Affinage

PPIF

Peptidyl-prolyl cis-trans isomerase F, mitochondrial · UniProt P30405

Round 2 corrected
Length
207 aa
Mass
22.0 kDa
Annotated
2026-04-28
75 papers in source corpus 23 papers cited in narrative 23 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

PPIF (cyclophilin D) is a mitochondrial matrix peptidyl-prolyl cis-trans isomerase that functions as the principal regulatory subunit of the mitochondrial permeability transition pore (mPTP), gating Ca²⁺- and oxidative stress-induced mitochondrial permeability transition to control necrosis, ferroptosis, and physiological Ca²⁺ efflux. CypD assembles with VDAC and ANT (binding ANT via Cys160) to form the minimal pore complex, and additionally interacts with SPG7, ATP5B, p53, and TRAP1/HSP90 to integrate diverse stress signals into mPTP opening (PMID:9874241, PMID:12149099, PMID:26387735, PMID:22726440, PMID:27515399, PMID:37717465). Its activity is tuned by acetylation at K166/K167 (promoted by GCN5L1, reversed by SIRT3), sulphenylation at C104, NEDD4-mediated ubiquitination, and RIPK3–PGAM5-dependent phosphorylation, with K166 deacetylation-mimetic knock-in mice showing protection from vascular oxidative stress and hypertension (PMID:36092157, PMID:38639088, PMID:35118072, PMID:36631006, PMID:29770487). CypD-dependent mPTP opening also drives oxidized mtDNA release to activate cGAS–STING signaling during ferroptosis and acts as an oncosuppressive mechanism in hormone receptor-positive mammary tumorigenesis (PMID:41700459, PMID:40494873).

Mechanistic history

Synthesis pass · year-by-year structured walk · 15 steps
  1. 1991 High

    Establishing that PPIF encodes a distinct mitochondrial cyclophilin with intrinsic PPIase activity resolved the identity of the cyclosporin A-sensitive isomerase in the mitochondrial matrix.

    Evidence cDNA cloning, recombinant expression, PPIase assay with CsA inhibition kinetics, subcellular fractionation

    PMID:1744118

    Open questions at the time
    • Physiological substrates of the PPIase activity were unknown
    • Relationship to the permeability transition pore had not been tested
  2. 1998 High

    Reconstitution of a Ca²⁺-sensitive, CsA-inhibitable pore from purified VDAC, ANT, and CypD in proteoliposomes established CypD as a core component of the mPTP, answering how cyclosporin A blocks permeability transition.

    Evidence GST-CypD affinity pulldown, VDAC/ANT co-purification, proteoliposome reconstitution with fluorescein sulphonate permeability assay

    PMID:9874241

    Open questions at the time
    • The stoichiometry and topology of the pore complex were undefined
    • Whether additional subunits are required in vivo was unknown
  3. 2002 High

    Mapping the ANT Cys160 thiol as the CypD docking site and showing that PPIase catalytic activity is required for cytoprotection but dispensable for ANT binding separated CypD's pore-regulatory role from its enzymatic function on other substrates.

    Evidence Site-directed mutagenesis of CypD PPIase site and ANT Cys160, GST pulldowns, mPTP Ca²⁺ sensitivity assays, live-cell two-photon imaging, apoptosis readouts

    PMID:12077116 PMID:12149099

    Open questions at the time
    • The identity of PPIase-dependent cytoprotective substrate(s) remained unknown
    • In vivo genetic confirmation (KO mice) was not yet available
  4. 2010 High

    High-resolution crystal structures of CypD revealed that the S2 surface outside the proline-binding pocket confers isoform specificity, providing a structural framework for selective CypD inhibitor design.

    Evidence X-ray crystallography, PPIase assay across 15 cyclophilin isoforms, CsA binding, computational docking

    PMID:20676357

    Open questions at the time
    • No co-crystal with a physiological substrate or mPTP component was obtained
    • Structure of CypD within the intact pore complex remained unknown
  5. 2012 High

    Discovery that mitochondrial p53 triggers mPTP-dependent necrosis through direct complex formation with CypD linked tumor suppressor signaling to the permeability transition pore during ischemia-reperfusion.

    Evidence Reciprocal Co-IP of p53–CypD in cells and in vivo mouse stroke model, genetic p53 knockdown and CsA pharmacological epistasis

    PMID:22726440

    Open questions at the time
    • Binding interface between p53 and CypD was not mapped
    • Whether p53 is a PPIase substrate or allosteric activator was unclear
  6. 2013 High

    Unbiased proteomics and metabolomics of CypD-knockout hearts revealed broad remodeling of Krebs cycle and fatty acid oxidation enzymes, establishing that CypD shapes mitochondrial metabolic pathway composition beyond its mPTP gating role.

    Evidence LC-MS/MS quantitative proteomics and acylcarnitine profiling in Ppif⁻/⁻ vs. WT mouse hearts

    PMID:23262437

    Open questions at the time
    • Whether metabolic effects are secondary to chronic mPTP dysregulation or reflect direct PPIase substrates was unresolved
    • Tissue-specificity of metabolic remodeling was not assessed
  7. 2015 High

    An unbiased RNAi screen identified SPG7 as a required mPTP component that must interact with CypD for pore opening, expanding the minimal pore model beyond VDAC and ANT.

    Evidence RNAi screen, reciprocal Co-IP of SPG7–CypD–VDAC, mitochondrial Ca²⁺ retention and cell death assays

    PMID:26387735

    Open questions at the time
    • Whether SPG7 is a structural pore subunit or a regulatory cofactor was debated
    • The exact molecular architecture of the pore remained unresolved
  8. 2016 High

    NMR mapping showed CypD catalytically drives p53 amyloid-type aggregation via active-site residues R55/F60/F113/W121, and TRAP1 normally sequesters CypD in an inhibited complex, explaining how oxidative stress derepresses CypD's pro-death activity.

    Evidence In vitro CypD–p53 aggregation reconstitution, NMR chemical shift mapping, Gamitrinib (mitochondria-targeted HSP90 inhibitor), genetic epistasis in MEFs

    PMID:27515399

    Open questions at the time
    • In vivo confirmation of TRAP1–CypD stoichiometry and dynamics was lacking
    • Relevance to non-p53 substrates was not tested
  9. 2018 Medium

    Identification of RIPK3–PGAM5-dependent CypD phosphorylation during cardiac ischemia-reperfusion connected necroptotic signaling to mPTP opening in endothelial cells.

    Evidence Ripk3 genetic ablation, phospho-CypD immunoblotting, PGAM5 pathway analysis, in vivo cardiac IR model

    PMID:29770487

    Open questions at the time
    • The specific CypD phosphorylation site(s) were not mapped by mass spectrometry
    • Independent replication in other tissues is needed
    • Kinase directly phosphorylating CypD was not definitively identified
  10. 2021 Medium

    Live imaging of CypD-overexpressing myofibers demonstrated that CypD dosage controls mitoflash frequency and perinuclear Ca²⁺ efflux, with S42 phosphorylation dispensable (S42A behaves as WT), linking CypD expression level to physiological mPTP-dependent Ca²⁺ dynamics in muscle.

    Evidence CypD-jRCaMP1b fusion live Ca²⁺ imaging, S42A phospho-resistant mutant, mitoflash quantification in isolated myofibers, SOD1-G93A ALS model

    PMID:34299032

    Open questions at the time
    • S42 phosphorylation role not fully excluded under all stress conditions
    • Overexpression system limits physiological interpretation
    • Single lab observation
  11. 2022 High

    Mapping K166 acetylation (by GCN5L1, reversed by SIRT3) and C104 sulphenylation as opposing regulatory switches resolved how post-translational modifications fine-tune CypD's mPTP-sensitizing activity: K166 acetylation promotes pore opening while C104 sulphenylation suppresses it.

    Evidence CypD-K166R point mutation with in vivo behavioral rescue, biotin-switch sulphenylation assay, C104S mutagenesis, mPTP opening and apoptosis assays in cardiomyocytes and spinal cord neurons

    PMID:35118072 PMID:36092157

    Open questions at the time
    • Interplay between acetylation and sulphenylation on the same CypD molecule was not tested
    • Crystal structure of modified CypD forms was not determined
  12. 2023 Medium

    Identification of NEDD4-mediated ubiquitination as a CypD degradation pathway, suppressed by exosomal miR-155-5p during I/R injury, revealed a post-translational mechanism controlling CypD protein levels rather than activity.

    Evidence miR-155-5p inhibitor, luciferase reporter for NEDD4 3′UTR, Co-IP of CypD ubiquitination, in vivo I/R model with infarct size assays

    PMID:36631006

    Open questions at the time
    • Ubiquitination site(s) on CypD not mapped
    • Independent replication needed
    • Whether NEDD4 directly ubiquitinates CypD or acts through an intermediate was not definitively shown
  13. 2024 High

    CypD-K166R deacetylation-mimetic knock-in mice demonstrated protection from Ang II-induced hypertension and endothelial dysfunction, and endothelial-specific GCN5L1 knockout prevented mitochondrial oxidative stress, translating the K166 acetylation switch to a defined cardiovascular disease mechanism in vivo.

    Evidence CypD-K166R knock-in mice, endothelial-specific GCN5L1 KO, human patient arteriole Co-IP, Ang II hypertension model, metabolic flux analysis

    PMID:38639088

    Open questions at the time
    • Whether K166 acetylation status is a viable therapeutic biomarker in humans was not tested
    • Tissue-specificity of GCN5L1-CypD axis beyond endothelium is unknown
  14. 2025 Medium

    Genetic epistasis studies in multiple disease models—tau-driven neurodegeneration, sepsis-induced pancreatic injury, and hormone-driven mammary carcinogenesis—collectively established CypD as a convergent downstream effector: its ablation protects against pathological mPTP opening in neuronal and acinar contexts while paradoxically increasing tumor susceptibility, revealing an oncosuppressive function of MPT-driven necrosis.

    Evidence Ppif⁻/⁻ mice with hippocampal AAV-tau injection, CLP sepsis model, MPA/DMBA mammary carcinogenesis model with comparison to Ripk3⁻/⁻ and Mlkl⁻/⁻ mice

    PMID:40023297 PMID:40494873 PMID:41270585

    Open questions at the time
    • Mechanism by which CypD-dependent necrosis specifically suppresses HR+ tumors is unknown
    • Whether CypD's oncosuppressive role involves its PPIase activity or mPTP gating is not distinguished
    • Independent replication of carcinogenesis finding is needed
  15. 2025 Medium

    CypD-dependent mPTP opening was shown to mediate oxidized mtDNA release during ferroptosis, activating the cGAS–STING pathway to promote ferritinophagy and amplify ferroptotic cell death, extending CypD's role to a new form of regulated cell death.

    Evidence CypD KO and CsA inhibition during ferroptosis, oxidized mtDNA release measurement, cGAS–STING activation assay, ferritinophagy assay, tumor xenograft model

    PMID:41700459

    Open questions at the time
    • Whether CypD directly senses lipid peroxidation signals or is activated indirectly is unknown
    • The ferroptosis findings have not been independently replicated
    • Structural basis for CypD-dependent mtDNA release channel is undefined

Open questions

Synthesis pass · forward-looking unresolved questions
  • The high-resolution structure of CypD within the assembled mPTP complex, the full catalog of PPIase substrates in the mitochondrial matrix, and the integration of multiple PTMs (acetylation, sulphenylation, phosphorylation, ubiquitination) into a unified regulatory model remain major open questions.
  • No cryo-EM or structural model of the intact mPTP with CypD bound
  • Comprehensive identification of mitochondrial PPIase substrates has not been performed
  • Quantitative model integrating combinatorial PTM effects on CypD activity is lacking

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098772 molecular function regulator activity 5 GO:0016853 isomerase activity 3 GO:0044183 protein folding chaperone 1
Localization
GO:0005739 mitochondrion 5
Pathway
R-HSA-5357801 Programmed Cell Death 6 R-HSA-8953897 Cellular responses to stimuli 4 R-HSA-168256 Immune System 2 R-HSA-1430728 Metabolism 1 R-HSA-9612973 Autophagy 1
Partners
ATP5F1BPGAM5SIRT3SLC25A4SPG7TP53TRAP1VDAC1
Complex memberships
mitochondrial permeability transition pore (mPTP)

Evidence

Reading pass · 23 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1991 PPIF (hCyP3/cyclophilin D) was identified as a distinct human cyclophilin isoform with a 42-amino acid N-terminal hydrophobic extension acting as a mitochondrial targeting sequence, and the purified recombinant protein was shown to possess active peptidyl-prolyl cis-trans isomerase (PPIase) activity that is inhibited by cyclosporin A. cDNA cloning, recombinant protein expression in E. coli, PPIase enzymatic assay with synthetic peptide substrates, CsA inhibition kinetics, subcellular fractionation/Western blot The Journal of biological chemistry High 1744118
1998 Cyclophilin D binds strongly to complexes of the voltage-dependent anion channel (VDAC) and the adenine nucleotide translocase (ANT) to form the core structure of the mitochondrial permeability transition pore (mPTP); reconstituted proteoliposomes containing purified VDAC, ANT, and CypD were permeabilized by Ca²⁺ plus phosphate in a cyclosporin A-sensitive manner, establishing the minimal pore composition. CypD-GST affinity matrix pulldown of mitochondrial membrane proteins, ANT/VDAC co-purification, proteoliposome reconstitution, fluorescein sulphonate permeability assay, CsA inhibition European journal of biochemistry High 9874241
2002 CypD overexpression in HEK293 and rat glioma C6 cells desensitizes them to apoptotic stimuli and hyperpolarizes mitochondrial membrane potential; this cytoprotective effect requires intact PPIase activity (shown by site-directed mutagenesis of the catalytic site), yet CypD binding to ANT in GST pulldowns is unaffected by loss of PPIase activity, indicating a PPIase-dependent protective target distinct from ANT. Live-cell two-photon imaging, site-directed mutagenesis of PPIase active site, mitochondrial membrane potential measurement, GST pulldown (CypD–ANT interaction), apoptosis assays The Journal of biological chemistry High 12077116
2002 CypD (cyclophilin D) interacts with the adenine nucleotide translocase (ANT) via ANT Cys160; oxidative cross-linking agents (diamide, phenylarsine oxide) stabilize the ANT 'c' conformation, enhance CypD–ANT binding, and sensitize mPTP opening to Ca²⁺, while alkylation of Cys160 prevents both CypD binding and ADP-mediated mPTP inhibition. ANT thiol modification with EMA/NEM/PAO/diamide, GST-CypD affinity pulldown, submitochondrial particle cross-linking, mPTP Ca²⁺ sensitivity assays The Biochemical journal High 12149099
2010 Crystal structures of the PPIF (CypD) isomerase domain were determined at high resolution; structural comparison across 14 human cyclophilin isoforms revealed that the substrate-binding S2 surface outside the proline-binding pocket confers isoform specificity for in vivo substrates and drug binding, explaining why CypD activity against short peptides correlates with cyclosporin A ligation. X-ray crystallography, PPIase enzymatic assay for 15 cyclophilin isoforms, CsA binding assays, computational substrate docking PLoS biology High 20676357
2012 In response to oxidative stress, p53 accumulates in the mitochondrial matrix and triggers mPTP opening and necrosis through direct physical interaction with CypD; a robust p53–CypD complex forms during brain ischemia/reperfusion in vivo, and reducing p53 levels or CsA pretreatment prevents complex formation and confers stroke protection. Co-immunoprecipitation (p53–CypD complex), subcellular fractionation, in vivo mouse stroke model, genetic p53 knockdown, CsA pharmacological inhibition, mPTP opening assay Cell High 22726440
2013 CypD knockout (Ppif−/−) hearts display altered proteomes with reductions in Krebs cycle enzymes, branched-chain amino acid degradation enzymes, and pyruvate metabolism proteins (including 23% decrease in CPT1), accompanied by decreased acylcarnitine levels, indicating that CypD regulates mitochondrial metabolic pathway composition independently of direct mPTP gating. Quantitative proteomics (LC-MS/MS) of CypD−/− vs. wild-type mouse hearts, metabolomics (acylcarnitine profiling), enzymatic activity assays (succinate dehydrogenase, electron transfer flavoprotein) Journal of molecular and cellular cardiology High 23262437
2013 CypD (PPIF) functions as a key physiologic regulator of the mPTP beyond cell death; review synthesizes genetic evidence (Ppif−/− mice) showing CypD regulates transient mPTP openings that modulate mitochondrial Ca²⁺ efflux, bioenergetics, and reactive oxygen species under non-pathological conditions. Review integrating Ppif−/− genetic mouse model data, mPTP patch-clamp, Ca²⁺ retention assays Circulation journal Medium 23538482
2015 RNAi screening identified SPG7 (paraplegin) as a necessary component of the mPTP; biochemical analyses showed the PTP is a heterooligomeric complex of VDAC, SPG7, and CypD; silencing or disruption of SPG7–CypD binding prevented Ca²⁺- and ROS-induced mitochondrial membrane potential depolarization and cell death, positioning CypD as a regulatory subunit whose interaction with SPG7 is required for pore opening. RNAi screen, Co-immunoprecipitation (SPG7–CypD–VDAC), mitochondrial Ca²⁺ retention assay, ΔΨm measurement, cell death assays Molecular cell High 26387735
2016 Catalytically active CypD causes aggregation of wild-type p53 into amyloid-type fibrils in vitro; NMR mapping identified CypD active-site residues R55, F60, F113, and W121 as responsible for this activity; Trap1 (mitochondrial Hsp90) normally sequesters CypD in an inhibited complex, and displacement of CypD from Trap1 by influx of unfolded p53 under oxidative stress activates CypD's isomerase activity to trigger mPTP opening. In vitro CypD–p53 aggregation assay, NMR chemical shift mapping of CypD active site, Gamitrinib (mitochondria-targeted HSP90 inhibitor) treatment, mPTP opening assay in primary MEFs, CypD/p53 genetic epistasis Journal of molecular biology High 27515399
2018 CypD phosphorylation is upregulated downstream of RIPK3–PGAM5 signaling during cardiac ischemia-reperfusion; PGAM5 increases CypD phosphorylation to promote mPTP opening and endothelial necroptosis, establishing a Ripk3–PGAM5–CypD–mPTP signaling axis in microvascular injury. Genetic ablation of Ripk3, melatonin pharmacology, immunoblotting for phospho-CypD and PGAM5, mPTP opening assay, in vivo cardiac IR model, endothelial barrier/permeability assays Journal of pineal research Medium 29770487
2022 SIRT3 deacetylates CypD at lysine 166 (K166); acetylation of CypD-K166 promotes mPTP opening, increases ROS and mitochondrial membrane potential collapse in spinal cord neurons during neuropathic pain; point mutation CypD-K166R (deacetylation mimetic) abrogates mPTP opening and pain hypersensitivity, identifying K166 acetylation as the functional switch governing CypD-mediated mPTP regulation. Spared nerve injury mouse model, SIRT3 overexpression/knockout, CypD-K166R point mutation, Co-immunoprecipitation for acetylation, mPTP opening assay, ROS/MMP measurement, behavioral pain assays Oxidative medicine and cellular longevity High 36092157
2022 Endogenous SO₂ sulphenylates CypD specifically at Cys104; C104S mutation in CypD abolishes SO₂-induced sulphenylation and blocks SO₂-mediated inhibition of mPTP opening and cardiomyocyte apoptosis, identifying Cys104 sulphenylation as a novel post-translational modification that suppresses CypD activity. Biotin-switch sulphenylation assay, site-directed mutagenesis of four CypD cysteine residues (C57S, C104S, C176S, C202S), mPTP opening assay, cytochrome c release, caspase activity, TUNEL assay in neonatal cardiomyocytes Frontiers in cell and developmental biology High 35118072
2024 GCN5L1 (mitochondrial acetyltransferase) promotes CypD acetylation at K166, which is counteracted by SIRT3 (deacetylase); in hypertensive patients, arteriolar CypD acetylation is elevated 280% with reduced Sirt3 and increased GCN5L1; deacetylation-mimetic CypD-K166R mice are protected from vascular oxidative stress, endothelial dysfunction, and Ang II-induced hypertension; endothelial-specific GCN5L1 knockout prevents mitochondrial oxidative stress and metabolic glycolytic switch. CypD-K166R knock-in mice, endothelial-specific GCN5L1 KO mice, Co-IP for K166 acetylation in patient arterioles, Ang II hypertension model, mitochondrial superoxide measurement, endothelial-dependent relaxation assays, metabolic flux analysis Circulation research High 38639088
2023 CypD directly interacts with ATP5B (ATP synthase beta subunit) to promote mitochondrial ROS release in vascular smooth muscle cells; CypD knockout or CsA inhibition reduces ROS, 8-OHdG production, NLRP3 inflammasome activation, and MMP9 upregulation, defining a CypD–ATP5B–ROS–8-OHdG–NLRP3–MMP9 pathway in intracranial aneurysm pathogenesis. Co-immunoprecipitation (CypD–ATP5B), CypD−/− mouse model, CsA pharmacological inhibition, ROS measurement, 8-OHdG/NLRP3/MMP9 functional assays, in vivo intracranial aneurysm model Redox biology Medium 37717465
2023 miR-155-5p in ischemia/reperfusion-derived serum exosomes suppresses NEDD4 expression; NEDD4 normally promotes CypD ubiquitination and degradation; loss of NEDD4 increases CypD protein levels, augmenting mPTP opening and cardiomyocyte apoptosis during myocardial I/R injury. miRNA inhibitor transfection, luciferase reporter (miR-155-5p targeting NEDD4 3'UTR), shRNA knockdown of NEDD4/CypD, Co-immunoprecipitation of CypD ubiquitination, in vivo I/R mouse model, apoptosis/infarct size assays ESC heart failure Medium 36631006
2024 PPIF (CypD) in neutrophils exacerbates lung ischemia-reperfusion injury by promoting store-operated calcium entry (SOCE)-mediated calcium overload, which activates calcineurin/NFAT signaling and drives neutrophil extracellular trap (NET) formation; PPIF inhibition (CsA) or PPIF knockdown alleviates mitochondrial dysfunction, ROS production, and NET formation in a lung transplant model. Orthotopic lung transplant mouse model, PPIF inhibitor (CsA) and PADI4 inhibitor in vivo, HL-60 neutrophil differentiation model, PPIF siRNA knockdown, SOCE measurement, calcineurin/NFAT pathway assays, NET quantification, mitochondrial function assays International immunopharmacology Medium 39236457
2025 Sirt3-mediated deacetylation of CypD at K167 alleviates P. gingivalis-induced mitochondrial and endothelial dysfunction; CypD-K167 point mutation plasmids and Co-immunoprecipitation confirmed the Sirt3–CypD interaction, and Sirt3 agonist Honokiol rescued endothelial function in vitro and restored vasorelaxation in vivo. Co-immunoprecipitation (Sirt3–CypD), CypD-K167 point mutation plasmids, Sirt3-specific agonist Honokiol, RNA sequencing of infected endothelial cells, mitochondrial ROS/ΔΨm assays, mouse aortic vasorelaxation ex vivo Journal of periodontal research Medium 40344434
2025 CypD (Ppif) ablation prevents cognitive decline, synaptic impairment, and mPTP-mediated mitochondrial damage induced by caspase-3-cleaved tau in the hippocampus; stereotaxic AAV injection of truncated tau in CypD−/− mice showed no mPTP opening or synaptic vesicle protein deregulation, establishing CypD as a necessary downstream effector of pathological tau-driven neurodegeneration. Stereotaxic hippocampal AAV injection (full-length vs. caspase-3-cleaved tau), CypD−/− and tau−/− KO mice, cognitive behavioral testing (Morris water maze, etc.), synaptic protein analysis, mitochondrial function/mPTP assays Free radical biology & medicine Medium 40023297
2025 Ppif (CypD) gene knockout in mice protects against sepsis-induced pancreatic injury; Ppif KO reduced serum IL-6 and amylase, improved pancreatic histopathology, decreased apoptosis indices, and ultrastructural analysis revealed that Ppif KO pancreatic acinar cells develop more autophagosomes rather than undergoing mitochondrial swelling and necrotic changes seen in wild-type CLP mice. Cecal ligation and puncture (CLP) sepsis model in Ppif KO vs. wild-type mice, serum IL-6/amylase ELISA, H&E histology, TUNEL apoptosis assay, transmission electron microscopy of pancreatic ultrastructure The Journal of surgical research Medium 41270585
2025 Female Ppif−/− (CypD-null) mice are more susceptible to hormone-driven (MPA/DMBA) mammary carcinogenesis than wild-type mice, while Ripk3−/− or Mlkl−/− mice are not, indicating that CypD-dependent MPT-driven necrosis acts as an oncosuppressive mechanism specifically restraining HR+ mammary tumor development. Whole-body Ppif KO, Ripk3 KO, and Mlkl KO female C57BL/6J mice in MPA/DMBA-driven mammary carcinogenesis model, tumor incidence and progression monitoring Cell death discovery Medium 40494873
2026 CypD-dependent mPTP opening is required for mitochondrial swelling and ferroptosis; during ferroptosis, oxidized mitochondrial DNAs (mtDNAs) are released through the CypD-regulated mPTP and activate the cGAS–STING pathway, which promotes ferritinophagy and amplifies ferroptotic signaling; mtDNA repair inhibition synergizes with ferroptosis inducers in suppressing tumor xenografts. CypD genetic KO and CsA pharmacological inhibition, mPTP opening assay during ferroptosis, oxidized mtDNA detection and release measurement, cGAS-STING pathway activation assay, ferritinophagy assay, xenograft tumor model Advanced science Medium 41700459
2021 CypD overexpression in skeletal muscle myofibers increases mitoflash frequency and area with accompanying perinuclear mitochondrial Ca²⁺ efflux; a phospho-resistant CypD-S42A mutant behaves similarly to wild-type CypD overexpression, while expression of only the mitochondrial targeting sequence (CypDN30) does not cause these phenotypes; sodium butyrate feeding reverses CypD-associated mitoflash phenotypes in an ALS mouse model, linking CypD expression level to mitochondrial Ca²⁺ dynamics and mPTP-associated mitoflash activity. CypD-jRCaMP1b fusion constructs (live Ca²⁺ imaging), CypD-S42A phospho-resistant mutation, mitoflash quantification in isolated myofibers, ALS (SOD1-G93A) mouse model, sodium butyrate dietary supplementation International journal of molecular sciences Medium 34299032

Source papers

Stage 0 corpus · 75 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2002 Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. Proceedings of the National Academy of Sciences of the United States of America 1479 12477932
2010 Hundreds of variants clustered in genomic loci and biological pathways affect human height. Nature 1451 20881960
2014 A proteome-scale map of the human interactome network. Cell 977 25416956
2005 Nucleolar proteome dynamics. Nature 934 15635413
2020 A reference map of the human binary protein interactome. Nature 849 32296183
2002 Directed proteomic analysis of the human nucleolus. Current biology : CB 780 11790298
2012 A census of human soluble protein complexes. Cell 689 22939629
2011 Phylogenetic-based propagation of functional annotations within the Gene Ontology consortium. Briefings in bioinformatics 656 21873635
2012 p53 opens the mitochondrial permeability transition pore to trigger necrosis. Cell 604 22726440
2018 High-Density Proximity Mapping Reveals the Subcellular Organization of mRNA-Associated Granules and Bodies. Molecular cell 580 29395067
2004 The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). Genome research 438 15489334
2022 OpenCell: Endogenous tagging for the cartography of human cellular organization. Science (New York, N.Y.) 432 35271311
2015 Panorama of ancient metazoan macromolecular complexes. Nature 407 26344197
1998 Cyclophilin-D binds strongly to complexes of the voltage-dependent anion channel and the adenine nucleotide translocase to form the permeability transition pore. European journal of biochemistry 395 9874241
2021 A proximity-dependent biotinylation map of a human cell. Nature 339 34079125
2019 Mitochondrial ClpP-Mediated Proteolysis Induces Selective Cancer Cell Lethality. Cancer cell 298 31056398
2002 Role of critical thiol groups on the matrix surface of the adenine nucleotide translocase in the mechanism of the mitochondrial permeability transition pore. The Biochemical journal 297 12149099
2003 The secreted protein discovery initiative (SPDI), a large-scale effort to identify novel human secreted and transmembrane proteins: a bioinformatics assessment. Genome research 285 12975309
2022 CST1 inhibits ferroptosis and promotes gastric cancer metastasis by regulating GPX4 protein stability via OTUB1. Oncogene 259 36369321
2021 Quantitative high-confidence human mitochondrial proteome and its dynamics in cellular context. Cell metabolism 239 34800366
2010 Structural and biochemical characterization of the human cyclophilin family of peptidyl-prolyl isomerases. PLoS biology 238 20676357
2018 Inhibitory effect of melatonin on necroptosis via repressing the Ripk3-PGAM5-CypD-mPTP pathway attenuates cardiac microvascular ischemia-reperfusion injury. Journal of pineal research 223 29770487
2007 hORFeome v3.1: a resource of human open reading frames representing over 10,000 human genes. Genomics 222 17207965
2013 Physiologic functions of cyclophilin D and the mitochondrial permeability transition pore. Circulation journal : official journal of the Japanese Circulation Society 219 23538482
2018 An AP-MS- and BioID-compatible MAC-tag enables comprehensive mapping of protein interactions and subcellular localizations. Nature communications 201 29568061
2011 Next-generation sequencing to generate interactome datasets. Nature methods 200 21516116
2020 Systems analysis of RhoGEF and RhoGAP regulatory proteins reveals spatially organized RAC1 signalling from integrin adhesions. Nature cell biology 194 32203420
1991 The cyclophilin multigene family of peptidyl-prolyl isomerases. Characterization of three separate human isoforms. The Journal of biological chemistry 185 1744118
2015 SPG7 Is an Essential and Conserved Component of the Mitochondrial Permeability Transition Pore. Molecular cell 169 26387735
2002 Mitochondrial targeted cyclophilin D protects cells from cell death by peptidyl prolyl isomerization. The Journal of biological chemistry 149 12077116
2008 Systematic identification of mRNAs recruited to argonaute 2 by specific microRNAs and corresponding changes in transcript abundance. PloS one 148 18461144
2008 Putative partners in Bax mediated cytochrome-c release: ANT, CypD, VDAC or none of them? Mitochondrion 72 18992370
2018 SIRT3 a Major Player in Attenuation of Hepatic Ischemia-Reperfusion Injury by Reducing ROS via Its Downstream Mediators: SOD2, CYP-D, and HIF-1α. Oxidative medicine and cellular longevity 68 30538800
2012 CypD(-/-) hearts have altered levels of proteins involved in Krebs cycle, branch chain amino acid degradation and pyruvate metabolism. Journal of molecular and cellular cardiology 49 23262437
2016 A Novel In Vitro CypD-Mediated p53 Aggregation Assay Suggests a Model for Mitochondrial Permeability Transition by Chaperone Systems. Journal of molecular biology 44 27515399
2022 Cationic antimicrobial peptide NRC-03 induces oral squamous cell carcinoma cell apoptosis via CypD-mPTP axis-mediated mitochondrial oxidative stress. Redox biology 34 35660629
2022 SIRT3-Mediated CypD-K166 Deacetylation Alleviates Neuropathic Pain by Improving Mitochondrial Dysfunction and Inhibiting Oxidative Stress. Oxidative medicine and cellular longevity 34 36092157
2024 Mitochondrial CypD Acetylation Promotes Endothelial Dysfunction and Hypertension. Circulation research 33 38639088
2015 CypD: The Key to the Death Door. CNS & neurological disorders drug targets 32 25921742
2019 PGAM5-CypD pathway is involved in bromocriptine-induced RIP3/MLKL-dependent necroptosis of prolactinoma cells. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 31 30611988
2023 CypD induced ROS output promotes intracranial aneurysm formation and rupture by 8-OHdG/NLRP3/MMP9 pathway. Redox biology 30 37717465
2018 CypD-mPTP axis regulates mitochondrial functions contributing to osteogenic dysfunction of MC3T3-E1 cells in inflammation. Journal of physiology and biochemistry 26 29679227
2013 Matrix metalloproteinase inhibition protects CyPD knockout mice independently of RISK/mPTP signalling: a parallel pathway to protection. Basic research in cardiology 26 23361433
2021 Mortalin depletion induces MEK/ERK-dependent and ANT/CypD-mediated death in vemurafenib-resistant B-RafV600E melanoma cells. Cancer letters 21 33440231
2023 MicroRNA-155-5p in serum derived-exosomes promotes ischaemia-reperfusion injury by reducing CypD ubiquitination by NEDD4. ESC heart failure 18 36631006
2021 Protection of pancreatic β-cell by phosphocreatine through mitochondrial improvement via the regulation of dual AKT/IRS-1/GSK-3β and STAT3/Cyp-D signaling pathways. Cell biology and toxicology 16 34455488
2019 CypD deficiency confers neuroprotection against mitochondrial abnormality caused by lead in SH-SY5Y cell. Toxicology letters 16 31874198
2018 Substrate specificity of the cypemycin decarboxylase CypD. Synthetic and systems biotechnology 15 30345401
2022 Sulphenylation of CypD at Cysteine 104: A Novel Mechanism by Which SO2 Inhibits Cardiomyocyte Apoptosis. Frontiers in cell and developmental biology 13 35118072
2021 In Silico Structural, Functional, and Phylogenetic Analysis of Cytochrome (CYPD) Protein Family. BioMed research international 13 34046497
2024 PDZD8 Augments Endoplasmic Reticulum-Mitochondria Contact and Regulates Ca2+ Dynamics and Cypd Expression to Induce Pancreatic β-Cell Death during Diabetes. Diabetes & metabolism journal 9 39069376
2015 Modelling the molecular mechanism of protein-protein interactions and their inhibition: CypD-p53 case study. Molecular diversity 7 26170095
2025 Extracellular vesicle-mediated delivery of circp53 suppresses the progression of multiple cancers by activating the CypD/TRAP/HSP90 pathway. Experimental & molecular medicine 6 40744997
2024 Neutrophil PPIF exacerbates lung ischemia-reperfusion injury after lung transplantation by promoting calcium overload-induced neutrophil extracellular traps formation. International immunopharmacology 6 39236457
2023 Lycium barbarum polysaccharide protects cardiomyocytes from hypoxia/reoxygenation injury via activation of SIRT3/CypD signaling. Annals of translational medicine 6 36819526
2023 Melatonin attenuates sevoflurane-induced hippocampal damage and cognitive deficits in neonatal mice by suppressing CypD in parvalbumin neurons. Brain research bulletin 6 37931809
2022 Cinnamtannin B-1 Inhibits the Progression of Osteosarcoma by Regulating the miR-1281/PPIF Axis. Biological & pharmaceutical bulletin 6 36273900
2022 CypD-mediated mitochondrial dysfunction contributes to titanium ion-induced MC3T3-E1 cell injury. Biochemical and biophysical research communications 6 36621148
2021 Butyrate Feeding Reverses CypD-Related Mitoflash Phenotypes in Mouse Myofibers. International journal of molecular sciences 6 34299032
2019 Movements of the Substrate-Binding Clamp of Cypemycin Decarboxylase CypD. Journal of chemical information and modeling 6 31033286
2025 Porphyromonas gingivalis Induces Endothelial Dysfunction Through Sirt3-Dependent CypD Acetylation. Journal of periodontal research 4 40344434
2025 Cyclophilin D (CypD) ablation prevents neurodegeneration and cognitive damage induced by caspase-3 cleaved tau. Free radical biology & medicine 3 40023297
2024 The cyclophilin D (CypD) of Toxoplasma gondii is involved in the parasite's response to oxidative stress damage. Parasitology research 2 39627473
2025 CYPD limits HR+ mammary carcinogenesis in mice. Cell death discovery 1 40494873
2025 Neonatal sevoflurane anesthesia induces persistent cognitive deficits in mice through CypD-dependent mitochondrial impairment in parvalbumin interneurons. Chemico-biological interactions 1 40784489
2025 Quercetin ameliorates oxidative stress in BMP15-deficient oocytes by regulating the ERK1/2-GSK3β-CypD pathway. Redox biology 1 41086612
2024 Neuroprotective Effect of 2-(Benzyloxy)arylureas Is Not Related to CypD Inhibition nor Suppression of mPTP Opening. ACS medicinal chemistry letters 1 39411525
2024 Role of the PGAM5-CypD mitochondrial pathway in methylglyoxal-induced bone loss in diabetic osteoporosis. Bone 1 39510433
2026 SIRT3 attenuates chronic pain-induced depressive-like behaviors by deacetylating CypD at lysine 166 in central amygdala. European journal of pharmacology 0 41643830
2026 CypD Dependent mPTP Opening Is Crucial for Oxidized Mitochondrial DNA Release in Ferroptosis. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 0 41700459
2025 Unveiling the role of PPIF and macrophage subtypes in LSCC progression via single-cell and exosome RNA sequencing. Scientific reports 0 40128571
2025 The Mechanism of a Novel Mitochondrial-Targeted Icaritin Derivative in Regulating Apoptosis of BEL-7402 Cells Based on the SIRT3 and CypD-Mediated ROS/p38 MAPK Signaling Pathway. Molecules (Basel, Switzerland) 0 40333582
2025 PPIF+ neutrophils promote mtROS driven NETosis mediated progression of colorectal cancer. Journal of translational medicine 0 41219985
2025 Ppif Gene Knockout Alleviates Pancreatic Injury in Mice With Cecal Ligation and Puncture-induced Sepsis. The Journal of surgical research 0 41270585
2024 Retracted: In Silico Structural, Functional, and Phylogenetic Analysis of Cytochrome (CYPD) Protein Family. BioMed research international 0 38550148