Affinage

PPIF

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

Audit flag: ungrounded claim
Length
207 aa
Mass
22.0 kDa
Annotated
2026-06-10
88 papers in source corpus 31 papers cited in narrative 30 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 5/5 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

PPIF encodes Cyclophilin D (CyP-D), a mitochondria-targeted peptidyl-prolyl cis-trans isomerase whose N-terminal hydrophobic extension directs it to mitochondrial membranes (PMID:1744118), and which functions as the principal regulatory sensitizer of the mitochondrial permeability transition pore (MPTP) (PMID:16167169). CyP-D binds inner-membrane components of the MPTP—the adenine nucleotide translocase (ANT/SLC25A4) and associated VDAC complexes at membrane contact sites—and its PPIase activity facilitates a Ca2+-triggered conformational change that opens the pore, an action blocked by cyclosporin A binding to CyP-D (PMID:10989666, PMID:10393078, PMID:12022946); CyP-D additionally binds the OSCP subunit of F-ATP synthase, inhibiting ATP synthase catalysis and favoring its transition to a pore, with calpain 1-mediated cleavage of the flexible CyP-D N-terminus strongly increasing OSCP affinity (PMID:39528709). Genetic ablation established that CyP-D is dispensable for pore formation per se but is required for Ca2+/oxidant-driven MPTP opening that executes regulated necrosis—not apoptosis—across many settings including ischemia/reperfusion, acetaminophen hepatotoxicity, crystal-induced kidney injury, dystrophic muscle, eosinophils, and atherosclerotic macrophages (PMID:17136322, PMID:20942566, PMID:26893161, PMID:31296606, PMID:37624892, PMID:38972156), and double-knockout epistasis with Slc25a4 confirms both as MPTP components in vivo (PMID:37624892). CyP-D is recruited into mitochondrial complexes with ROS-activated p53 or MST1 to amplify programmed necrosis (PMID:26024660, PMID:24732633), and its abundance is transcriptionally tuned—repressed by BMP/Smad during osteogenesis and by the repressor Nynrin in cardiomyocytes, and activated by C/EBPα/NF-κB during adipogenesis—thereby setting MPTP sensitivity (PMID:35645445, PMID:37949231, PMID:38955185, PMID:41077266). Beyond cell death, CyP-D governs physiological transient pore openings (mitoflashes/flickering) that mediate mitochondrial Ca2+ efflux required for senescent-cell survival (PMID:26746144, PMID:39448884), and supports fibroblast collagen secretion and wound healing (PMID:38564292).

Mechanistic history

Synthesis pass · year-by-year structured walk · 20 steps
  1. 1991 High

    Established that PPIF is an enzyme—a bona fide peptidyl-prolyl isomerase—and that its N-terminal extension targets it to organellar membranes, defining it as a mitochondria-associated cyclophilin rather than a cytosolic one.

    Evidence Recombinant expression in E. coli, PPIase activity assays with synthetic peptides, CsA-analogue inhibition kinetics, and subcellular fractionation

    PMID:1744118

    Open questions at the time
    • No in vivo substrate identified at this stage
    • Functional consequence of the isomerase activity in mitochondria unknown
  2. 1999 High

    Connected CyP-D enzymology to a physiological structure by showing it binds VDAC/ANT complexes at membrane contact sites and is the molecular target through which CsA inhibits the MPTP, explaining how a matrix isomerase controls inner-membrane permeability.

    Evidence CyP-D fusion-protein affinity pulldown of VDAC/ANT, photoaffinity labelling with a CsA derivative, and pore reconstitution from protein fractions

    PMID:10393078 PMID:10989666

    Open questions at the time
    • Whether CyP-D is a structural pore component or a regulator unresolved
    • Exact inner-membrane protein undergoing the conformational change not pinned down
  3. 2002 High

    Defined the mechanism of pore facilitation: CyP-D's PPIase activity drives a Ca2+-triggered conformational change in ANT (sensitized by oxidation of specific cysteines), and minimal pore formation requires neither VDAC nor outer-membrane proteins.

    Evidence Reconstitution of MPTP from purified ANT ± CyP-D, cysteine-specific chemical modification, and correlation of CsA-inhibited PPIase activity with pore inhibition

    PMID:12022946

    Open questions at the time
    • Identity of the physiological inner-membrane target still debated
    • Direct structural proof of the isomerized proline lacking
  4. 2005 High

    Genetic knockout resolved the structural-versus-regulatory question, demonstrating that the pore can still form and open without CyP-D, redefining CyP-D as a regulatory sensitizer rather than a pore-forming subunit.

    Evidence Ca2+-induced swelling assays in CyP-D-knockout mouse mitochondria ± CsA

    PMID:16167169

    Open questions at the time
    • Did not identify the structural pore-forming component
    • Endogenous trigger of CyP-D recruitment in vivo unclear
  5. 2007 High

    Assigned CyP-D-dependent MPT to a specific death modality, showing it is required for necrosis but not apoptosis and is central to ischemia/reperfusion injury, establishing the therapeutic rationale for CyP-D inhibition.

    Evidence Ppif−/− mice in necrosis vs apoptosis assays and ischemia/reperfusion models

    PMID:17136322

    Open questions at the time
    • Molecular events linking pore opening to necrotic execution incomplete
    • Tissue-specific thresholds for MPT engagement not defined
  6. 2008 Medium

    Refined the substrate model by showing ANT acts regulatorily and proposing the phosphate carrier (PiC) as the inner-membrane protein whose CyP-D-facilitated conformational change opens the pore.

    Evidence Genetic KO of ANT isoforms and CyP-D plus biochemical interaction studies

    PMID:18407825

    Open questions at the time
    • PiC as CyP-D substrate awaits knockdown/reconstitution confirmation
    • Single-lab proposal not yet independently validated
  7. 2010 High

    Extended CyP-D function beyond cell death to physiology, linking it to acetaminophen hepatotoxicity downstream of MPT and to hippocampal neurotransmitter release underlying learning and memory.

    Evidence Ppif−/− mice with liver injury markers; behavioral testing, hippocampal microdialysis, and CsA infusion

    PMID:19437409 PMID:20942566

    Open questions at the time
    • Mechanism coupling CyP-D to neurotransmitter release at synapses unknown
    • Whether memory effect requires transient pore opening vs another CyP-D function unclear
  8. 2013 Medium

    Revealed a retrograde signaling role, showing CyP-D loss activates STAT3 and a Cxcl12-Cxcr4 chemokine program that accelerates proliferation and migration, implicating CyP-D in mitochondria-to-nucleus inflammatory signaling.

    Evidence CyP-D KO/knockdown cells with proliferation, migration, transcriptome, and STAT3 assays

    PMID:23303179

    Open questions at the time
    • Signal transmitted from mitochondria to STAT3 not identified
    • Single lab; relationship to MPTP activity unclear
  9. 2014 Medium

    Identified ROS-induced partner complexes (p53 and MST1) that translocate to mitochondria and bind CyP-D to drive programmed necrosis, providing a mechanism for upstream death-signal coupling to the pore.

    Evidence Reciprocal co-IP of p53/CyP-D and MST1/CyP-D at mitochondria with genetic and pharmacological knockdown across glioma, prostate, and pancreatic cancer cells

    PMID:24732633 PMID:24946211 PMID:26024660

    Open questions at the time
    • Whether p53/MST1 binding directly alters pore conformation or acts indirectly unresolved
    • Binding interface on CyP-D not mapped
  10. 2015 High

    Demonstrated a physiological, sub-lethal CyP-D function by showing it sets the frequency of transient mitoflash openings and influences respiratory capacity, with tissue-specific magnitude tracking CyP-D expression.

    Evidence Reciprocal gain/loss-of-function in cardiomyocytes and skeletal muscle with live mitoflash imaging and Seahorse respirometry

    PMID:26746144

    Open questions at the time
    • Trigger distinguishing transient mitoflash from lethal pore opening unclear
    • Bioenergetic consequence mechanism not fully defined
  11. 2015 Medium

    Placed CyP-D within necroptotic crosstalk, showing necroptosis requires both Bax/Bak outer-membrane oligomerization and CyP-D-dependent MPTP opening, with MLKL/cofilin-1 mitochondrial translocation partly CyP-D-dependent.

    Evidence Ppif−/− and Bax/Bak-null fibroblasts with necroptosis induction and mitochondrial fractionation

    PMID:26061004

    Open questions at the time
    • Mechanistic link between MLKL and MPTP not established
    • Single lab; degree of MPT contribution to necroptosis varies by stimulus
  12. 2019 High

    Generalized CyP-D-driven necrosis to crystal-induced kidney injury and quantified its partial redundancy with necroptosis via double-knockout epistasis.

    Evidence Ppif−/− and Ppif−/−Mlkl−/− mice with crystal exposure, histology, and pharmacological MPTP inhibition

    PMID:31296606

    Open questions at the time
    • Signal from lysosomal cathepsin/ROS to MPTP not molecularly defined
    • Quantitative split between MPT-necrosis and necroptosis context-dependent
  13. 2022 High

    Showed that CyP-D abundance is a regulated transcriptional node, with BMP/Smad repressing Ppif to deactivate the MPTP as a functional requirement for osteoblast differentiation.

    Evidence BMP/Smad activation in MSCs, Ppif promoter reporters, and CyP-D gain-of-function in vitro and in mice

    PMID:35645445

    Open questions at the time
    • Direct Smad binding elements on Ppif not exhaustively mapped
    • Connection between MPTP deactivation and osteogenic gene program mechanistic detail limited
  14. 2023 High

    Provided direct in vivo genetic evidence for CyP-D and ANT1 as MPTP components, with combined deletion almost fully preventing necrotic muscular dystrophy.

    Evidence Single and double KO (Slc25a4−/−, Ppif−/−) in δ-sarcoglycan-null dystrophic mice with histopathology

    PMID:37624892

    Open questions at the time
    • Residual MPT activity in double KO indicates additional components
    • Stoichiometry of CyP-D–ANT1 interaction in the pore not defined
  15. 2023 Medium

    Identified an opposing transcriptional input, C/EBPα synergizing with NF-κB p65 to activate Ppif during adipogenesis, linking adipogenic and inflammatory signaling to MPTP gain-of-function.

    Evidence Ppif promoter reporters and ChIP for C/EBPα and NF-κB p65 in adipogenically induced BMSCs

    PMID:37949231

    Open questions at the time
    • Functional consequence of increased MPTP for adipocyte biology incomplete
    • Single lab; two-method support only
  16. 2024 High

    Provided structural and proteolytic mechanism for CyP-D engagement of ATP synthase, showing the flexible N-terminus suppresses OSCP binding and that calpain 1 cleavage generates a ΔN-CyP-D that binds OSCP, inhibits ATP synthesis, and favors pore transition.

    Evidence NMR of FL- and ΔN-CyP-D, OSCP binding assays, calpain 1 treatment, and mass-spec detection of ΔN-CyP-D in cells

    PMID:39528709

    Open questions at the time
    • Whether OSCP- vs ANT-binding represent distinct or unified pore models unresolved
    • Physiological stimulus driving calpain 1 cleavage not defined
  17. 2024 High

    Established a survival role of transient CyP-D pore opening, showing that in senescent cells CyP-D flickering provides Ca2+ efflux and that its inhibition causes toxic Ca2+ overload and senolysis, with MCU/NCLX epistasis defining the Ca2+ circuit.

    Evidence Genome-wide CRISPR screen, Ppif KO, CsA, MCU/NCLX perturbation, and mitochondrial Ca2+ imaging in senescent cells

    PMID:39448884

    Open questions at the time
    • What renders senescent cells uniquely dependent on CyP-D efflux unclear
    • Generality of senolytic effect across senescence inducers untested
  18. 2024 High

    Expanded CyP-D into tissue-repair biology, demonstrating it promotes fibroblast collagen secretion (preventing ER retention) and keratinocyte reepithelialization required for wound closure.

    Evidence Reciprocal gain/loss-of-function in keratinocytes and fibroblasts, Ppif-KO mice, and human/pig wound models with collagen and closure readouts

    PMID:38564292

    Open questions at the time
    • Mechanism linking a mitochondrial isomerase to ER collagen secretion unknown
    • Whether this reflects MPTP activity or a non-pore CyP-D function unclear
  19. 2024 Medium

    Detailed post-translational control, showing acetylated/oxidized CyP-D (as in sepsis) promotes MPTP opening and lysosomal dysfunction and is reversed via the NAD+/SIRT3 deacetylation axis.

    Evidence LPS sepsis mice, PPIF knockdown in cardiomyocytes, NMN and mito-TEMPO treatment, and CyP-D acetylation/oxidation assays

    PMID:39623043

    Open questions at the time
    • Specific acetylated/oxidized residues not all mapped
    • Single lab; direct SIRT3–CyP-D enzymatic step inferred
  20. 2024 High

    Implicated CyP-D in atherosclerotic necrotic-core formation by linking it to macrophage death, ER-stress cytochrome c release, and necroptosis in vivo.

    Evidence Apoe−/−Ppif−/− double-KO mice and CyP-D siRNA in macrophages with cytochrome c release and necroptosis readouts

    PMID:38972156

    Open questions at the time
    • Mechanism by which CyP-D promotes cytochrome c release not defined
    • Relative contribution of apoptosis vs necroptosis in lesions unresolved

Open questions

Synthesis pass · forward-looking unresolved questions
  • The identity of the structural pore-forming element of the MPTP and the precise inner-membrane protein whose proline CyP-D isomerizes (ANT vs PiC vs OSCP/F-ATP synthase) remain unresolved, as does how a single matrix isomerase governs both lethal and physiological pore openings and non-pore functions such as collagen secretion.
  • No unified structural model reconciling ANT-, PiC-, and OSCP-based mechanisms
  • Mechanism distinguishing transient mitoflash/flickering from lethal sustained opening unknown
  • Non-mitochondrial-death functions (collagen secretion, neurotransmission) mechanistically unexplained

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0016853 isomerase activity 2 GO:0098772 molecular function regulator activity 2 GO:0140096 catalytic activity, acting on a protein 2 GO:0140313 molecular sequestering activity 1
Localization
GO:0005739 mitochondrion 3
Pathway
R-HSA-5357801 Programmed Cell Death 4 R-HSA-382551 Transport of small molecules 2 R-HSA-8953897 Cellular responses to stimuli 2
Partners
HK2MST1OSCPSLC25A4TP53VDAC
Complex memberships
F-ATP synthase (OSCP-bound)mitochondrial permeability transition pore (MPTP)

Evidence

Reading pass · 30 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1991 PPIF (hCyP3) encodes a mitochondria-associated peptidyl-prolyl cis-trans isomerase. The protein was expressed in E. coli, purified, and shown to be an active PPIase; its NH2-terminal hydrophobic extension (42 aa) acts as a signal peptide directing it to subcellular organelles/membranes. Substrate specificity with synthetic Suc-Xaa-Yaa-Pro-Phe-nitroanilide peptides and inhibition by cyclosporin A analogues were characterized. Recombinant protein expression in E. coli, PPIase activity assay with synthetic peptide substrates, kinetic characterization with CsA analogues, protein-specific antibody subcellular fractionation, Northern/Western blot The Journal of Biological Chemistry High 1744118
1999 CyP-D (PPIF) is a key structural component of the mitochondrial permeability transition pore (MPTP). Using a CyP-D fusion protein as affinity matrix, CyP-D was shown to bind strongly to 1:1 complexes of VDAC (outer membrane) and adenine nucleotide translocase (ANT; inner membrane). Covalent labelling of CyP-D in situ by a photoactive CsA derivative demonstrated that pore ligands have the same effects on pore block and CyP-D binding, confirming CsA inhibits the MPTP by binding CyP-D. CyP-D fusion protein affinity pulldown of VDAC/ANT complexes; photoaffinity labelling of CyP-D in situ with CsA derivative; pore reconstitution from protein fractions Biochemical Society Symposium High 10989666
1999 CyP-D forms a complex with VDAC and ANT at contact sites between the mitochondrial inner and outer membranes to constitute the MPTP. Cyclosporin A inhibits pore opening by binding CyP-D, reducing its Ca2+ binding affinity and blocking pore flickering. Under oxidative stress and high Ca2+, the complex opens to allow free diffusion of low-molecular-weight solutes (<1.5 kDa) across the inner membrane. CyP-D affinity matrix pulldown, pore reconstitution, CsA photolabelling, Ca2+ flux assays in isolated mitochondria The Biochemical Journal High 10393078
2002 CyP-D facilitates a Ca2+-triggered conformational change of the ANT that induces MPTP opening; its PPIase activity mediates this conformational facilitation. Oxidative modification of ANT Cys56 increases CyP-D binding to the ANT (likely at Pro61), while modification of Cys159 inhibits adenine nucleotide binding. Reconstitution studies demonstrated that neither VDAC nor other outer membrane proteins are required for minimal MPTP formation. Reconstitution of MPTP from purified ANT ± CyP-D ± VDAC; cysteine-specific chemical modification of ANT; CsA inhibition of PPIase activity correlated with pore inhibition Biochimie High 12022946
2005 Genetic knockout of CyP-D (PPIF) in mice demonstrated that CyP-D is the target for MPTP inhibition by CsA; however, MPTP can still form and open in the absence of CyP-D, indicating that CyP-D is a regulatory sensitizer rather than a structural pore-forming component of the inner mitochondrial membrane. CyP-D knockout mouse mitochondria; MPTP activity assays (Ca2+-induced swelling) ± CsA Journal of Bioenergetics and Biomembranes High 16167169
2007 CyP-D knockout mice (Ppif−/−) showed that CyP-D-dependent MPT is essential for necrotic but not apoptotic cell death, and plays a crucial role in ischemia/reperfusion injury. CyP-D-null mice develop normally and show no protection against diverse apoptotic stimuli. Genetic KO mouse model (Ppif−/−); cell death assays distinguishing necrosis vs apoptosis; ischemia/reperfusion injury models Apoptosis High 17136322
2008 CyP-D's peptidyl-prolyl cis-trans isomerase activity facilitates a conformational change in an inner membrane protein (proposed to be the mitochondrial phosphate carrier, PiC) to induce MPTP opening. ANT knockout studies showed ANT plays a regulatory rather than pore-forming role. CyP-D is proposed to bind PiC and facilitate its Ca2+-triggered conformational change. Genetic KO of ANT isoforms in mice; CyP-D KO; biochemical interaction studies; review of reconstitution data Biochimica et Biophysica Acta Medium 18407825
2010 CyP-D deletion (Ppif−/−) protected mice completely against acetaminophen-induced liver necrosis and DNA fragmentation, demonstrating that CyP-D-dependent MPT is a critical downstream event in APAP hepatotoxicity. Oxidative stress (GSSG levels) and peroxynitrite formation were blunted but not eliminated in CypD-deficient mice, placing oxidant stress at least partly downstream of MPT. Ppif−/− knockout mice treated with APAP; liver histology, DNA fragmentation assay, GSSG measurement, nitrotyrosine immunostaining Free Radical Research High 20942566
2010 CyP-D is required for normal learning and memory: Ppif−/− mice showed deficits in short-term memory, object recognition, reference memory, and associative learning. Hippocampal infusion of CsA replicated these deficits. CyP-D absence reduced stimulus-evoked hippocampal glutamate and acetylcholine release, linking CyP-D to regulation of neurotransmission. Ppif−/− KO mice; behavioral tests (Y-maze, novel object recognition, water maze, fear conditioning); hippocampal microdialysis; CsA hippocampal infusion Hippocampus Medium 19437409
2013 CyP-D (PPIF) deletion or knockdown results in increased cell proliferation, enhanced migration and invasion, and transcriptional upregulation of a chemokine/chemokine receptor gene signature. In the absence of CyP-D, STAT3 is activated, drives accelerated S-phase entry via cell proliferation, and stimulates autocrine/paracrine Cxcl12-Cxcr4-directed chemotaxis, indicating that CyP-D controls mitochondria-to-nucleus inflammatory gene expression. CyP-D knockout/knockdown cells; proliferation assays; migration/invasion assays; transcriptome profiling; STAT3 activation assays; Cxcl12-Cxcr4 signaling analysis The Journal of Biological Chemistry Medium 23303179
2014 In glioma cells, ROS production induced by salinomycin drives p53 translocation to mitochondria, where p53 forms a physical complex with CyP-D. This p53/CyP-D complex is required for MPTP opening and programmed necrosis. Blocking CyP-D by siRNA or pharmacological inhibitors (CsA, sanglifehrin A), or p53 knockdown, suppressed necrosis but not apoptosis. siRNA-mediated CyP-D depletion; Co-immunoprecipitation of p53/CyP-D complex at mitochondria; pharmacological inhibition (CsA, SFA); mitochondrial membrane potential assay; cell death quantification Journal of Experimental & Clinical Cancer Research Medium 26024660
2014 CyP-D is required for berberine-induced programmed necrosis in prostate cancer cells. Berberine-induced ROS production drives p53 mitochondrial translocation, where p53 physically interacts with CyP-D to open the MPTP. shRNA depletion of CyP-D or p53 inhibited necrosis but not apoptosis. CyP-D shRNA; Co-immunoprecipitation of p53/CyP-D at mitochondria; CsA/SFA pharmacological inhibition; mitochondrial membrane potential; flow cytometry Biochemical and Biophysical Research Communications Medium 24946211
2014 MST1 translocates to mitochondria in response to gemcitabine-induced ROS and forms a direct physical complex with CyP-D. This MST1/CyP-D mitochondrial complex is required for MPTP-dependent pancreatic cancer cell death. CsA (CyP-D inhibitor) prevented the MST1/CyP-D complexation and cell death. Co-immunoprecipitation of MST1/CyP-D at mitochondria; shRNA silencing of MST1 or CyP-D; CsA inhibition; overexpression studies; ROS measurement Biochimie Medium 24732633
2015 CyP-D regulates the frequency of mitochondrial 'mitoflash' events (transient MPTP openings under physiological conditions) in cardiomyocytes. CyP-D overexpression increased, and knockout halved, cardiac mitoflash frequency. CyP-D ablation reduced mitochondrial maximal respiration rate and reserved respiratory capacity in cardiomyocytes. The effect of CyP-D on mitoflashes was tissue-specific (cardiac vs skeletal muscle), correlating with 4-fold higher CyP-D expression in cardiac muscle. CyP-D overexpression and knockout in isolated cardiomyocytes, beating hearts, and skeletal muscles in vivo; live imaging of mitochondrial flash activity; Seahorse respirometry Journal of Molecular and Cellular Cardiology High 26746144
2015 PPIF (CyP-D) regulates necrosis but not apoptosis in eosinophils. Ppif−/− eosinophils were protected from Ca2+-overload (ionomycin)- and oxidative stress (H2O2)-induced necrosis and from Siglec-F cross-linking-induced necrosis, with no difference in apoptosis. In vivo, Ppif−/− mice showed reduced eosinophil cytolysis in DSS-induced colitis. Ppif−/− KO mice; ionomycin/H2O2 necrosis assays; flow cytometry for apoptosis vs necrosis; DSS colitis in vivo model American Journal of Physiology: Gastrointestinal and Liver Physiology High 26893161
2015 Necroptotic stimuli require both Bax/Bak oligomerization in the outer mitochondrial membrane and MPTP (CyP-D-dependent) opening in the inner membrane. Ppif−/− fibroblasts are resistant to necroptotic cell death inducers. MLKL and cofilin-1 translocate to mitochondria following necroptosis induction; some of these effects are lost in Ppif−/− cells. Ppif−/− KO fibroblasts; Bax/Bak double-null cells; MLKL/cofilin-1 mitochondrial fractionation; necroptosis induction with TNF/zVAD; cell death assays PLoS ONE Medium 26061004
2019 PPIF-dependent mitochondrial permeability transition mediates crystal-induced (calcium oxalate, monosodium urate, calcium pyrophosphate, silica) necrosis in renal tubular cells. The pathway involves crystal phagocytosis, lysosomal cathepsin leakage, and ROS release. Ppif−/− mice displayed attenuated AKI; dual deletion of Ppif and Mlkl showed partial redundancy between MPT-driven necrosis and necroptosis. Ppif−/− KO mice; Ppif−/−Mlkl−/− double KO mice; in vitro crystal exposure in mouse/human tubular cells; pharmacological MPTP inhibition; histology; fractionation Journal of the American Society of Nephrology High 31296606
2022 BMP/Smad signaling transcriptionally represses the CyP-D gene (Ppif) during osteogenic differentiation of mesenchymal lineage cells, thereby deactivating MPTP. CyP-D 'rescue' via gain-of-function negatively affected osteogenesis both in vitro and in a mouse model, demonstrating that BMP/Smad-driven CyP-D downregulation is functionally required for efficient osteoblast differentiation. BMP/Smad pathway activation in MSCs; Ppif promoter reporter assays; CyP-D overexpression (gain-of-function) in vitro and in mouse model; osteogenic differentiation assays eLife High 35645445
2023 ANT1 (SLC25A4) and CyP-D (PPIF) are both required components of the MPTP governing necrotic cell death in vivo. Deletion of Slc25a4 in dystrophic (Sgcd−/−) mice partially protected from MD pathology; combined deletion of Slc25a4 and Ppif almost completely prevented necrotic cell death and muscular dystrophy disease, providing direct genetic evidence for both proteins as MPTP components. Genetic epistasis: single KO (Slc25a4−/− or Ppif−/−) and double KO (Slc25a4−/−Ppif−/−) in δ-sarcoglycan-null muscular dystrophy mice; histopathology; cell death quantification Science Advances High 37624892
2023 C/EBPα transcriptionally activates the CyP-D gene (Ppif) during adipogenesis of bone marrow stromal cells, increasing CyP-D expression and MPTP activity. NF-κB p65 subunit acts synergistically with C/EBPα to induce Ppif expression, linking adipogenic and inflammatory signaling to MPTP gain-of-function. Ppif promoter reporter assays; ChIP for C/EBPα and NF-κB p65 at Ppif promoter; adipogenic induction of BMSCs; CyP-D/MPTP activity measurement The Journal of Biological Chemistry Medium 37949231
2024 N-terminal cleavage of CyP-D (removing first 13 human residues) by calpain 1 generates a ΔN-CyPD form. NMR studies showed the N-terminus of full-length CyP-D is highly flexible. ΔN-CyPD binds the OSCP subunit of F-ATP synthase in saline media, whereas FL-CyPD does not, indicating the N-terminus substantially reduces affinity for OSCP. CyP-D binding to OSCP inhibits ATP synthase catalysis and favors transition of the enzyme to the permeability transition pore. NMR structure of FL- and ΔN-CyPD; binding assays with F-ATP synthase OSCP subunit; calpain 1 treatment of cells; mass spectrometry identification of ΔN-CyPD in cells Communications Biology High 39528709
2024 Senescent cells exhibit high frequency of transient CyP-D/MPTP opening events ('flickering'). Genetic or pharmacological inhibition of CyP-D (PPIF) causes toxic mitochondrial Ca2+ accumulation and selective death of senescent cells (senolysis). Inhibition of NCLX (another mitochondrial Ca2+ efflux channel) also induces senolysis, while inhibition of MCU (Ca2+ influx) prevents CyP-D inhibition-induced senolysis, placing transient CyP-D/MPTP opening as a Ca2+ efflux mechanism critical for senescent cell survival. Genome-wide CRISPR/Cas9 screen; Ppif genetic KO; CsA pharmacological inhibition; NCLX and MCU inhibition/knockout; mitochondrial Ca2+ imaging; senescent cell viability assays The EMBO Journal High 39448884
2024 Nynrin is a transcriptional repressor of Ppif (CyP-D gene). Nynrin knockout in cardiomyocytes enhanced Ppif transcription, increased CyP-D expression, promoted MPTP opening, and exacerbated ischemia/reperfusion injury. CsA treatment reversed the exacerbated phenotype. Nynrin overexpression blunted Ppif/CyP-D upregulation and reduced cardiomyocyte damage during OGD/R. Tamoxifen-inducible cardiomyocyte-specific Nynrin KO; Nynrin overexpression in primary cardiomyocytes; Ppif promoter regulation assays; MPTP opening assay; I/R injury model Cell Stem Cell (for PMID 38955185); Journal of Molecular and Cellular Cardiology (for PMID 41077266) High 38955185 41077266
2024 CyP-D (PPIF) is upregulated in wounds and venous ulcers. Inhibition of CyP-D impaired keratinocyte reepithelialization, granulation tissue formation, and wound closure in human and pig models. CyP-D inhibition in fibroblasts reduced collagen secretion and caused ER collagen accumulation; CyP-D overexpression increased collagen secretion. Ppif-KO mice showed reduced skin collagen. CyP-D inhibition (CsA) in human and pig wound models; CyP-D overexpression in keratinocytes/fibroblasts; Ppif-KO mice; collagen secretion and ER retention assays; migration assays JCI Insight High 38564292
2024 CyP-D mediates macrophage death in atherosclerotic lesions and necrotic core formation. CyP-D knockdown in macrophages attenuated cytochrome c release from mitochondria induced by ER stress (thapsigargin) and blocked necroptosis induced by TNF-α/caspase inhibitor. Apoe−/−Ppif−/− double-KO mice had smaller necrotic cores with reduced macrophage apoptosis and decreased inflammatory monocytes. Apoe−/−Ppif−/− double-KO mouse model; siRNA knockdown of CyP-D in RAW264.7 cells; cytochrome c release assay; necroptosis induction; atherosclerosis lesion histology Atherosclerosis High 38972156
2024 Neutrophil PPIF exacerbates lung ischemia-reperfusion injury by promoting calcium overload-induced NETosis. PPIF inhibition (CsA) protected mitochondrial function by alleviating store-operated calcium entry (SOCE) during calcium overload in neutrophils. The reduction in calcium was accompanied by inhibition of calcineurin and NFAT, preventing NETs formation. Orthotopic lung transplant I/R model in mice; PPIF inhibitor (CsA) in vivo; HL-60-derived neutrophil model in vitro; SOCE measurement; calcineurin/NFAT assays; NETs quantification International Immunopharmacology Medium 39236457
2024 PPIF (CyP-D), when acetylated and oxidized (as occurs in sepsis), promotes MPTP opening and lysosomal dysfunction. NMN treatment prevented PPIF acetylation and oxidation via NAD+/Sirtuin 3 axis, reduced mitochondrial ROS, and protected against sepsis-induced myocardial dysfunction. PPIF knockdown replicated the beneficial effects of NMN or mitochondria-targeted ROS scavenging. LPS-induced sepsis in mice; PPIF knockdown in neonatal cardiomyocytes; NMN and mito-TEMPO treatment; PPIF acetylation and oxidation assays; lysosomal function assays; echocardiography Acta Pharmacologica Sinica Medium 39623043
2023 PPIF/CyP-D mediates the effect of CsA and alisporivir (ALV) on increasing mutant type IV collagen α345 trimer secretion in Alport syndrome cells. Knockdown of PPIF abolished the trimer secretion-enhancing activity of CsA and ALV, identifying CyP-D as a regulator of intracellular type IV collagen processing and secretion. Nanoluciferase-based α345(IV) trimer secretion assay; siRNA knockdown of PPIF and other cyclophilins; CsA/ALV treatment; comparison of Cn-binding vs Cyp-binding CsA derivatives Kidney360 Medium 37143203
2022 All eight cyclophilins tested, including PPIF (cyclophilin D), prevented in vitro tau aggregation in a Thioflavin T fluorescence assay. However, in a cellular model of tau accumulation, PPIF did not reduce insoluble tau levels, unlike most other cyclophilins, suggesting PPIF's enzymatic activity can suppress tau fibrillation in vitro but this does not translate to cellular protection against tau accumulation. Thioflavin T fluorescence aggregation assay with recombinant cyclophilins; cellular tau accumulation model; tau seeding assays Protein Science Low 36305768
2025 Hexokinase 2 (HK2) regulates airway epithelial apoptosis and inflammation via physical interaction with PPIF, independent of VDAC1. HK2 knockdown and pharmacological inhibition attenuated airway inflammation and hyperresponsiveness in asthma mouse models. HK2-PPIF co-immunoprecipitation/interaction assay; airway epithelium-specific HK2 knockdown; 2-DG pharmacological inhibition; OVA/LPS asthma mouse model; apoptosis and inflammation readouts Cells Low 40643524

Source papers

Stage 0 corpus · 88 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1999 The mitochondrial permeability transition pore and its role in cell death. The Biochemical journal 1892 10393078
2009 What is the mitochondrial permeability transition pore? Journal of molecular and cellular cardiology 749 19265700
2002 The permeability transition pore complex: another view. Biochimie 591 12022946
2021 Genome-wide enhancer maps link risk variants to disease genes. Nature 477 33828297
2007 Role of the mitochondrial membrane permeability transition in cell death. Apoptosis : an international journal on programmed cell death 449 17136322
2006 Calcium, mitochondria and reperfusion injury: a pore way to die. Biochemical Society transactions 414 16545083
2009 The role of the mitochondrial permeability transition pore in heart disease. Biochimica et biophysica acta 293 19168026
2008 Recent progress in elucidating the molecular mechanism of the mitochondrial permeability transition pore. Biochimica et biophysica acta 266 18407825
1991 The cyclophilin multigene family of peptidyl-prolyl isomerases. Characterization of three separate human isoforms. The Journal of biological chemistry 185 1744118
2003 Cyclophilin D as a drug target. Current medicinal chemistry 184 12871122
1999 The mitochondrial permeability transition pore. Biochemical Society symposium 165 10989666
2010 Signal transduction to the permeability transition pore. FEBS letters 151 20153328
2006 Mitochondrial membrane permeability transition and cell death. Biochimica et biophysica acta 148 16716247
2013 Mitochondrial permeability transition and cell death: the role of cyclophilin d. Frontiers in physiology 133 23596421
2010 Cyclophilin D deficiency protects against acetaminophen-induced oxidant stress and liver injury. Free radical research 110 20942566
1999 Cyclophilins and their possible role in the stress response. International journal of experimental pathology 110 10632780
2019 Mitochondria Permeability Transition versus Necroptosis in Oxalate-Induced AKI. Journal of the American Society of Nephrology : JASN 98 31296606
2011 The mitochondrial permeability transition pore and cyclophilin D in cardioprotection. Biochimica et biophysica acta 97 21295622
2015 ROS-p53-cyclophilin-D signaling mediates salinomycin-induced glioma cell necrosis. Journal of experimental & clinical cancer research : CR 96 26024660
2024 Nynrin preserves hematopoietic stem cell function by inhibiting the mitochondrial permeability transition pore opening. Cell stem cell 91 38955185
2009 Mitochondria and reperfusion injury of the heart--a holey death but not beyond salvation. Journal of bioenergetics and biomembranes 90 19357938
2015 Necroptosis Interfaces with MOMP and the MPTP in Mediating Cell Death. PloS one 89 26061004
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
2005 Genetic dissection of the permeability transition pore. Journal of bioenergetics and biomembranes 61 16167169
2019 Deficiency of Mitochondrial Glycerol 3-Phosphate Dehydrogenase Contributes to Hepatic Steatosis. Hepatology (Baltimore, Md.) 49 30653687
2019 Alcohol and DNA Methylation: An Epigenome-Wide Association Study in Blood and Normal Breast Tissue. American journal of epidemiology 48 30938765
2014 Mitochondrial protein cyclophilin-D-mediated programmed necrosis attributes to berberine-induced cytotoxicity in cultured prostate cancer cells. Biochemical and biophysical research communications 45 24946211
2013 Cyclophilin D extramitochondrial signaling controls cell cycle progression and chemokine-directed cell motility. The Journal of biological chemistry 42 23303179
2014 Gemcitabine-induced pancreatic cancer cell death is associated with MST1/cyclophilin D mitochondrial complexation. Biochimie 39 24732633
2023 ANT-dependent MPTP underlies necrotic myofiber death in muscular dystrophy. Science advances 35 37624892
2019 Downregulation of microRNA‑199a‑5p attenuates hypoxia/reoxygenation‑induced cytotoxicity in cardiomyocytes by targeting the HIF‑1α‑GSK3β‑mPTP axis. Molecular medicine reports 35 31059047
2018 DNA Methylation and Age-Independent Cardiovascular Risk, an Epigenome-Wide Approach: The REGICOR Study (REgistre GIroní del COR). Arteriosclerosis, thrombosis, and vascular biology 35 29326313
2018 Mitochondrial permeability regulates cardiac endothelial cell necroptosis and cardiac allograft rejection. American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons 35 30203531
2015 Cyclophilin D regulates mitochondrial flashes and metabolism in cardiac myocytes. Journal of molecular and cellular cardiology 26 26746144
2022 Transcriptional regulation of cyclophilin D by BMP/Smad signaling and its role in osteogenic differentiation. eLife 23 35635445
2024 Cyclophilin D plays a critical role in the survival of senescent cells. The EMBO journal 20 39448884
2022 Regulation of p53 Function by Formation of Non-Nuclear Heterologous Protein Complexes. Biomolecules 20 35204825
2010 The role of cyclophilin D in learning and memory. Hippocampus 19 19437409
2019 CypD deficiency confers neuroprotection against mitochondrial abnormality caused by lead in SH-SY5Y cell. Toxicology letters 18 31874198
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 17 34455488
2022 Targeting mitochondrial dysfunctions in pancreatic cancer evokes new therapeutic opportunities. Critical reviews in oncology/hematology 16 36257540
2024 Activation of BK channels prevents diabetes-induced osteopenia by regulating mitochondrial Ca2+ and SLC25A5/ANT2-PINK1-PRKN-mediated mitophagy. Autophagy 14 38873928
2022 Chaperoning activity of the cyclophilin family prevents tau aggregation. Protein science : a publication of the Protein Society 13 36305768
2019 Cyclophilin D knockout protects the mouse kidney against cyclosporin A-induced oxidative stress. American journal of physiology. Renal physiology 13 31188033
2023 Mitochondrial permeability transition regulator, cyclophilin D, is transcriptionally activated by C/EBP during adipogenesis. The Journal of biological chemistry 12 37949231
2022 Inhibition of the BNIP3/NIX-dependent mitophagy aggravates copper-induced mitochondrial dysfunction in duck renal tubular epithelial cells. Environmental toxicology 12 36378575
2024 Nicotinamide mononucleotide protects septic hearts in mice via preventing cyclophilin F modification and lysosomal dysfunction. Acta pharmacologica Sinica 11 39623043
2023 Identification of novel immune subtypes and potential hub genes of patients with psoriasis. Journal of translational medicine 11 36890558
2016 Cyclophilin D regulates necrosis, but not apoptosis, of murine eosinophils. American journal of physiology. Gastrointestinal and liver physiology 9 26893161
2024 Neutrophil PPIF exacerbates lung ischemia-reperfusion injury after lung transplantation by promoting calcium overload-induced neutrophil extracellular traps formation. International immunopharmacology 8 39236457
2022 Global landscape of protein complexes in postprandial-state livers from diet-induced obese and lean mice. Biochemical and biophysical research communications 8 36099783
2020 Genome Regulation and Gene Interaction Networks Inferred From Muscle Transcriptome Underlying Feed Efficiency in Pigs. Frontiers in genetics 8 32655625
2022 miR-23a contributes to T cellular redox metabolism in juvenile idiopathic oligoarthritis. Rheumatology (Oxford, England) 7 34559194
2024 Role of the mitochondrial protein cyclophilin D in skin wound healing and collagen secretion. JCI insight 6 38564292
2024 Cyclophilin D induces necrotic core formation by mediating mitochondria-associated macrophage death in advanced atherosclerotic lesions. Atherosclerosis 6 38972156
2024 N-terminal cleavage of cyclophilin D boosts its ability to bind F-ATP synthase. Communications biology 6 39528709
2023 Preliminary Study of the Distinctive Mechanism of Shenqi Compound in Treating Rats with Type 2 Diabetes Mellitus by Comparing with Metformin. Current vascular pharmacology 6 36752289
2022 Cinnamtannin B-1 Inhibits the Progression of Osteosarcoma by Regulating the miR-1281/PPIF Axis. Biological & pharmaceutical bulletin 6 36273900
2025 Senolysis by GLS1 Inhibition Ameliorates Kidney Aging by Inducing Excessive mPTP Opening Through MFN1. The journals of gerontology. Series A, Biological sciences and medical sciences 5 39697097
2016 Silence of the ROS. Immunity 5 26982360
2023 Neutrophil extracellular trap is an important connection between hemodialysis and acute myocardial infarction. Renal failure 4 37246754
2023 Molecular signature associated with cladribine treatment in patients with multiple sclerosis. Frontiers in immunology 4 37559720
2022 Integrated transcriptomics and metabolomics unravel the metabolic pathway variations for barley β-glucan before and after fermentation with L. plantarum DY-1. Food & function 4 35302565
2020 Trypanosoma cruzi infection in Cyclophilin D deficient mice. Experimental parasitology 4 33253715
2025 Upregulated Hexokinase-2 in Airway Epithelium Regulates Apoptosis and Drives Inflammation in Asthma via Peptidylprolyl Isomerase F. Cells 3 40643524
2025 PPIF+ neutrophils promote mtROS driven NETosis mediated progression of colorectal cancer. Journal of translational medicine 3 41219985
2024 Cyclophilin D, regulator of the mitochondrial permeability transition, impacts bone development and fracture repair. Bone 3 39299628
2023 CyclosporinA Derivative as Therapeutic Candidate for Alport Syndrome by Inducing Mutant Type IV Collagen Secretion. Kidney360 3 37143203
2023 A ferroptosis-related ceRNA network in hepatocellular carcinoma for potential clinical applications. American journal of translational research 3 37434825
2016 Autumnalamide targeted proteins of the immunophilin family. Immunobiology 3 27720433
2025 Genetic Markers of Postmortem Brain Iron. Journal of neurochemistry 2 39918201
2025 Housekeeping gene dysregulation in psoriasis: integrative multi-cohort and single-cell analysis reveals keratinocyte-centric molecular mechanisms and diagnostic biomarkers. Frontiers in immunology 2 40959079
2025 Nynrin enhances cardiac function by inhibiting mitochondrial permeability transition pore opening upon myocardial ischemia/reperfusion injury. Journal of molecular and cellular cardiology 2 41077266
2023 Mitochondrial Permeability Transition in Stem Cells, Development, and Disease. Advances in experimental medicine and biology 2 35739412
2022 Characterization of DNA methylation as well as mico-RNA expression and screening of epigenetic markers in adipogenesis. Journal of translational medicine 2 35168604
2026 Apolipoprotein E drives microglia activation in the development of autoimmune uveitis through up-regulation of peptidyl prolyl isomerase F. Science advances 1 41477830
2025 CNV-mediated dysregulation of the ceRNA network mechanism revealed heterogeneity in diffuse and intestinal gastric cancers. Journal of translational medicine 1 40069783
2025 Discovery of novel ancestry specific genes for androgens and hypogonadism in Million Veteran Program Men. Nature communications 1 40316537
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
2023 Computational insight of antioxidant and doxorubicin combination for effective cancer therapy. Journal of biomolecular structure & dynamics 1 37545163
2020 Constitutive cyclophilin-D ablation in mice increases exercise and cognitive-behavioral performance under normoxic and hypoxic conditions. Physiology & behavior 1 32061681
2026 Integrated single-cell and transcriptomic profiling identifies machine-learning-based pyroptosis biomarkers in IBD. Frontiers in immunology 0 41716401
2025 Unveiling the role of PPIF and macrophage subtypes in LSCC progression via single-cell and exosome RNA sequencing. Scientific reports 0 40128571
2025 Identification and experimental validation of mitochondrial and endoplasmic reticulum stress related gene in diabetic nephropathy. Scientific reports 0 40775242
2025 Interplay between acute Type A aortic dissection and pan-cancer: Clinical evidence, bioinformatics, and experimental validation. iScience 0 41142117
2025 Ppif Gene Knockout Alleviates Pancreatic Injury in Mice With Cecal Ligation and Puncture-induced Sepsis. The Journal of surgical research 0 41270585
2024 Genetic analysis from multiple cohorts implies causality between 2200 druggable genes, telomere length, and leukemia. Computers in biology and medicine 0 39216403

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