Affinage

HSPA9

Stress-70 protein, mitochondrial · UniProt P38646

Length
679 aa
Mass
73.7 kDa
Annotated
2026-06-10
100 papers in source corpus 47 papers cited in narrative 47 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 8/8 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

HSPA9 (mortalin/GRP75) is a HSP70-family chaperone that is imported into the mitochondrial matrix via a cleavable N-terminal presequence in a membrane-potential- and ATP-dependent manner, with its ATPase cycle stimulated by the co-chaperone DNLZ acting through a conserved histidine (PMID:7865888, PMID:21530495). Within mitochondria it supports iron-sulfur cluster biogenesis by physically binding and stabilizing frataxin, Nfs1, ISCU, and Nfu, such that its loss reduces aconitase activity and perturbs erythroid heme synthesis through the IRP/IRE axis (PMID:26702583, PMID:30590615). As a canonical HSP70, it engages client proteins through its substrate-binding cavity to control their stability, signaling, and localization: it facilitates PP1α-mediated dephosphorylation of MEK1/2 to negatively regulate Raf/MEK/ERK signaling (PMID:23959801, PMID:28674184), and it acts on adenine nucleotide translocases—inhibiting ANT3-CypD interaction to suppress mitochondrial permeability transition and promote survival of BRAF- and KRAS-mutant tumor cells (PMID:32156782, PMID:32291414). A central, well-characterized role is as the tether of the IP3R-GRP75-VDAC1 complex at mitochondria-associated ER membranes (MAMs), where it bridges ER and mitochondria to govern Ca2+ transfer and downstream bioenergetics, oxidative stress, and apoptosis (PMID:12009301, PMID:30590033, PMID:35344886). Independently of its mitochondrial function, a cytoplasmic pool of mortalin binds the C-terminal cytoplasmic-sequestration domain of p53 (residues 312–352) through mortalin residues 253–282, retaining p53 in the cytoplasm to repress its transcriptional and apoptotic activity; the small molecule MKT-077 competes for this site to release and reactivate p53 (PMID:9792667, PMID:11156371, PMID:11420746, PMID:11900485, PMID:28178280). Mortalin further serves as a scaffold for deubiquitination complexes (USP1-SIX1, USP14-SLC7A11) and stabilizes diverse clients against ubiquitin-proteasome degradation (PMID:34079090, PMID:40372919). Under ferroptotic stress, PKA anchored by AKAP1 phosphorylates GRP75 at S148, driving its translocation to MAMs/cytosol where it competes with Nrf2 for Keap1 binding to activate antioxidant transcription (PMID:39537840). Biallelic HSPA9 mutations cause EVEN-PLUS syndrome and autosomal-recessive congenital sideroblastic anemia, consistent with its essential roles in mitochondrial protein folding and Fe-S cluster biogenesis (PMID:26598328, PMID:26491070).

Mechanistic history

Synthesis pass · year-by-year structured walk · 12 steps
  1. 1994 High

    Established where HSPA9 acts and how it gets there, defining it as a mitochondrial matrix protein dependent on an N-terminal targeting sequence.

    Evidence Epitope-tagging, cell fractionation, and in vitro import into isolated mitochondria with presequence deletion

    PMID:7865888

    Open questions at the time
    • Did not address extra-mitochondrial pools later observed
    • Chaperone substrates within the matrix not yet defined
  2. 1998 High

    Revealed a non-canonical cytoplasmic function: HSPA9 sequesters p53 to block its nuclear activity, linking the chaperone to tumor suppression control.

    Evidence Immunofluorescence colocalization, p53 reporter assays, and target-gene Western blotting comparing mot-1 vs mot-2

    PMID:9792667

    Open questions at the time
    • Binding interface not mapped at this stage
    • Mechanism by which a matrix chaperone reaches cytoplasmic p53 unresolved
  3. 2001 Medium

    Mapped the p53-binding region on mortalin and showed it overlaps the MKT-077 site, providing a structural rationale for pharmacological p53 reactivation.

    Evidence In vitro binding with His-tagged deletion mutants and peptide competition; MKT-077 binding/rescue assays

    PMID:11156371 PMID:11420746

    Open questions at the time
    • In vitro mapping only
    • Single lab
  4. 2002 High

    Defined both sides of the mortalin-p53 interaction and identified VDAC1 as a direct partner, foreshadowing the MAM tethering role.

    Evidence Co-IP with p53 deletion mutants; yeast two-hybrid, recombinant overlay, and planar lipid bilayer electrophysiology for VDAC1

    PMID:11900485 PMID:12009301

    Open questions at the time
    • Functional consequence of VDAC1 modulation in cells not yet established
    • Link to ER-mitochondria contact sites not yet drawn
  5. 2005 High

    Connected HSPA9 loss to a vertebrate disease phenotype, implicating mitochondrial dysfunction and oxidative stress in ineffective hematopoiesis.

    Evidence Positional cloning, rescue, and morpholino knockdown in the zebrafish crimsonless mutant

    PMID:15650063

    Open questions at the time
    • Molecular substrate driving the hematopoietic defect not identified at the time
    • Domain-specific mechanism unresolved
  6. 2015 High

    Defined a core matrix function in Fe-S cluster biogenesis and tied HSPA9 mutations directly to human Mendelian disease.

    Evidence Co-IP and stabilization of frataxin/Nfs1/ISCU/Nfu plus aconitase and IRP1 assays; exome/genome sequencing of EVEN-PLUS and sideroblastic anemia families

    PMID:26491070 PMID:26598328 PMID:26702583

    Open questions at the time
    • Genetic disease studies lacked in vitro functional reconstitution
    • Hierarchy of client stabilization within the ISC machinery not resolved
  7. 2017 High

    Provided a chaperone-mechanistic basis for MEK/ERK regulation, mapping the substrate-binding region required for facilitating PP1α-MEK1/2 dephosphorylation.

    Evidence Co-IP, in vitro binding, domain-mutant analysis, and PP1α inhibitor experiments

    PMID:23959801 PMID:28674184

    Open questions at the time
    • Whether PP1α recruitment occurs at a specific subcellular site not defined
    • Single lab for the interactome mapping
  8. 2020 High

    Identified ANT3 as a client and showed mortalin gates mitochondrial permeability transition, explaining a survival dependency in oncogene-mutant tumors.

    Evidence Proteomic substrate screening, ANT3/CypD/MCU knockdown and inhibitor epistasis, permeability assays, and xenografts

    PMID:32156782 PMID:32291414

    Open questions at the time
    • Direct structural mode of ANT3 engagement not resolved
    • Generality across non-BRAF/KRAS contexts unclear
  9. 2021 High

    Consolidated the IP3R-GRP75-VDAC1 tether as the operative MAM Ca2+ transfer machine and showed disease-relevant regulators perturb it.

    Evidence Co-IP, proximity ligation, Ca2+ imaging, and TEM in TG2-, alpha-synuclein-, and palmitate-context models

    PMID:30590033 PMID:34510532 PMID:34756890

    Open questions at the time
    • Stoichiometry and dynamics of the tripartite complex not resolved
    • How GRP75 distinguishes IP3R isoforms unclear
  10. 2021 Medium

    Demonstrated a scaffolding role in deubiquitination, mapping the C-terminal peptide-binding domain as required for recruiting USP1 to stabilize clients.

    Evidence Co-IP, ubiquitination assays, GRP75 domain deletions, and xenografts for the GRP75-USP1-SIX1 axis

    PMID:34079090

    Open questions at the time
    • Single lab
    • Whether scaffolding occurs at mitochondria or cytosol not defined
  11. 2024 Medium

    Established stress-induced relocalization and post-translational control as switches that redirect HSPA9 from mitochondrial chaperone to nuclear/cytosolic signaling roles.

    Evidence MUL1-mediated K612 SUMOylation with mutagenesis driving nuclear SUZ12/EZH2 degradation; OMA1 competitive binding driving cGAS-STING/PD-L1

    PMID:38604814 PMID:39113711

    Open questions at the time
    • Single-lab observations
    • Quantitative fraction of relocalized protein not established
  12. 2024 High

    Defined a phosphorylation-gated antiferroptotic axis: PKA-mediated S148 phosphorylation redirects GRP75 to compete with Nrf2 for Keap1, activating antioxidant transcription.

    Evidence PKA phosphorylation and S148A mutagenesis, Keap1 co-IP, Nrf2 reporter, and in vivo ferroptosis xenografts

    PMID:39537840 PMID:40372919

    Open questions at the time
    • Structural basis of the ETGE-motif competition not resolved
    • Interplay with mitochondrial functions during ferroptosis unclear

Open questions

Synthesis pass · forward-looking unresolved questions
  • How a single matrix-imported chaperone is partitioned among its mitochondrial, MAM, cytoplasmic, and nuclear pools to execute distinct functions remains unresolved.
  • No unified model linking import, retention, and stress-induced export
  • Quantitative regulation of pool distribution unknown
  • Structural understanding of client selectivity lacking

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060090 molecular adaptor activity 4 GO:0044183 protein folding chaperone 3 GO:0098772 molecular function regulator activity 3 GO:0140657 ATP-dependent activity 2
Localization
GO:0005739 mitochondrion 3 GO:0005829 cytosol 3 GO:0005634 nucleus 2 GO:0005783 endoplasmic reticulum 2
Pathway
R-HSA-5357801 Programmed Cell Death 4 R-HSA-162582 Signal Transduction 3 R-HSA-1643685 Disease 3 R-HSA-392499 Metabolism of proteins 3 R-HSA-1430728 Metabolism 2
Partners
ANT3FXNITPR1KEAP1MEK1/2TP53USP14VDAC1
Complex memberships
IP3R-GRP75-VDAC1 (MAM Ca2+ transfer complex)

Evidence

Reading pass · 47 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1994 PBP74/HSPA9 is a mitochondrial protein that is imported into the mitochondrial matrix in a membrane potential- and ATP-dependent manner; the N-terminal 46-amino acid presequence is required for mitochondrial targeting, and deletion of this presequence results in cytosolic localization. Confocal immunofluorescence, epitope-tagging, cell fractionation, in vitro import into isolated yeast mitochondria, mitochondrial subfractionation Molecular biology of the cell High 7865888
1998 Mot-2 (HSPA9) binds to and inactivates the tumor suppressor p53 by sequestering it in the cytoplasm, preventing its nuclear translocation; mot-2 but not mot-1 represses p53-mediated transactivation and down-regulates p53-responsive genes p21(WAF-1) and mdm-2. Co-localization by immunofluorescence, p53-responsive reporter assays, Western blot of p53 target genes, GFP-tagged mot-2 nuclear translocation assay The Journal of biological chemistry High 9792667
2000 MKT-077 binds to mortalin/mot-2 (HSPA9) and abrogates its interaction with p53, releasing cytoplasmically sequestered wild-type p53 and restoring its transcriptional activation function in cancer cells. Binding assay, co-immunoprecipitation, p53 transcriptional reporter assay, immunofluorescence Cancer research High 11156371
2000 Mortalin/HSPA9 is present not only in mitochondria but also in the endoplasmic reticulum fraction; in certain immortal cell lines it additionally localizes to an extra-organelle cytosolic pool. Subcellular fractionation, immunofluorescence microscopy Biochemical and biophysical research communications Medium 10944461
2001 The p53-binding domain of mot-2/HSPA9 was mapped in vitro to its N-terminal amino acid residues 253–282; this region overlaps with the MKT-077-binding region, suggesting MKT-077 restores p53 function by competing with p53 for the same binding site on mot-2. In vitro binding assay with His-tagged deletion mutants, peptide competition assay Neoplasia Medium 11420746
2001 Mortalin/GRP75 (HSPA9) physically interacts with GRP94 (an Hsp90-family ER protein); interacting domains were mapped by mutational analysis using far-Western screening, yeast two-hybrid, and co-immunoprecipitation. Far-Western screening, in vivo reporter assay, co-immunoprecipitation, mutational analysis The Biochemical journal Medium 11439088
2002 The mot-2/HSPA9 binding site on p53 was mapped by in vivo co-immunoprecipitation to the C-terminal residues 312–352, which includes p53's cytoplasmic sequestration domain, demonstrating the mechanism by which mot-2 retains p53 in the cytoplasm. In vivo co-immunoprecipitation of mot-2 with p53 deletion mutants Experimental cell research Medium 11900485
2002 VDAC1 physically interacts with PBP74/GRP75/HSPA9 in vivo (yeast two-hybrid) and in vitro (overlay assay with recombinant proteins); GRP75 co-localizes with VDAC1 in HeLa cells and modulates VDAC1 electrophysiological properties, drastically reducing its voltage-dependence in planar lipid bilayer experiments. Sos recruitment system yeast two-hybrid, overlay assay with recombinant proteins, immunofluorescence co-localization, planar lipid bilayer electrophysiology The international journal of biochemistry & cell biology High 12009301
1999 GRP75/mortalin (HSPA9) is a direct intracellular binding partner of fibroblast growth factor-1 (FGF-1); the interaction was identified by affinity purification, confirmed by co-immunoprecipitation, immunohistochemical co-localization, yeast two-hybrid, and direct in vitro binding with recombinant proteins. Affinity adsorption/purification, co-immunoprecipitation, immunohistochemical co-localization, yeast two-hybrid, in vitro binding assay with recombinant proteins The Biochemical journal High 10510314
2005 Loss-of-function mutation of HSPA9B within the substrate-binding domain in zebrafish (crimsonless mutant) causes MDS-like ineffective hematopoiesis including anemia, dysplasia, increased apoptosis, and multilineage cytopenia, by compromising mitochondrial function and inducing oxidative stress specifically in blood cells. Positional cloning, rescue experiment, morpholino knockdown in zebrafish Blood High 15650063
2005 Mortalin/GRP75 binds complement C8 and C9, promotes shedding of membrane vesicles loaded with complement MAC, and protects cells from complement-mediated lysis; anti-mortalin antibodies reduced vesicle release and elevated complement-mediated cell death. Mass spectrometry identification, Western blot, vesiculation assay, antibody blocking International immunology Medium 16091382
2010 GRP75/HSPA9 is a functional constituent of noncaveolar, membrane raft-associated endocytic vesicles; RNAi-mediated knockdown of GRP75 and GRP75-blocking antibodies inhibit HSPG-mediated macromolecular endocytosis, and this pathway requires the RhoA GTPase family member CDC42. Antibody-conjugated magnetic nanoparticle vesicle isolation, RNAi knockdown, antibody blocking, co-localization, CDC42 involvement assessed Proceedings of the National Academy of Sciences of the United States of America Medium 20624969
2011 GRP75/HSPA9 overexpression suppresses apoptosis during glucose deprivation by inhibiting Bax conformational change through activation of AKT via a PI3K-independent, Raf/MEK/ERK-dependent pathway. Pharmacological inhibitors (LY294002, U0126), Western blot of pAKT and Bax conformational change, PC12 cell glucose deprivation model Journal of molecular biology Medium 21964438
2011 HSPA9 knockdown in primary human CD34+ hematopoietic progenitor cells leads to increased TP53 expression and nuclear TP53 accumulation; HSPA9 protein interacts with TP53 in CD34+ cells, and concurrent knockdown of TP53 rescues the increased apoptosis caused by HSPA9 knockdown. Lentiviral shRNA knockdown, co-immunoprecipitation, nuclear/cytoplasmic fractionation, genetic epistasis (double knockdown rescue) PloS one High 28178280
2013 Mortalin/HSPA9 is present in the MEK1/MEK2 proteome and acts as a negative regulator of Raf/MEK/ERK signaling; mortalin depletion increases MEK/ERK activity and MEK/ERK-dependent p21(CIP1) transcription, while mortalin overexpression suppresses B-Raf(V600E)-induced MEK/ERK activation and cell cycle arrest. Proteomics (MEK1/2 interactome), shRNA depletion, Western blot, reporter assays in multiple cancer cell lines Molecular and cellular biology Medium 23959801
2014 Mortalin/GRP75 binds complement C9 (and C8) through its N-terminal ATPase domain (not the substrate-binding domain), via an ionic, nucleotide-sensitive interaction; the ATPase domain inhibits zinc-induced C9 polymerization; overexpression of mortalin confers resistance to CDC while knockdown increases sensitivity; cytosolic mortalin (lacking mitochondrial targeting) has reduced protective capacity. Co-immunoprecipitation, recombinant domain expression (ATPase vs. substrate-binding domain), C9 polymerization inhibition assay, mortalinΔ51-EGFP localization and CDC assay The Journal of biological chemistry High 24719326
2015 HSPA9 functions in mitochondrial iron-sulfur cluster (ISC) biogenesis; HSPA9 physically interacts with and stabilizes the ISC biogenesis proteins frataxin, Nfs1, ISCU, and Nfu; HSPA9 depletion decreases aconitase activity (ISC-requiring) but not malate dehydrogenase activity, increases IRP1 binding, and inhibits erythroid differentiation by post-transcriptionally reducing Alas2 and FeCH expression through the IRP/IRE pathway. Co-immunoprecipitation, aconitase activity assay, IRP1 binding assay, RNAi knockdown, erythroid differentiation assay, rescue with Alas2 ORF Mitochondrion High 26702583
2015 Biallelic mutations in HSPA9 cause EVEN-PLUS syndrome, a human disease featuring epiphyseal, vertebral, ear, nose, and other malformations, establishing HSPA9 as essential for mitochondrial protein import/folding and human embryonic morphogenesis. Whole-exome/genome sequencing in affected families, genetic analysis Scientific reports Medium 26598328
2015 Mutations in HSPA9 (a mitochondrial HSP70 involved in mitochondrial Fe-S cluster biogenesis) cause congenital sideroblastic anemia inherited as an autosomal recessive trait; haploinsufficiency can be expressed clinically when a common hypomorphic SNP is present in trans. Genetic sequencing of affected families, functional genetic analysis Blood Medium 26491070
2017 Mortalin/HSPA9 facilitates PP1α-mediated dephosphorylation of MEK1/2 by promoting the PP1α-MEK1/2 physical interaction in an ATP-sensitive manner; the region Val482–Glu491 in mortalin's substrate-binding cavity and substrate lid is required for these interactions, consistent with canonical HSP70-client interaction mechanisms. Co-immunoprecipitation, in vitro binding assay, PP1α inhibitor experiments, mortalin domain mutant analysis, Western blot of phospho-MEK1/2 Molecular and cellular biology High 28674184
2018 TG2 (transglutaminase type 2) interacts with GRP75/HSPA9 at mitochondria-associated membranes (MAMs); absence of the TG2-GRP75 interaction increases IP3R-3–GRP75 interaction, decreases ER-mitochondria contact sites, impairs ER-to-mitochondria Ca2+ flux, and alters the MAM proteome. Co-immunoprecipitation (TG2 interactome), proximity ligation assay, TEM quantification of ER-mitochondria contacts, Ca2+ flux measurement, MAM proteomics Cell reports High 30590033
2019 GRP75/HSPA9 directly interacts with frataxin both in vivo in mouse cortex and in vitro in cortical neurons; GRP75 overexpression increases frataxin levels and stabilizes clinically relevant missense frataxin variants; clinical GRP75 variants (R126W, A476T, P509S) impair GRP75-frataxin binding; GRP75 physically interacts with mitochondrial processing peptidase (MPP), potentially facilitating frataxin processing. Co-immunoprecipitation in vivo and in vitro, GRP75 overexpression/variant rescue experiments in FRDA patient-derived cells, mitochondrial network and ATP level assays Human molecular genetics High 30590615
2020 Mortalin/HSPA9 identifies adenine nucleotide translocase 3 (ANT3) as a substrate; mortalin inhibits ANT3-CypD interaction to reduce mitochondrial membrane permeability; in BRAF(V600E) cells, mortalin depletion increases mitochondrial permeability (via ANT3-CypD interaction) to a lethal extent, while MEK-ERK activity opposes mortalin by promoting ANT3-CypD interaction. Proteomics screening, co-immunoprecipitation, ANT3/CypD/MCU knockdown and inhibitor rescue, mitochondrial membrane permeability assay, xenograft in vivo model Science signaling High 32156782
2020 Mortalin/HSPA9 depletion selectively kills KRAS-mutant cells through a mitochondria-originated death mechanism involving ANT, CypD, and MCU; this cell death occurs independently of TP53 and p21CIP1 and is phenocopied by HSP70 inhibitor JG-98. Genetic knockdown, ANT/CypD/MCU inhibitor/knockdown rescue, xenograft in vivo model Oncogene Medium 32291414
2021 GRP75/HSPA9 forms the IP3R-GRP75-VDAC1 complex that mediates Ca2+ transfer from the ER to mitochondria; α-synuclein overexpression impairs the GRP75-IP3R interaction (but not VDAC1-GRP75 interaction) at MAMs, reducing ER-mitochondria contact sites and mitochondrial Ca2+ buffering. Co-immunoprecipitation, proximity ligation assay, mitochondrial Ca2+ imaging, ER-mitochondria contact site quantification Journal of neuroscience research Medium 34510532
2021 GRP75/HSPA9 serves as a scaffold to recruit deubiquitinating enzyme USP1 to inhibit K48-linked polyubiquitination of SIX1, thereby stabilizing SIX1 protein; the C-terminal peptide-binding domain of GRP75 (residues 433–679) is required for GRP75-USP1-SIX1 complex formation. Co-immunoprecipitation, ubiquitination assay, GRP75 domain deletion analysis, xenograft mouse model Oncogene Medium 34079090
2021 GRP75/HSPA9 palmitate-induced increase in pancreatic β-cells increases ER-mitochondria physical coupling and mitochondrial Ca2+ transfer leading to apoptosis; GRP75 overexpression alone is sufficient to impair mitochondrial membrane potential, increase mitochondrial Ca2+, and induce apoptosis; GRP75 inhibition prevents palmitate-induced aberrations. GRP75 overexpression/knockdown, mitochondrial Ca2+ measurement, mitochondrial membrane potential assay, ROS assay, TEM for ER-mitochondria contacts, in vivo palmitate injection model The Journal of biological chemistry Medium 34756890
2021 HSPA9/mortalin down-regulation induces mitochondrial fragmentation and axonal damage in primary neurons, while overexpression confers protection against rotenone-induced axonal degeneration; mortalin modulates mitochondrial morphology by acting on DRP1 phosphorylation. Lentiviral over-expression and knockdown, microfluidic-based axonal compartment cultures, mitochondrial morphology quantification, DRP1 phosphorylation Western blot Scientific reports Medium 34489498
2022 GRP75/HSPA9 regulates mitochondrial supercomplex assembly and stabilization to modulate insulin sensitivity; GRP75 induction prevents high-fat diet-induced obesity and insulin resistance in mice; GRP75 knockdown increases mitochondrial fragmentation, triggers cytosolic mtDNA release, and activates the cGAS/STING-dependent proinflammatory response. In vivo GRP75 induction mouse model (HFD), GRP75 knockdown, mitochondrial supercomplex analysis, respiratory chain complex activity assay, cGAS/STING activation assay Diabetes Medium 34810178
2022 The IP3R1-GRP75-VDAC1 complex mediates ER stress-mitochondrial oxidative stress and Ca2+ transfer in diabetic atrial remodeling; GRP75 conditional cardiac knockout impairs calcium transport from ER to mitochondria and attenuates atrial remodeling and AF progression. siRNA silencing, conditional knockout mouse (Myh6-Cre+/Hspa9flox/flox), proximity ligation assay, Ca2+ imaging, in situ PLA Redox biology High 35344886
2011 DNLZ/HEP stimulates HSPA9 ATPase activity through a conserved histidine (H107) residue; DNLZ-H107A fails to stimulate HSPA9 catalytic activity even at concentrations 10-fold above the half-maximal effective concentration, while retaining reduced binding to nucleotide-free HSPA9. Alanine mutagenesis scan, ATPase activity measurement, tryptophan fluorescence binding assay, E. coli co-expression solubility assay Biochemical and biophysical research communications High 21530495
2011 Nuclear GRP75/HSPA9 physically interacts with retinoic acid receptors RARα and RXRα in neuroblastoma cells upon RA treatment; GRP75 is required for RARα/RXRα-mediated transcriptional regulation and reduces proteasome-mediated degradation of RARα/RXRα in a RA-dependent manner. Co-immunoprecipitation, transcriptional reporter assay, proteasome inhibitor experiments, immunofluorescence nuclear localization, in vivo xenograft PloS one Medium 22022577
2016 Complement activation triggers redistribution of mortalin/GRP75 from mitochondria to the plasma membrane within minutes; cytoplasmic mortalin levels increase in complement-treated cells, as shown by immunoblotting and STED nanoscopy showing juxtaposition of mortalin and C5b-9 at the plasma membrane. STED super-resolution microscopy, immunoblotting of cytoplasmic fraction, complement treatment kinetics Immunobiology Medium 27475989
2016 GRP75/HSPA9 upregulates clathrin-independent endocytosis (CIE) and inhibits clathrin-mediated endocytosis (CME) through its mitochondria-localized ATPase domain; this regulation is mediated by concurrent activation of Cdc42 and RhoA, inducing stress fibers and filopodia; silencing either Cdc42 or RhoA impairs GRP75-driven CIE enhancement. Mitochondrial signal peptide-directed expression constructs, endocytosis functional assays (transferrin/CTB uptake), Rho GTPase activity assay, siRNA silencing of Cdc42/RhoA, actin cytoskeleton imaging Experimental cell research Medium 27090015
2018 GRP75/HSPA9 is associated with proto-Dbl inside cells and promotes proto-Dbl degradation through the CHIP-mediated ubiquitin-proteasome pathway, acting as a cooperator with CHIP and competitor to Hsc70/Hsp90 in the chaperone-assisted degradation machinery. Co-immunoprecipitation, endocytosis assays (macropinocytosis, CME, CIE), siRNA knockdown, GRP75 inhibitor MKT-077, Rho GTPase activation assay Cell death & disease Medium 30250167
2018 Hsp90 directly binds mortalin/GRP75; geldanamycin-mediated Hsp90 inhibition failed to sensitize cells with knocked-down mortalin to complement-dependent cytotoxicity, establishing mortalin as epistatic to Hsp90 in CDC resistance. Co-immunoprecipitation of Hsp90 with mortalin in cell extracts and with purified recombinant proteins, genetic epistasis (Hsp90 inhibitor in mortalin-KD cells), CDC assay Cell death & disease Medium 29396434
2020 Grp75/HSPA9 mediates mitochondrial import of DJ-1; resveratrol enhances Grp75-DJ-1 interaction and promotes DJ-1 translocation to mitochondria; Grp75 knockdown abolishes resveratrol-induced DJ-1 mitochondrial translocation and prevents subsequent preservation of mitochondrial complex I activity. Co-immunoprecipitation, siRNA knockdown, mitochondrial fractionation, complex I activity assay, ROS measurement Journal of cardiovascular pharmacology Medium 32040033
2024 OMA1 competitively binds HSPA9 to induce mitophagy and GBM immune escape; OMA1-HSPA9 interaction (identified by Co-IP and mass spectrometry) promotes mitochondrial DNA release, activates cGAS-STING, and upregulates PD-L1 transcription. Co-immunoprecipitation, mass spectrometry, siRNA knockdown, immunofluorescence, immunohistochemistry, Western blot Journal for immunotherapy of cancer Medium 38604814
2024 MUL1 SUMOylates HSPA9 at K612, causing HSPA9 export from mitochondria and nuclear interaction with SUZ12 and EZH2; HSPA9 nuclear translocation leads to ubiquitination-mediated degradation of SUZ12 and EZH2 and downstream STAT3 pathway inhibition; mutation of K612 blocks HSPA9 translocation and abolishes MUL1-mediated tumor suppression. Co-immunoprecipitation, mass spectrometry, site-directed mutagenesis (K612), SUMOylation assay, immunofluorescence localization, in vitro and in vivo functional assays International journal of biological sciences Medium 39113711
2024 Under ferroptotic conditions, lipid peroxidation activates cAMP-dependent PKA anchored by AKAP1 at the outer mitochondrial membrane, which phosphorylates GRP75 at S148; phosphorylated GRP75 translocates from mitochondria to MAMs/cytosol, where it competes with Nrf2 for Keap1 binding through a conserved ETGE motif, stabilizing and activating Nrf2 to transcribe antiferroptotic genes. PKA phosphorylation assay, GRP75 S148A mutagenesis, Keap1 co-immunoprecipitation, Nrf2 target gene reporter, in vivo xenograft ferroptosis model Cell death and differentiation High 39537840
2024 Tumor-derived GRP75 binds adenine nucleotide translocase 2 (ANT2) to form a GRP75-ANT2 complex; stabilized ANT2 enhances its interaction with uncoupling protein 1 (UCP1), promoting white adipose tissue browning and cancer-associated cachexia. Co-immunoprecipitation, GRP75 inhibitor (withanone) treatment, in vivo mouse cachexia models Signal transduction and targeted therapy Medium 39327432
2025 HSPA9 serves as a scaffold to strengthen the USP14-SLC7A11 interaction, promoting USP14-mediated SLC7A11 deubiquitination and thereby suppressing ferroptosis in multiple myeloma; inhibition of USP14 enhances SLC7A11 ubiquitination and degradation, promoting ferroptosis. Proteomics screening, co-immunoprecipitation, ubiquitination assay, USP14 inhibitor IU1, xenograft mouse model Cell reports Medium 40372919
2010 Ca2+-induced release of mitochondrial outer membrane-bound m-calpain large subunit requires free calpain small subunit (located in the IMS), Grp75, ATP, and Ca2+; the OM-bound m-calpain large subunit is not associated with the small subunit or Grp75 prior to activation. DEAE-Sepharose column chromatography of solubilized OM proteins, calpain activity assay, co-immunoprecipitation, immunoblot Archives of biochemistry and biophysics Medium 21145877
2022 GRP75/HSPA9 mediates ER-mitochondria Ca2+ transfer via the IP3R1-GRP75-VDAC1 axis in retinal vascular endothelial cells under diabetic conditions; elevated mitochondrial Ca2+ leads to increased ROS, decreased mitochondrial membrane potential, cytochrome c release, and caspase-3 activation leading to apoptosis. siRNA knockdown, proximity ligation assay, Ca2+ imaging, mitochondrial membrane potential assay, ROS assay, in vivo STZ-induced DR rat model Biomolecules Medium 36551205
2022 DAB2IP competitively binds GRP75 through its Ras-GAP domain, reducing GRP75-driven p53 ubiquitination and proteasomal degradation; mass spectrometry identified GRP75 as an interaction partner of both DAB2IP and p53 in this ubiquitin-related complex. Mass spectrometry profiling, co-immunoprecipitation, ubiquitination assay, DAB2IP domain mapping, in vivo tumor model Cancer letters Medium 35150809
2024 METTL3-mediated m6A methylation at the HSPA9 mRNA 3'UTR increases mortalin mRNA stability and translation efficiency in cervical cancer cells; exosomal mortalin suppresses cellular senescence and promotes malignant transformation by blocking nuclear transport of p53 and preventing the p53-Gadd45A interaction. m6A methylation assay (3'UTR), mRNA stability assay, exosome isolation, co-immunoprecipitation (mortalin-p53), p53 nuclear/cytoplasmic fractionation, in vivo xenograft Cancer letters Medium 38253218
2021 GRP75/HSPA9 inhibits ubiquitination-mediated HMGA1 degradation by directly binding to HMGA1, causing HMGA1 upregulation and activation of JNK/c-JUN signaling in lung adenocarcinoma. Co-immunoprecipitation, ubiquitination assay, mRNA sequencing, in vitro and in vivo KD/OE experiments Thoracic cancer Medium 33755320

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2002 An Hsp70 family chaperone, mortalin/mthsp70/PBP74/Grp75: what, when, and where? Cell stress & chaperones 211 12482206
2006 Proteomic identification of a stress protein, mortalin/mthsp70/GRP75: relevance to Parkinson disease. Molecular & cellular proteomics : MCP 200 16565515
2000 Selective toxicity of MKT-077 to cancer cells is mediated by its binding to the hsp70 family protein mot-2 and reactivation of p53 function. Cancer research 195 11156371
2006 Upregulation of mortalin/mthsp70/Grp75 contributes to human carcinogenesis. International journal of cancer 186 16425258
1998 Inactivation of tumor suppressor p53 by mot-2, a hsp70 family member. The Journal of biological chemistry 185 9792667
2002 Extended longevity of Caenorhabditis elegans by knocking in extra copies of hsp70F, a homolog of mot-2 (mortalin)/mthsp70/Grp75. FEBS letters 170 11959102
2000 Extramitochondrial localization of mortalin/mthsp70/PBP74/GRP75. Biochemical and biophysical research communications 149 10944461
2018 Transglutaminase Type 2 Regulates ER-Mitochondria Contact Sites by Interacting with GRP75. Cell reports 148 30590033
2002 Hsp70 family member, mot-2/mthsp70/GRP75, binds to the cytoplasmic sequestration domain of the p53 protein. Experimental cell research 137 11900485
2007 Association of mortalin (HSPA9) with liver cancer metastasis and prediction for early tumor recurrence. Molecular & cellular proteomics : MCP 134 17934217
2022 IP3R1/GRP75/VDAC1 complex mediates endoplasmic reticulum stress-mitochondrial oxidative stress in diabetic atrial remodeling. Redox biology 132 35344886
2002 Voltage-dependent anion-selective channel (VDAC) interacts with the dynein light chain Tctex1 and the heat-shock protein PBP74. The international journal of biochemistry & cell biology 132 12009301
2005 Effect of GRP75/mthsp70/PBP74/mortalin overexpression on intracellular ATP level, mitochondrial membrane potential and ROS accumulation following glucose deprivation in PC12 cells. Molecular and cellular biochemistry 110 15724436
2018 IP3R-Grp75-VDAC1-MCU calcium regulation axis antagonists protect podocytes from apoptosis and decrease proteinuria in an Adriamycin nephropathy rat model. BMC nephrology 106 29907098
2005 Mortalin/GRP75 promotes release of membrane vesicles from immune attacked cells and protection from complement-mediated lysis. International immunology 95 16091382
2022 GRP75-faciliated Mitochondria-associated ER Membrane (MAM) Integrity controls Cisplatin-resistance in Ovarian Cancer Patients. International journal of biological sciences 93 35541901
1995 Cloning of rat grp75, an hsp70-family member, and its expression in normal and ischemic brain. Journal of neuroscience research 93 7629893
2005 Loss of Hspa9b in zebrafish recapitulates the ineffective hematopoiesis of the myelodysplastic syndrome. Blood 82 15650063
2003 Overexpressed mortalin (mot-2)/mthsp70/GRP75 and hTERT cooperate to extend the in vitro lifespan of human fibroblasts. Experimental cell research 80 12729798
1999 Fibroblast growth factor-1 interacts with the glucose-regulated protein GRP75/mortalin. The Biochemical journal 75 10510314
1998 Malignant transformation of NIH3T3 cells by overexpression of mot-2 protein. Oncogene 74 9780007
1997 Induction of PBP74/mortalin/Grp75, a member of the hsp70 family, by low doses of ionizing radiation: a possible role in induced radioresistance. International journal of radiation biology 73 9416787
2014 Mortalin (GRP75/HSPA9) upregulation promotes survival and proliferation of medullary thyroid carcinoma cells. Oncogene 68 25435367
2013 A mortalin/HSPA9-mediated switch in tumor-suppressive signaling of Raf/MEK/extracellular signal-regulated kinase. Molecular and cellular biology 65 23959801
2023 β-carotene targets IP3R/GRP75/VDAC1-MCU axis to renovate LPS-induced mitochondrial oxidative damage by regulating STIM1. Free radical biology & medicine 64 37270031
2013 Resveratrol protects DAergic PC12 cells from high glucose-induced oxidative stress and apoptosis: effect on p53 and GRP75 localization. Neurotoxicity research 64 24218232
2020 A trio has turned into a quartet: DJ-1 interacts with the IP3R-Grp75-VDAC complex to control ER-mitochondria interaction. Cell calcium 63 32120195
2015 Congenital sideroblastic anemia due to mutations in the mitochondrial HSP70 homologue HSPA9. Blood 63 26491070
2015 Mutations in the heat-shock protein A9 (HSPA9) gene cause the EVEN-PLUS syndrome of congenital malformations and skeletal dysplasia. Scientific reports 63 26598328
2000 Inactivation of p53 and life span extension of human diploid fibroblasts by mot-2. FEBS letters 62 10838077
2023 TGR5 supresses cGAS/STING pathway by inhibiting GRP75-mediated endoplasmic reticulum-mitochondrial coupling in diabetic retinopathy. Cell death & disease 60 37658045
2011 Crosstalk between Raf/MEK/ERK and PI3K/AKT in suppression of Bax conformational change by Grp75 under glucose deprivation conditions. Journal of molecular biology 58 21964438
2021 Overexpression of α-synuclein inhibits mitochondrial Ca2+ trafficking between the endoplasmic reticulum and mitochondria through MAMs by altering the GRP75-IP3R interaction. Journal of neuroscience research 56 34510532
2010 Magnetic nanoparticle-based isolation of endocytic vesicles reveals a role of the heat shock protein GRP75 in macromolecular delivery. Proceedings of the National Academy of Sciences of the United States of America 56 20624969
2009 Mutational screening of the mortalin gene (HSPA9) in Parkinson's disease. Journal of neural transmission (Vienna, Austria : 1996) 55 19657588
2001 An N-terminal region of mot-2 binds to p53 in vitro. Neoplasia (New York, N.Y.) 52 11420746
2014 Analysis of HSPA8 and HSPA9 mRNA expression and promoter methylation in the brain and blood of Alzheimer's disease patients. Journal of Alzheimer's disease : JAD 50 23948933
2001 Identification and characterization of molecular interactions between glucose-regulated proteins (GRPs) mortalin/GRP75/peptide-binding protein 74 (PBP74) and GRP94. The Biochemical journal 47 11439088
2010 Knockdown of Hspa9, a del(5q31.2) gene, results in a decrease in hematopoietic progenitors in mice. Blood 46 21123823
2019 Mortalin (GRP75/HSPA9) Promotes Survival and Proliferation of Thyroid Carcinoma Cells. International journal of molecular sciences 45 31027376
1994 PBP74, a new member of the mammalian 70-kDa heat shock protein family, is a mitochondrial protein. Molecular biology of the cell 44 7865888
2021 ApoE4 (Δ272-299) induces mitochondrial-associated membrane formation and mitochondrial impairment by enhancing GRP75-modulated mitochondrial calcium overload in neuron. Cell & bioscience 43 33676568
2021 GRP75 mediates endoplasmic reticulum-mitochondria coupling during palmitate-induced pancreatic β-cell apoptosis. The Journal of biological chemistry 42 34756890
2022 GRP75 Modulates Endoplasmic Reticulum-Mitochondria Coupling and Accelerates Ca2+-Dependent Endothelial Cell Apoptosis in Diabetic Retinopathy. Biomolecules 41 36551205
2010 The repressive effect of NF-kappaB on p53 by mot-2 is involved in human keratinocyte transformation induced by low levels of arsenite. Toxicological sciences : an official journal of the Society of Toxicology 40 20375080
2002 Implication of PBP74/mortalin/GRP75 in the radio-adaptive response. International journal of radiation biology 39 11869473
2020 Mortalin/HSPA9 targeting selectively induces KRAS tumor cell death by perturbing mitochondrial membrane permeability. Oncogene 36 32291414
2014 Targeting GRP75 improves HSP90 inhibitor efficacy by enhancing p53-mediated apoptosis in hepatocellular carcinoma. PloS one 36 24465691
2023 IP3R at ER-Mitochondrial Contact Sites: Beyond the IP3R-GRP75-VDAC1 Ca2+ Funnel. Contact (Thousand Oaks (Ventura County, Calif.)) 35 37426575
2021 A new role of GRP75-USP1-SIX1 protein complex in driving prostate cancer progression and castration resistance. Oncogene 35 34079090
2020 Mortalin (HSPA9) facilitates BRAF-mutant tumor cell survival by suppressing ANT3-mediated mitochondrial membrane permeability. Science signaling 35 32156782
2014 Mortalin/GRP75 binds to complement C9 and plays a role in resistance to complement-dependent cytotoxicity. The Journal of biological chemistry 34 24719326
1997 Induction of novel Grp75 isoforms by 2-deoxyglucose in human and murine fibroblasts. Cancer letters 34 9570370
2024 OMA1 competitively binds to HSPA9 to promote mitophagy and activate the cGAS-STING pathway to mediate GBM immune escape. Journal for immunotherapy of cancer 33 38604814
2021 Loss and gain of function of Grp75 or mitofusin 2 distinctly alter cholesterol metabolism, but all promote triglyceride accumulation in hepatocytes. Biochimica et biophysica acta. Molecular and cell biology of lipids 33 34419589
1999 NIH 3T3 cells malignantly transformed by mot-2 show inactivation and cytoplasmic sequestration of the p53 protein. Cell research 33 10628835
2018 HMGB1-induced asthmatic airway inflammation through GRP75-mediated enhancement of ER-mitochondrial Ca2+ transfer and ROS increased. Journal of cellular biochemistry 31 29292841
2015 Mitochondrial Hspa9/Mortalin regulates erythroid differentiation via iron-sulfur cluster assembly. Mitochondrion 31 26702583
2022 PolyGA targets the ER stress-adaptive response by impairing GRP75 function at the MAM in C9ORF72-ALS/FTD. Acta neuropathologica 29 36121477
2022 Preserving mitochondrial function by inhibiting GRP75 ameliorates neuron injury under ischemic stroke. Molecular medicine reports 27 35293600
2013 Label-free proteomics identifies Calreticulin and GRP75/Mortalin as peripherally accessible protein biomarkers for spinal muscular atrophy. Genome medicine 27 24134804
2022 GRP75 Regulates Mitochondrial-Supercomplex Turnover to Modulate Insulin Sensitivity. Diabetes 25 34810178
2017 Knockdown of HSPA9 induces TP53-dependent apoptosis in human hematopoietic progenitor cells. PloS one 25 28178280
2000 Human mortalin (HSPA9): a candidate for the myeloid leukemia tumor suppressor gene on 5q31. Leukemia 25 11187902
2024 METTL3-mediated HSPA9 m6A modification promotes malignant transformation and inhibits cellular senescence by regulating exosomal mortalin protein in cervical cancer. Cancer letters 24 38253218
2022 Abrogating the Interaction Between p53 and Mortalin (Grp75/HSPA9/mtHsp70) for Cancer Therapy: The Story so far. Frontiers in cell and developmental biology 24 35493098
2017 Steady-State Levels of Phosphorylated Mitogen-Activated Protein Kinase Kinase 1/2 Determined by Mortalin/HSPA9 and Protein Phosphatase 1 Alpha in KRAS and BRAF Tumor Cells. Molecular and cellular biology 24 28674184
2016 A mitochondrial HSP70 (HSPA9B) is linked to miltefosine resistance and stress response in Leishmania donovani. Parasites & vectors 24 27906059
2015 Involvement of mortalin/GRP75/mthsp70 in the mitochondrial impairments induced by A53T mutant α-synuclein. Brain research 24 25665531
2011 Nuclear GRP75 binds retinoic acid receptors to promote neuronal differentiation of neuroblastoma. PloS one 24 22022577
2005 The effects of some Mannich bases on heat shock proteins HSC70 and GRP75, and thioredoxin and glutaredoxin levels in Jurkat cells. Toxicology in vitro : an international journal published in association with BIBRA 24 15896550
2010 mot-2-Mediated cross talk between nuclear factor-B and p53 is involved in arsenite-induced tumorigenesis of human embryo lung fibroblast cells. Environmental health perspectives 23 20199942
2000 Structurally and functionally distinct mouse hsp70 family members Mot-1 and Mot-2 proteins are encoded by two alleles. DNA research : an international journal for rapid publication of reports on genes and genomes 23 10907855
2022 DAB2IP suppresses tumor malignancy by inhibiting GRP75-driven p53 ubiquitination in colon cancer. Cancer letters 22 35150809
2018 Cooperation between Hsp90 and mortalin/GRP75 in resistance to cell death induced by complement C5b-9. Cell death & disease 21 29396434
2024 GRP75 triggers white adipose tissue browning to promote cancer-associated cachexia. Signal transduction and targeted therapy 19 39327432
2024 AKAP1/PKA-mediated GRP75 phosphorylation at mitochondria-associated endoplasmic reticulum membranes protects cancer cells against ferroptosis. Cell death and differentiation 19 39537840
2021 27-Hydroxycholesterol is a specific factor in the neoplastic microenvironment of HCC that causes MDR via GRP75 regulation of the redox balance and metabolic reprogramming. Cell biology and toxicology 19 33880675
2016 Complement triggers relocation of Mortalin/GRP75 from mitochondria to the plasma membrane. Immunobiology 19 27475989
2024 Targeting GRP75 with a Chlorpromazine Derivative Inhibits Endometrial Cancer Progression Through GRP75-IP3R-Ca2+-AMPK Axis. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 18 38342610
2024 Potential targets for the treatment of MI: GRP75-mediated Ca2+ transfer in MAM. European journal of pharmacology 18 38527700
2021 GRP75-mediated upregulation of HMGA1 stimulates stage I lung adenocarcinoma progression by activating JNK/c-JUN signaling. Thoracic cancer 18 33755320
2018 GRP75 modulates oncogenic Dbl-driven endocytosis derailed via the CHIP-mediated ubiquitin degradation pathway. Cell death & disease 18 30250167
2024 Human salivary histatin 1 regulating IP3R1/GRP75/VDAC1 mediated mitochondrial-associated endoplasmic reticulum membranes (MAMs) inhibits cell senescence for diabetic wound repair. Free radical biology & medicine 17 39343182
2023 Mortalin/Hspa9 involvement and therapeutic perspective in Parkinson's disease. Neural regeneration research 17 35900406
2021 LOXL1‑AS1 promotes thymoma and thymic carcinoma progression by regulating miR‑525‑5p‑HSPA9. Oncology reports 17 33907842
2021 HSPA9/Mortalin mediates axo-protection and modulates mitochondrial dynamics in neurons. Scientific reports 17 34489498
2020 Mitochondrial Translocation of DJ-1 Is Mediated by Grp75: Implication in Cardioprotection of Resveratrol Against Hypoxia/Reoxygenation-Induced Oxidative Stress. Journal of cardiovascular pharmacology 17 32040033
2007 Confinement exposure induces glucose regulated protein 75 (GRP75/mortalin/mtHsp70/PBP74/HSPA9B) in the hepatic tissue of gilthead sea bream (Sparus aurata L.). Comparative biochemistry and physiology. Part B, Biochemistry & molecular biology 17 18164226
2017 Mitochondria chaperone GRP75 moonlighting as a cell cycle controller to derail endocytosis provides an opportunity for nanomicrosphere intracellular delivery. Oncotarget 16 28938577
2019 GRP75 overexpression rescues frataxin deficiency and mitochondrial phenotypes in Friedreich ataxia cellular models. Human molecular genetics 15 30590615
2019 PCDHGB7 Increases Chemosensitivity to Carboplatin by Inhibiting HSPA9 via Inducing Apoptosis in Breast Cancer. Disease markers 15 31379979
2019 75-kDa glucose-regulated protein (GRP75) is a novel molecular signature for heat stress response in avian species. American journal of physiology. Cell physiology 15 31800296
2016 GRP75 upregulates clathrin-independent endocytosis through actin cytoskeleton reorganization mediated by the concurrent activation of Cdc42 and RhoA. Experimental cell research 15 27090015
2014 Reduced levels of Hspa9 attenuate Stat5 activation in mouse B cells. Experimental hematology 15 25550197
2023 Enhanced primary ciliogenesis via mitochondrial oxidative stress activates AKT to prevent neurotoxicity in HSPA9/mortalin-depleted SH-SY5Y cells. Molecular brain 14 37170364
2010 Ca²+-induced release of mitochondrial m-calpain from outer membrane with binding of calpain small subunit and Grp75. Archives of biochemistry and biophysics 14 21145877
2025 HSPA9 contributes to tumor progression and ferroptosis resistance by enhancing USP14-driven SLC7A11 deubiquitination in multiple myeloma. Cell reports 13 40372919
2024 SUMO E3 ligase MUL1 inhibits lymph node metastasis of bladder cancer by mediating mitochondrial HSPA9 translocation. International journal of biological sciences 13 39113711
2011 A conserved histidine in human DNLZ/HEP is required for stimulation of HSPA9 ATPase activity. Biochemical and biophysical research communications 13 21530495

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