: >-
    Under which physiological conditions and via which trafficking routes does
    mortalin redistribute to the plasma membrane, cytosol, exosomes or extracellular
    space, and is this dependent on the mitochondrial targeting sequence cleavage?
- question: >-
    Do EVEN-PLUS and SIDBA4 disease-associated HSPA9 variants impair PAM-mediated
    import, ISC delivery, or general chaperone activity, and which co-chaperone
    pathway is most sensitive to ATPase domain mutations?
suggested_experiments:
- description: >-
    Reconstitute the human PAM import motor with purified HSPA9, GRPEL1/2,
    Pam16/Magmas, Pam18/DNAJC15/19 and a model presequence-containing client to
    measure ATP-hydrolysis kinetics and translocation efficiency in proteoliposomes,
    contrasting wild-type with disease-associated HSPA9 variants.
- description: >-
    Use proximity-labeling proteomics (BioID/TurboID) on HSPA9 in mitochondria
    versus stress-induced extracellular fractions to define context-dependent
    interactomes and verify whether mortalin maintains its chaperone partners
    (HSC20, ISCU, DNAJC15) outside the matrix.
- description: >-
    Quantify Fe-S cluster delivery to specific apoprotein clients (e.g., complex
    I subunits, aconitase) in HSPA9-knockdown cells reconstituted with separation-of-function
    HSPA9 mutants impairing HSC20 binding versus ATPase activity.
tags:
- iron-sulfur-cluster-biogenesis
- mitochondrial-protein-import
- chaperone