Affinage

PGAM5

Serine/threonine-protein phosphatase PGAM5, mitochondrial · UniProt Q96HS1

Length
289 aa
Mass
32.0 kDa
Annotated
2026-06-10
100 papers in source corpus 46 papers cited in narrative 46 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

PGAM5 is a mitochondrial Ser/Thr/His phosphatase that functions as a stress-responsive signaling hub coupling mitochondrial status to dynamics, programmed cell death, immune signaling, and metabolism (PMID:22265414, PMID:31367011, PMID:30705304). It is anchored in the mitochondrial membrane through an N-terminal transmembrane domain and, upon loss of membrane potential, is cleaved within that domain by the rhomboid protease PARL, which reciprocally dissociates from PINK1 to associate with PGAM5; uncoupling triggers disassembly of membrane-embedded PGAM5 oligomers into PARL-cleavable monomers, releasing active PGAM5 into the cytosol and nucleus (PMID:22915595, PMID:35921890, PMID:30247576). PGAM5 catalytic activity is allosterically governed by its oligomeric state: N-terminal regulatory motifs order the catalytic loop and drive assembly into enzymatically active dimers, dodecamers, and filaments, and the oligomeric equilibrium dictates substrate selection, with dimers dephosphorylating BCL-xL-Ser62 to restrain apoptosis and multimerization redirecting activity toward FUNDC1 to activate mitophagy (PMID:28648608, PMID:30705304, PMID:31367011). Through its phosphatase activity PGAM5 controls mitochondrial dynamics by dephosphorylating Drp1-Ser637 to drive fission and necrosis, and by dephosphorylating MFN2 to protect it from degradation and promote fusion (PMID:22265414, PMID:37498743, PMID:32439975). It activates receptor-mediated mitophagy by dephosphorylating FUNDC1-Ser13 and stabilizes the PINK1 mitophagy pathway, loss of which causes dopaminergic neurodegeneration in mice (PMID:24746696, PMID:25222142). PGAM5 additionally acts as a scaffold: it forms a ternary complex with KEAP1 and Nrf2 that tethers antioxidant signaling to mitochondria and whose disruption by ROS-mediated KEAP1 oxidation stabilizes PGAM5, and it engages MAVS to promote TBK1/IRF3-dependent IFN-β production and phase-separates with MAVS to recruit NLRP3 (PMID:18387606, PMID:34801863, PMID:32433485, PMID:38409220). Released cytosolic PGAM5 antagonizes Wnt/β-catenin signaling by dephosphorylating DVL2 and activates YAP signaling by dephosphorylating MST3 (PMID:28506997, PMID:39915446). PGAM5 protein levels are tuned by KEAP1-Cul3 and MARCH2-mediated ubiquitination versus OTUD1- and USP11-mediated deubiquitination and SIRT2-mediated deacetylation (PMID:18387606, PMID:38409220, PMID:39309432, PMID:39300548, PMID:37580952).

Mechanistic history

Synthesis pass · year-by-year structured walk · 22 steps
  1. 2006 High

    Established that PGAM5 is a regulated target of the KEAP1-Cul3 ubiquitin ligase and physically links to apoptotic machinery, framing it as a stress-regulated protein rather than a constitutive enzyme.

    Evidence Co-IP, domain-mapping, and ubiquitination/proteasome assays in cells

    PMID:17046835

    Open questions at the time
    • Did not define PGAM5 catalytic substrates
    • Functional consequence of Bcl-XL binding not established
  2. 2008 High

    Showed PGAM5 is mitochondrially targeted and bridges KEAP1 to Nrf2 in a ternary complex, defining a scaffolding role that tethers antioxidant signaling to mitochondria.

    Evidence Fractionation, live-cell imaging, co-IP, and siRNA with Nrf2 reporter assays

    PMID:18387606

    Open questions at the time
    • Mechanism connecting complex to Nrf2 release unresolved
    • No phosphatase activity addressed
  3. 2010 High

    Placed PGAM5 genetically in the PINK1 mitochondrial maintenance pathway, the first in vivo link between PGAM5 and mitochondrial quality control.

    Evidence PINK1 co-purification and Drosophila genetic epistasis

    PMID:21151955

    Open questions at the time
    • Biochemical mechanism downstream of PINK1 binding unclear
    • Relationship to Parkin ambiguous
  4. 2012 High

    Identified PGAM5 as a Drp1-Ser637 phosphatase within RIP1/RIP3 necrotic complexes, providing the first defined substrate and linking it to mitochondrial fission and necrosis execution.

    Evidence In vitro phosphatase assay on Drp1-S637, co-IP, knockdown with morphology readouts

    PMID:22265414

    Open questions at the time
    • Necrosis-promoting role later contested by KO studies
    • Isoform-specific contributions not fully resolved
  5. 2012 High

    Defined the PARL-mediated intramembrane cleavage that converts membrane-potential loss into PGAM5 activation, with reciprocal PARL handling of PINK1 versus PGAM5.

    Evidence Cleavage assays, reciprocal co-IP, PARL knockout, membrane-potential manipulation

    PMID:22915595

    Open questions at the time
    • Fate of cleaved PGAM5 not yet traced
    • Structural basis of differential cleavage unaddressed
  6. 2014 High

    Showed PGAM5 dephosphorylates FUNDC1-Ser13 to activate receptor-mediated mitophagy, and that BCL-xL inhibits this via its BH3 domain, establishing a substrate-level switch for mitophagy.

    Evidence In vitro phosphatase assays, domain mapping, mitophagy flux assays, knockdown

    PMID:24746696 PMID:25126723

    Open questions at the time
    • How CK2 and PGAM5 competition is spatially controlled unknown
    • Trigger for PGAM5 activation under hypoxia incompletely defined
  7. 2014 High

    Demonstrated PGAM5 is required to stabilize PINK1 on damaged mitochondria, with loss causing parkinsonian neurodegeneration in mice, establishing physiological relevance to neurodegeneration.

    Evidence Pgam5 KO mice, PINK1 fractionation, mitophagy assays, behavioral and histological phenotyping

    PMID:25222142

    Open questions at the time
    • Direct biochemical mechanism of PINK1 stabilization unclear
    • No Mendelian disease mutation identified in humans
  8. 2015 Medium

    Extended PGAM5 function to adaptive and innate immunity, showing roles in RIPK3-driven NKT cell activation and in NLRP3/AIM2 inflammasome-dependent IL-1β secretion via ASC polymerization and ROS.

    Evidence Ripk3-/- and Pgam5-/- mice, NFAT localization, IL-1β ELISA, ASC speck and ROS assays

    PMID:26381214 PMID:26582950

    Open questions at the time
    • Direct substrates in immune cells not all defined
    • Necroptosis dependence varies between models
  9. 2016 High

    Revised the necroptosis model by showing PGAM5 loss exacerbates rather than blocks necroptosis through failed PINK1-dependent mitophagy and ROS accumulation, reframing its role as mitochondrial quality control.

    Evidence Pgam5 KO mice, EM, ischemia/reperfusion models

    PMID:26807733

    Open questions at the time
    • Context-dependence of pro- vs anti-necroptotic roles unresolved
    • Reconciliation with earlier necrosome data incomplete
  10. 2016 High

    Identified PGAM5 as a phosphohistidine phosphatase acting on NDPK-B, expanding its catalytic repertoire beyond Ser/Thr and linking it to ion-channel control and T-cell activation.

    Evidence In vitro pHis phosphatase assay, phospho-His antibodies, KCa3.1 channel and T-cell cytokine assays

    PMID:27453048

    Open questions at the time
    • Breadth of pHis substrate repertoire unknown
    • In vivo relevance of T-cell phenotype not tested
  11. 2017 High

    Solved structures showing oligomerization-coupled allosteric activation, defining how N-terminal motifs assemble active dimers and dodecamers and order the catalytic loop.

    Evidence X-ray crystallography, HX-MS, SEC, analytical ultracentrifugation

    PMID:28648608

    Open questions at the time
    • How physiological signals shift oligomeric state in cells not addressed structurally
    • Filament-level assembly not yet resolved
  12. 2017 High

    Established PGAM5 as a phosphatase-dependent antagonist of Wnt/β-catenin via DVL2 dephosphorylation, with developmental importance for axis patterning.

    Evidence In vitro DVL2 dephosphorylation, co-IP, Xenopus loss-of-function, phosphatase-dead mutants

    PMID:28506997

    Open questions at the time
    • Apparent contradiction with later cytosolic β-catenin-promoting role via axin
    • Spatial control of opposing Wnt outputs unclear
  13. 2017 Medium

    Linked the PGAM5-KEAP1-Nrf2 complex to mitochondrial retrograde trafficking by controlling KEAP1-Cul3-mediated Miro2 degradation, and connected mitochondrial stress to FoxO/ASK1/JNK longevity signaling.

    Evidence Component knockdown with rescue, Miro2 degradation assays, Drosophila lifespan epistasis

    PMID:28839075 PMID:28891792

    Open questions at the time
    • Direct phosphatase substrates in trafficking unidentified
    • Mammalian relevance of FoxO axis untested
  14. 2018 High

    Traced the fate of cleaved PGAM5 to the cytosol where it binds axin and promotes β-catenin-driven mitochondrial biogenesis, establishing a mitochondrion-to-nucleus retrograde signal.

    Evidence Co-IP, β-catenin reporters, Pgam5/PARL KO cells, mitochondrial number quantification

    PMID:29438981

    Open questions at the time
    • How this reconciles with PGAM5 inhibition of β-catenin via DVL2 unresolved
    • Determinants of cytosolic substrate switching unclear
  15. 2018 Medium

    Identified Syntaxin 17 and an AMPK-KEAP1 axis as upstream regulators of PGAM5 localization, aggregation, and ubiquitin-dependent turnover during necroptosis and mitophagy.

    Evidence Stx17 knockdown with morphology/co-IP readouts; AMPK-PGAM5-Keap1 co-IP and ubiquitination assays

    PMID:29579593 PMID:30237312

    Open questions at the time
    • Mechanism of Stx17-controlled PGAM5 distribution incompletely defined
    • AMPK study from single lab
  16. 2019 High

    Unified oligomeric state with substrate choice, showing dimeric PGAM5 targets BCL-xL-Ser62 (anti-apoptotic) while multimerization redirects activity to FUNDC1 (mitophagy), and resolved dodecamer/filament assembly by cryo-EM.

    Evidence In vitro phosphatase assays on two substrates, oligomeric analysis, cryo-EM and crystallography

    PMID:30705304 PMID:31367011

    Open questions at the time
    • In-cell triggers driving the dimer-multimer transition not fully mapped
    • Filament function beyond catalysis incompletely defined
  17. 2019 Medium

    Refined the release mechanism (proteasome-dependent OMM rupture) and broadened substrate scope to nuclear SR proteins, Lipin-1, and the PHB2/PARL/PINK1 mitophagy axis.

    Evidence Fractionation in ±Parkin cells, co-IP, MS substrate ID, nuclear phosphatase assays

    PMID:30247576 PMID:30642635 PMID:31177901 PMID:33872670

    Open questions at the time
    • Functional impact of nuclear SR-protein dephosphorylation unconfirmed in vivo
    • Several substrates from single-lab co-IP/MS
  18. 2020 High

    Demonstrated that PGAM5-driven Drp1 dephosphorylation restrains senescence and mTOR/IFN signaling, and that PGAM5 cleavage suppresses UCP1 in brown adipocytes, tying it to aging and metabolism.

    Evidence PGAM5 KO cells/mice with Drp1 mutant rescue; phosphatase-dead rescue and siRNA screen in adipocytes

    PMID:32144202 PMID:32439975

    Open questions at the time
    • UCP1 study confidence moderate and single lab
    • Direct substrate mediating UCP1 suppression unidentified
  19. 2021 Medium

    Established PGAM5 as a node in antiviral and ROS-sensing signaling: it engages MAVS to drive TBK1/IRF3-dependent IFN-β, and the ROS-sensitive KEAP1-PGAM5 interaction controls PINK1 processing and mitophagy.

    Evidence Co-IP, PGAM5 KO MEFs, IFN/VSV assays; KEAP1-PGAM5 disruption and PINK1 processing assays

    PMID:32433485 PMID:33913175 PMID:34801863

    Open questions at the time
    • Whether IFN-β signaling effects require catalysis or scaffolding unclear
    • STAT5-PGAM5-Drp1 axis from single lab
  20. 2022 High

    Resolved the structural logic of PARL cleavage by NMR, identifying polar TM residues and a membrane-potential-dependent oligomeric switch, and added PHB2-Ser91 as a disease-relevant substrate.

    Evidence NMR of TM domain with mutagenesis and cleavage assays; PHB2-S91 phospho-mutants and knockin mice

    PMID:35921890 PMID:39285950

    Open questions at the time
    • How uncoupling mechanically destabilizes oligomers not visualized
    • Generality of substrate phosphosite recognition unknown
  21. 2023 Medium

    Expanded PGAM5 substrate networks to MFN2 (promoting fusion), Bax (promoting apoptosis), MST3 (activating YAP), and ME1 (lipid metabolism via SIRT2 deacetylation), and added BNIP3 stabilization and ASK1-coupled inflammation.

    Evidence Co-IP, in vitro dephosphorylation, KO/KI mice, Drosophila epistasis, enzyme-activity assays

    PMID:37498743 PMID:37580952 PMID:37684381 PMID:37882521 PMID:38919131 PMID:39915446

    Open questions at the time
    • Several substrates rest on single-lab co-IP/dephosphorylation
    • How one phosphatase achieves opposing fusion/fission and pro/anti-apoptotic outputs context-dependently unresolved
  22. 2024 Medium

    Defined phase separation with MAVS to recruit NLRP3 and a ubiquitin/deubiquitin code (MARCH2 degradation; OTUD1, USP11 stabilization) and cytosolic RIPK1-Ser166 phosphorylation driving PANoptosis.

    Evidence Phase separation and K48-ubiquitination assays, KO/AAV rescue, deubiquitination assays, co-IP, in vivo disease models

    PMID:38409220 PMID:38433252 PMID:39300548 PMID:39309432 PMID:39603487

    Open questions at the time
    • Whether RIPK1-Ser166 is a direct kinase activity of PGAM5 needs reconciliation with its phosphatase identity
    • Tissue-specific dominance of competing regulators unclear

Open questions

Synthesis pass · forward-looking unresolved questions
  • How a single mitochondrial phosphatase selects among dozens of opposing substrates and outputs (fission vs fusion, apoptosis vs survival, pro- vs anti-inflammatory) in a context-specific manner remains the central unresolved question.
  • No unified model linking oligomeric state, localization, and substrate selection across all reported substrates
  • Apparent kinase-like activity on RIPK1 conflicts with phosphatase mechanism
  • No human Mendelian disease association established despite mouse neurodegeneration phenotype

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 9 GO:0016787 hydrolase activity 4 GO:0098772 molecular function regulator activity 4 GO:0060090 molecular adaptor activity 3
Localization
GO:0005739 mitochondrion 5 GO:0005829 cytosol 3 GO:0005634 nucleus 1
Pathway
R-HSA-168256 Immune System 5 R-HSA-9612973 Autophagy 5 R-HSA-162582 Signal Transduction 4 R-HSA-5357801 Programmed Cell Death 4 R-HSA-1852241 Organelle biogenesis and maintenance 3
Partners
BCL2L1DNM1LDVL2FUNDC1KEAP1MAVSMFN2PARL
Complex memberships
PGAM5 dodecamer/filamentPGAM5-KEAP1-Nrf2 complexPGAM5-MAVS condensateRIP1/RIP3 necrosome

Evidence

Reading pass · 46 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2006 PGAM5 was identified as a novel substrate for the Keap1-Cul3 ubiquitin ligase complex. The N-terminal NXESGE motif of PGAM5 binds the Kelch domain of Keap1, leading to Keap1-dependent ubiquitination and proteasomal degradation of PGAM5. Oxidative stress (quinone, sulforaphane) inhibits this ubiquitination. The C-terminal PGAM domain binds Bcl-XL. Co-immunoprecipitation, ubiquitination assays, domain-mapping pulldowns, proteasome inhibitor experiments The Journal of biological chemistry High 17046835
2008 PGAM5 is targeted to the outer membrane of mitochondria by an N-terminal mitochondrial-localization sequence and forms a ternary complex with both Keap1 and Nrf2, in which dimeric Keap1 simultaneously binds PGAM5 and Nrf2 through their conserved E(S/T)GE motifs. Knockdown of either Keap1 or PGAM5 activates Nrf2-dependent gene expression. Subcellular fractionation, live-cell imaging, co-immunoprecipitation, siRNA knockdown with reporter assays Experimental cell research High 18387606
2010 In Drosophila, PGAM5 (dPGAM5) physically binds PINK1 and acts as a negative regulator in the PINK1 pathway for mitochondrial maintenance. Loss of dPGAM5 suppresses muscle degeneration, motor defects, and shortened lifespan caused by dPINK1 inactivation, but does not modify parkin mutant phenotypes, placing PGAM5 between PINK1 and Parkin or independently of Parkin downstream of PINK1. Biochemical co-purification of PINK1-binding proteins, Drosophila genetic epistasis (double mutants), overexpression phenotype analysis PLoS genetics High 21151955
2012 PGAM5 (as two splice variants, PGAM5L and PGAM5S) is a component of RIP1- and RIP3-containing necrotic complexes. Upon necrosis induction, PGAM5S recruits the mitochondrial fission factor Drp1 and activates its GTPase activity by dephosphorylating Drp1 at serine 637, causing mitochondrial fragmentation required for necrosis execution. Knockdown of either PGAM5 isoform attenuated necrosis induced by TNF-α, ROS, and calcium ionophore. Co-immunoprecipitation, in vitro phosphatase assay with Drp1-S637, siRNA knockdown, mitochondrial morphology imaging Cell High 22265414
2012 PGAM5 is cleaved within its N-terminal transmembrane domain by the mitochondrial rhomboid protease PARL in response to mitochondrial membrane potential (ΔΨm) loss. PARL dissociates from PINK1 and reciprocally associates with PGAM5 upon ΔΨm loss, providing a mechanism for differential cleavage of PINK1 vs. PGAM5 depending on mitochondrial health. Biochemical cleavage assays, co-immunoprecipitation, PARL knockout/knockdown, membrane potential manipulation The Journal of biological chemistry High 22915595
2014 PGAM5 interacts with and dephosphorylates the mitophagy receptor FUNDC1 at serine 13 (Ser-13) upon hypoxia or FCCP treatment, enhancing FUNDC1's interaction with LC3 to activate mitophagy. CK2 phosphorylates FUNDC1 at Ser-13 to reverse this effect. BCL2L1/Bcl-xL inhibits PGAM5 to prevent FUNDC1 dephosphorylation and suppress mitophagy. Co-immunoprecipitation, in vitro phosphatase assay, cell-permeable peptide experiments, siRNA knockdown, mitophagy flux assays Molecular cell High 24746696
2014 BCL2L1/Bcl-xL (but not BCL2) suppresses FUNDC1-mediated mitophagy through interaction with and inhibition of PGAM5 via its BH3 domain, preventing dephosphorylation of FUNDC1 at Ser13. Loss of BCL2L1 releases PGAM5 to activate hypoxia-induced mitophagy. Co-immunoprecipitation, domain mapping (BH3 domain), mitophagy assays, siRNA knockdown Autophagy High 25126723
2014 PGAM5 is required for stabilization of PINK1 on damaged mitochondria. Loss of PGAM5 disables PINK1-mediated mitophagy in vitro and leads to dopaminergic neurodegeneration in vivo in Pgam5-deficient mice, which display a Parkinson's-like movement phenotype. Pgam5 knockout mice, biochemical fractionation of PINK1 on mitochondria, in vitro mitophagy assays, behavioral phenotyping, dopaminergic neuron histology Nature communications High 25222142
2015 RIPK3 activates PGAM5, which promotes NFAT nuclear translocation and dephosphorylation of Drp1, facilitating cytokine expression in NKT cells. Pharmacological inhibition of Drp1 or deletion of RIPK3 protects mice from NKT cell-mediated acute liver damage, defining a RIPK3-PGAM5-Drp1/NFAT signaling axis in NKT cell activation. Genetic knockout mice (Ripk3-/-), pharmacological Drp1 inhibition, NKT cell activation assays, cytokine measurement, NFAT localization Nature communications Medium 26381214
2015 In Pgam5-/- macrophages, PGAM5 is dispensable for necroptosis but is required for NLRP3 and AIM2 inflammasome-mediated IL-1β secretion. PGAM5 promotes ASC polymerization, mitochondrial integrity, and optimal ROS production in response to inflammasome signals, functioning independently of RIPK3. Pgam5-/- knockout mice, cell death assays, IL-1β ELISA, ASC speck formation, ROS measurement, mitochondrial integrity assays Journal of immunology High 26582950
2016 PGAM5-deficient mice show exacerbated necroptosis rather than protection, because PGAM5 is indispensable for PINK1-dependent mitophagy. Loss of PGAM5/PINK1-mediated mitophagy causes accumulation of abnormal mitochondria and ROS overproduction that worsen necroptosis, revising the model that PGAM5 acts downstream of RIP1/RIP3 to mediate necroptosis. Pgam5 knockout mice, electron microscopy, biochemical analysis, confocal imaging, ischemia/reperfusion injury models PloS one High 26807733
2016 PGAM5 identifies as a mammalian phosphohistidine phosphatase that specifically associates with and dephosphorylates the catalytic histidine on nucleoside diphosphate kinase B (NDPK-B). By dephosphorylating NDPK-B, PGAM5 inhibits NDPK-B-mediated histidine phosphorylation and activation of the K+ channel KCa3.1, thereby negatively regulating TCR-stimulated Ca2+ influx and cytokine production in CD4+ T cells. Co-immunoprecipitation, in vitro phosphatase assay on phosphohistidine substrate, phospho-specific monoclonal antibodies (1-pHis, 3-pHis), KCa3.1 channel activity assay, T cell cytokine production assay, siRNA knockdown Molecular cell High 27453048
2016 PGAM5 regulates Keap1-mediated Bcl-xL degradation in cardiomyocytes. A PGAM5-Bcl-xL-Keap1 interaction was identified by co-immunoprecipitation; PGAM5 silencing promoted apoptosis and inhibited Bcl-xL expression, while Keap1 overexpression further inhibited Bcl-xL and PGAM5. Co-immunoprecipitation, siRNA knockdown, overexpression, apoptosis assays in cardiomyocytes In vitro cellular & developmental biology. Animal Medium 27815660
2016 PGAM5 overexpression (both isoforms) triggers mitophagic cell death. AIF binds both PGAM5 isoforms and reduces PGAM5-stimulated caspase activation. XIAP inhibits PGAM5-mediated cell death through its ubiquitin ligase activity. Only PGAM5L (long isoform) is catalytically competent as a phosphatase and forms dimers/higher-order oligomers more efficiently than PGAM5S. Co-immunoprecipitation (AIF-PGAM5), overexpression cell death assays, phosphatase activity assays comparing isoforms, oligomerization analysis Biochemistry Medium 27218139
2017 Crystal structures of PGAM5 including activating N-terminal regulatory sequences revealed: (1) PGAM5 dimerizes through its catalytic domain; (2) assembles into an enzymatically active dodecameric form; (3) the N-terminal WDPNWD motif acts as a structural integrator assembling the dodecamer and allosterically activates the phosphatase by ordering the catalytic loop; (4) active site plasticity enables visualization of catalytic conformational rearrangements. X-ray crystallography, hydrogen-exchange mass spectrometry, size-exclusion chromatography, analytical ultracentrifugation Structure High 28648608
2017 PGAM5 antagonizes Wnt/β-catenin signaling by interacting with and dephosphorylating Dishevelled2 (DVL2), causing decreased DVL2 phosphorylation in cytoplasm and nucleus, reduced DVL2-Tcf1-β-catenin interaction, and inhibition of β-catenin transcriptional activity. This function requires PGAM5 phosphatase activity and is essential for anterior-posterior axis patterning in Xenopus embryos. Co-immunoprecipitation, in vitro dephosphorylation assay on DVL2, Xenopus embryo loss-of-function, Wnt reporter assays, phosphatase-dead mutant analysis Development High 28506997
2017 PGAM5-KEAP1-Nrf2 mitochondrial complex is required for mitochondrial retrograde trafficking upon proteasome inhibition stress. Depletion of Nrf2 or PGAM5 (but not KEAP1) inhibits retrograde trafficking through aberrant KEAP1-cullin-3-mediated proteasomal degradation of Miro2, a GTPase linking mitochondria to microtubules. Knockdown of each complex component, mitochondrial morphology and distribution assays, Miro2 degradation assays, rescue experiments Journal of cell science Medium 28839075
2017 In Drosophila, PGAM5 mediates lifespan extension by developmental mitochondrial stress through activation of FoxO via ASK1 and JNK signaling, which induces chaperone expression. Persistent FoxO activation requires PGAM5. Drosophila genetics, genetic knockdown/overexpression, lifespan assays, pathway epistasis (ASK1, JNK, FoxO mutants) eLife Medium 28891792
2018 PGAM5 is cleaved by PARL and released from mitochondria into the cytosol after mitochondrial stress; cytosolic Pgam5 interacts with axin in the cytosol, blocks axin-mediated β-catenin degradation, and induces β-catenin dephosphorylation (in an axin-dependent manner), leading to increased β-catenin-dependent transcription and mitochondrial biogenesis. Pgam5 and PARL knockout cells abolish this response. Co-immunoprecipitation (Pgam5-axin), β-catenin reporter assays, CCCP/hypoxia treatment, Pgam5/PARL knockout cells, mitochondrial number quantification The Journal of cell biology High 29438981
2018 Syntaxin 17 (Stx17) regulates PGAM5 localization and function: in healthy cells, Stx17 loss causes PGAM5 aggregation within mitochondria, preventing Drp1 dephosphorylation and causing mitochondrial elongation. In Parkin-mediated mitophagy, Stx17 is prerequisite for PGAM5 to interact with FUNDC1. siRNA knockdown of Stx17, mitochondrial morphology imaging, Drp1 phosphorylation western blot, co-immunoprecipitation (PGAM5-FUNDC1), mitophagy assays The EMBO journal High 30237312
2018 AMPK physically associates with a complex containing PGAM5 and Keap1, facilitating Keap1-mediated PGAM5 ubiquitination upon necroptosis induction. AMPK activation promotes Keap1-mediated PGAM5 degradation to protect against necroptosis. Co-immunoprecipitation (AMPK-PGAM5-Keap1 complex), ubiquitination assays, dominant-negative/constitutively-active AMPK constructs, necroptosis assays International journal of cardiology Medium 29579593
2019 PGAM5 exists in an equilibrium between dimeric and multimeric states and dephosphorylates distinct substrates depending on its oligomeric state: dimeric PGAM5 dephosphorylates BCL-xL at Ser62 (inhibiting apoptosis by restoring BCL-xL sequestration of BAX/BAK), while oxidative stress-induced multimerization causes PGAM5 dissociation from BCL-xL and increased multimerization leads to FUNDC1 dephosphorylation (activating mitofission and mitophagy). In vitro phosphatase assays on BCL-xL-Ser62 and FUNDC1, co-immunoprecipitation, oligomerization state analysis, apoptosis and mitophagy functional assays Cell death and differentiation High 31367011
2019 Cleaved PGAM5 is released from mitochondria during Parkin-mediated mitophagy in a manner dependent on proteasome-mediated rupture of the outer mitochondrial membrane. In cells lacking Parkin, mitophagy-inducing agents cause PGAM5 cleavage but not release, indicating PGAM5 senses mitochondrial dysfunction in the inner membrane and signals upon cleavage and release. Parkin-expressing vs. parkin-deficient HeLa cells, proteasome inhibitors, subcellular fractionation during mitophagy, western blot for cleaved PGAM5 Journal of biochemistry Medium 30247576
2019 Using cryo-EM, PGAM5 forms dodecamers in solution; a crystal structure reveals the determinants of dodecamer formation. PGAM5 dodecamers assemble into filaments both in vitro and in cells. Dodecamer oligomerization is essential for catalytic activation and also plays a structural role on mitochondrial membranes independent of phosphatase activity. Electron cryo-microscopy (cryo-EM), X-ray crystallography, in vitro filament assembly, cell imaging of PGAM5 filaments, phosphatase activity assays Nature communications High 30705304
2019 PHB2-mediated mitophagy depends on the PARL-PGAM5-PINK1 axis: PHB2 depletion destabilizes PINK1 in mitochondria (blocking Parkin recruitment), and this pathway requires PARL. PGAM5, processed by PARL, participates in PHB2-mediated PINK1 stabilization. PHB2 knockdown/overexpression, co-immunoprecipitation (PARL-PHB2), PINK1 stabilization assays, mitophagy flux assays, Parkin recruitment imaging Autophagy Medium 31177901
2019 Lipin-1 is a substrate of PGAM5: PGAM5 was identified as a regulator of Lipin-1 by co-immunoprecipitation/LC-MS/MS. Activation of endogenous PGAM5 by CCCP promoted dephosphorylation and nuclear accumulation of Lipin-1 in hepatocellular carcinoma cells. Co-immunoprecipitation, LC-MS/MS substrate identification, CCCP activation, Lipin-1 phosphorylation and localization assays Biochemical and biophysical research communications Medium 30642635
2020 Deletion of PGAM5 in retinal pigment epithelial cells leads to accelerated cellular senescence in vitro and in vivo. Mechanistically, PGAM5 is required for mitochondrial fission through dephosphorylating DRP1; PGAM5 deletion leads to increased mitochondrial fusion, elevated ATP and ROS, and enhanced mTOR and IRF/IFN-β signaling causing senescence. Overexpression of DRP1-S637A (constitutively dephosphorylated) rescues mTOR activation and senescence in PGAM5-/- cells. PGAM5 knockout cells and mice, DRP1 phosphorylation assays, mitochondrial morphology imaging, mTOR/IRF signaling assays, DRP1 mutant rescue experiments, in vivo RPE senescence Nature communications High 32439975
2020 PGAM5 interacts with MAVS and promotes TBK1/IRF3-dependent antiviral IFN-β production. PGAM5-deficient cells show diminished IFNβ expression, reduced IRF3 and TBK1 phosphorylation upon poly(I:C) challenge, and increased VSV replication. Upon poly(I:C) challenge, PGAM5 oligomers accumulate in mitochondrial aggregates. Co-immunoprecipitation (PGAM5-MAVS), PGAM5 knockout MEFs, TBK1/IRF3 phosphorylation western blot, IFNβ expression assays, VSV replication assay Scientific reports Medium 32433485
2021 IFN-β induces mitochondrial fission in neurons by phosphorylating STAT5, which upregulates PGAM5; PGAM5 then phosphorylates serine 622 of Drp1, and IFN-β signaling recruits and oligomerizes Drp1 to mitochondria, engaging INF2 to stabilize mitochondria-ER platforms for fission. Loss of neuronal IFN-β disrupts STAT5-PGAM5-Drp1 signaling, impairing fission. Ifnb-/- mouse model, STAT5 phosphorylation assays, PGAM5 overexpression, Drp1-S622 phosphorylation mapping, mitochondrial morphology imaging, ER-mitochondria contact site analysis The EMBO journal Medium 33913175
2021 KEAP1/PGAM5 complex acts as an ROS sensor for mitophagy: moderate mitochondrial ROS oxidizes KEAP1, breaking the KEAP1-PGAM5 interaction and inhibiting PGAM5 proteasomal degradation. Accumulated PGAM5 interferes with PINK1 processing, causing PINK1 accumulation on the outer mitochondrial membrane and sensitizing mitochondria to autophagic removal via Parkin recruitment. KEAP1-PGAM5 interaction disruption assays, ROS manipulation, PINK1 processing assays, mitophagy flux measurement, pharmacological KEAP1-PGAM5 interaction inhibitors (CPUY192018) Redox biology Medium 34801863
2021 Cleaved PGAM5 translocates to the nucleus during mitophagy and dephosphorylates nuclear serine/arginine-rich proteins including SRm160/SRRM1 and SRSF1 (SR proteins involved in mRNA metabolism). This nuclear activity of released PGAM5 may coordinate cellular responses to mitochondrial stress via post-transcriptional regulation. Deletion mutants mimicking cleaved PGAM5, nuclear fractionation during mitophagy, co-immunoprecipitation (PGAM5-SRm160), phosphatase assay on SR protein substrates, PGAM5-deficient cell lysates Biochimica et biophysica acta. Molecular cell research Medium 33872670
2022 PGAM5 dephosphorylates PHB2 at Ser91. Transfection of phosphodefective or phosphomimetic PHB2-Ser91 mutants confirmed that PGAM5-mediated dephosphorylation of PHB2 causes mitochondrial dysfunction under hyperglycemic stress. Knockin mice expressing phosphomimetic PHB2-S91D were resistant to diabetes-induced cardiac dysfunction. Co-immunoprecipitation, phospho-mutant transfection (PHB2-S91 phosphodefective/phosphomimetic), cardiomyocyte-specific Pgam5 KO, PHB2-S91D knockin mice, mitochondrial function assays Research High 39285950
2022 NMR analysis and cleavage studies show that PGAM5 cleavage by PARL is governed by: (1) polar transmembrane residues distant from the cleavage site as PARL-recognition determinants; (2) a short N-terminal amphipathic helix followed by a kink and transmembrane helix as key structural features; (3) membrane potential-dependent oligomeric switch — PGAM5 is stably inserted as oligomers in the inner mitochondrial membrane until uncoupling triggers disassembly into PARL-cleavable monomers. NMR spectroscopy of transmembrane domain, site-directed mutagenesis of polar TM residues, cleavage assays with membrane potential manipulation, oligomeric state analysis The Journal of biological chemistry High 35921890
2023 PGAM5 interacts with MFN2 and DRP1 in a stress-sensitive manner, and acts as an MFN2 phosphatase: PGAM5 dephosphorylates MFN2 to protect it from ubiquitination and degradation and to promote mitochondrial network formation (fusion). Phosphorylation of MFN2 enhances fission and degradation, while dephosphorylation enhances fusion. Drosophila genetic model confirms Marf (MFN2 homolog) and dPGAM5 function in the same pathway. Co-immunoprecipitation (stress-sensitive), MFN2 phosphorylation/ubiquitination assays, mitochondrial morphology imaging, Drosophila genetic epistasis (Marf-dPGAM5) Cell reports High 37498743
2023 PGAM5 dephosphorylates Bax to facilitate Bax translocation to the mitochondrial membrane, increasing membrane permeability, decreasing mitochondrial membrane potential, and facilitating cytochrome c release into the cytoplasm, thereby initiating mitochondria-dependent apoptosis in acute kidney injury. PGAM5 knockout mice (AKI model), PGAM5 overexpression, Bax dephosphorylation assay, Bax knockdown rescue experiment, cytochrome c release measurement, mitochondrial membrane potential assay Acta pharmacologica Sinica Medium 37684381
2023 SIRT2 deacetylates PGAM5, and deacetylated PGAM5 activates malic enzyme 1 (ME1) activity by dephosphorylating ME1, leading to ME1-dependent lipid accumulation and proliferation of liver cancer cells. The SIRT2-PGAM5-ME1 axis regulates lipid metabolism in cancer. Co-immunoprecipitation, immunoprecipitation-mass spectrometry, ME1 activity assay, acetylation site analysis, siRNA knockdown Acta biochimica et biophysica Sinica Medium 37580952
2023 PGAM5 interacts with BNIP3 via its NH2-terminal region binding to the PEST motif-containing region of BNIP3, dampening BNIP3 ubiquitination and degradation to maintain continuous mitophagy. The AGER-PGAM5-BNIP3 axis is activated by S100A9/AGER signaling in cancer-associated muscle wasting. Co-immunoprecipitation (PGAM5-BNIP3), domain-mapping pulldowns, ubiquitination assays, Pgam5 knockout mice, mitophagy flux assays, tumor-bearing mouse models Autophagy Medium 38919131
2023 PGAM5 interacts with MyD88 and TRAF3 to activate the IFN signaling pathway, resulting in inhibition of viral (PDCoV) replication. PGAM5 also degrades PDCoV N protein through autophagy by interacting with cargo receptor P62 and E3 ubiquitin ligase STUB1. Co-immunoprecipitation (PGAM5-MyD88, PGAM5-TRAF3, PGAM5-P62, PGAM5-STUB1), IFN pathway activation assays, viral replication assays, autophagy-dependent degradation assay Journal of virology Medium 37882521
2024 PGAM5 acts as a novel regulator of MAVS-NLRP3 signaling by forming liquid-liquid phase separation condensates with MAVS, fostering NLRP3 recruitment. MARCH2 directly interacts with PGAM5 to promote its K48-linked polyubiquitination and proteasomal degradation, reducing PGAM5-MAVS co-condensation and inhibiting NLRP3 inflammasome activation and cardiomyocyte pyroptosis. Co-immunoprecipitation, phase separation assays (PGAM5-MAVS condensates), K48-ubiquitination assay, MARCH2 KO mice, AAV re-introduction, single-cell RNA-seq Cell discovery High 38409220
2024 PGAM5 directly binds and phosphorylates (activates) RIPK1 at Ser166 in the cytosol after subarachnoid hemorrhage, triggering assembly of the RIPK1-PANoptosome complex. This requires cytosolic PGAM5 (released from mitochondria) and was demonstrated by co-immunoprecipitation. Co-immunoprecipitation (PGAM5-RIPK1), PGAM5 siRNA, western blotting for RIPK1-Ser166 phosphorylation, RIPK1 activator rescue, PANoptosome assembly assays, in vivo SAH rat model Experimental neurology Medium 39603487
2024 PGAM5 directly dephosphorylates DVL2 (Dishevelled Segment Polarity Protein 2), inhibiting β-catenin and promoting repolarization of M2 macrophages to M1 in the context of osteoarthritis. Conditional knockout of both PGAM5 and β-catenin in macrophages significantly exacerbated osteoarthritis, confirming the PGAM5-DVL2-β-catenin axis in macrophage polarization. Co-immunoprecipitation (PGAM5-DVL2), DVL2 dephosphorylation assay, macrophage-specific conditional knockout mice, double KO epistasis, polarization assays, in vivo OA model Bone research Medium 38433252
2024 OTUD1 deubiquitinates PGAM5, stabilizing it and activating ASK1-p38/JNK signaling to promote cardiac hypertrophy. METTL3-mediated m6A modification of OTUD1 mRNA promotes OTUD1 expression. Cardiac-specific Otud1 knockout reduces hypertrophy while Otud1 overexpression worsens it; pro-hypertrophy effects of OTUD1 were abolished by ASK1 knockdown. Co-immunoprecipitation (OTUD1-PGAM5), deubiquitination assay, cardiac-specific KO mice (TAC model), AAV9 overexpression, RNA immunoprecipitation (m6A-OTUD1 mRNA), ASK1 knockdown epistasis International journal of biological sciences Medium 39309432
2024 USP11 stabilizes PGAM5 via deubiquitination, protecting PGAM5 from proteasome-mediated degradation. The USP11/PGAM5 complex promotes breast cancer cell proliferation by activating ferroptosis-related proteins. Co-immunoprecipitation (USP11-PGAM5), deubiquitination assay, siRNA knockdown of USP11, in vitro and in vivo tumor growth assays Breast cancer research Medium 39300548
2025 Upon excessive mitochondrial ROS, PGAM5 undergoes PARL-mediated cleavage and is released into the cytoplasm, where it directly binds and dephosphorylates MST3 kinase. Cytosolic PGAM5 dephosphorylation of MST3 prevents STK25-mediated LATS1/2 phosphorylation, leading to YAP activation and colorectal cancer progression. MST3 depletion reciprocally promotes cytosolic PGAM5 accumulation by inducing mitochondrial damage, forming a positive feedback loop. Co-immunoprecipitation (PGAM5-MST3), in vitro dephosphorylation assay (MST3), PGAM5 depletion/rescue, LATS1/2 and YAP phosphorylation assays, CRC mouse models Nature communications High 39915446
2025 PGAM5 binds and activates ASK1 (apoptotic signaling-regulated kinase 1), increasing p-ASK1-T838, triggering NF-κB pathway activation, stimulating M1 macrophage polarization, and producing pro-inflammatory factors. These effects were reversed by PGAM5 silencing. Co-immunoprecipitation (PGAM5-ASK1), ASK1 phosphorylation assays, siRNA knockdown, macrophage polarization assays, NF-κB pathway activation International journal of chronic obstructive pulmonary disease Medium 40078929
2020 PGAM5 phosphatase activity and intramembrane cleavage by PARL are required for suppression of UCP1 expression in brown adipocytes; phosphatase-dead mutants cannot suppress UCP1. PISD (phosphatidylserine decarboxylase) was identified as a regulator of PGAM5 cleavage via a genome-wide siRNA screen. PGAM5 KO brown adipocytes, phosphatase-dead mutant rescue, UCP1 expression and oxygen consumption assays, genome-wide siRNA screen The Journal of biological chemistry Medium 32144202

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2012 The mitochondrial phosphatase PGAM5 functions at the convergence point of multiple necrotic death pathways. Cell 807 22265414
2014 A regulatory signaling loop comprising the PGAM5 phosphatase and CK2 controls receptor-mediated mitophagy. Molecular cell 496 24746696
2019 PHB2 (prohibitin 2) promotes PINK1-PRKN/Parkin-dependent mitophagy by the PARL-PGAM5-PINK1 axis. Autophagy 342 31177901
2008 PGAM5 tethers a ternary complex containing Keap1 and Nrf2 to mitochondria. Experimental cell research 254 18387606
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 227 29770487
2020 Mitochondrial phosphatase PGAM5 modulates cellular senescence by regulating mitochondrial dynamics. Nature communications 221 32439975
2006 PGAM5, a Bcl-XL-interacting protein, is a novel substrate for the redox-regulated Keap1-dependent ubiquitin ligase complex. The Journal of biological chemistry 171 17046835
2014 The BCL2L1 and PGAM5 axis defines hypoxia-induced receptor-mediated mitophagy. Autophagy 156 25126723
2017 PGAM5 regulates PINK1/Parkin-mediated mitophagy via DRP1 in CCCP-induced mitochondrial dysfunction. Toxicology letters 153 29241732
2012 Rhomboid protease PARL mediates the mitochondrial membrane potential loss-induced cleavage of PGAM5. The Journal of biological chemistry 150 22915595
2016 Mitochondrial Protein PGAM5 Regulates Mitophagic Protection against Cell Necroptosis. PloS one 134 26807733
2020 PGAM5: A crucial role in mitochondrial dynamics and programmed cell death. European journal of cell biology 130 33370650
2015 Regulation of NKT cell-mediated immune responses to tumours and liver inflammation by mitochondrial PGAM5-Drp1 signalling. Nature communications 129 26381214
2014 Genetic deficiency of the mitochondrial protein PGAM5 causes a Parkinson's-like movement disorder. Nature communications 129 25222142
2019 Dynamic PGAM5 multimers dephosphorylate BCL-xL or FUNDC1 to regulate mitochondrial and cellular fate. Cell death and differentiation 122 31367011
2020 Empagliflozin improves diabetic renal tubular injury by alleviating mitochondrial fission via AMPK/SP1/PGAM5 pathway. Metabolism: clinical and experimental 106 32777444
2015 The Mitochondrial Phosphatase PGAM5 Is Dispensable for Necroptosis but Promotes Inflammasome Activation in Macrophages. Journal of immunology (Baltimore, Md. : 1950) 104 26582950
2016 PGAM5-mediated programmed necrosis of hepatocytes drives acute liver injury. Gut 93 27566130
2024 The E3 ubiquitin ligase MARCH2 protects against myocardial ischemia-reperfusion injury through inhibiting pyroptosis via negative regulation of PGAM5/MAVS/NLRP3 axis. Cell discovery 90 38409220
2017 A PGAM5-KEAP1-Nrf2 complex is required for stress-induced mitochondrial retrograde trafficking. Journal of cell science 90 28839075
2018 Pgam5 released from damaged mitochondria induces mitochondrial biogenesis via Wnt signaling. The Journal of cell biology 88 29438981
2018 Syntaxin 17 regulates the localization and function of PGAM5 in mitochondrial division and mitophagy. The EMBO journal 88 30237312
2016 Identification of PGAM5 as a Mammalian Protein Histidine Phosphatase that Plays a Central Role to Negatively Regulate CD4(+) T Cells. Molecular cell 86 27453048
2021 A novel role of KEAP1/PGAM5 complex: ROS sensor for inducing mitophagy. Redox biology 76 34801863
2023 Human umbilical cord mesenchymal stem cell exosome-derived miR-874-3p targeting RIPK1/PGAM5 attenuates kidney tubular epithelial cell damage. Cellular & molecular biology letters 75 36750776
2010 The loss of PGAM5 suppresses the mitochondrial degeneration caused by inactivation of PINK1 in Drosophila. PLoS genetics 72 21151955
2021 IFN-β rescues neurodegeneration by regulating mitochondrial fission via STAT5, PGAM5, and Drp1. The EMBO journal 50 33913175
2017 PGAM5 promotes lasting FoxO activation after developmental mitochondrial stress and extends lifespan in Drosophila. eLife 46 28891792
2022 PGAM5-Mediated PHB2 Dephosphorylation Contributes to Diabetic Cardiomyopathy by Disrupting Mitochondrial Quality Surveillance. Research (Washington, D.C.) 41 39285950
2018 AMP-activated protein kinase protects against necroptosis via regulation of Keap1-PGAM5 complex. International journal of cardiology 41 29579593
2017 Structures of PGAM5 Provide Insight into Active Site Plasticity and Multimeric Assembly. Structure (London, England : 1993) 40 28648608
2023 PGAM5 is an MFN2 phosphatase that plays an essential role in the regulation of mitochondrial dynamics. Cell reports 37 37498743
2024 Targeted knockdown of PGAM5 in synovial macrophages efficiently alleviates osteoarthritis. Bone research 36 38433252
2019 Functional role of PGAM5 multimeric assemblies and their polymerization into filaments. Nature communications 35 30705304
2016 Apoptosis Inducing Factor Binding Protein PGAM5 Triggers Mitophagic Cell Death That Is Inhibited by the Ubiquitin Ligase Activity of X-Linked Inhibitor of Apoptosis. Biochemistry 34 27218139
2023 PGAM5 exacerbates acute renal injury by initiating mitochondria-dependent apoptosis by facilitating mitochondrial cytochrome c release. Acta pharmacologica Sinica 33 37684381
2019 Postconditioning with inhaled hydrogen attenuates skin ischemia/reperfusion injury through the RIP-MLKL-PGAM5/Drp1 necrotic pathway. American journal of translational research 33 30788005
2016 Mitochondrial phosphatase PGAM5 regulates Keap1-mediated Bcl-xL degradation and controls cardiomyocyte apoptosis driven by myocardial ischemia/reperfusion injury. In vitro cellular & developmental biology. Animal 33 27815660
2019 PGAM5-CypD pathway is involved in bromocriptine-induced RIP3/MLKL-dependent necroptosis of prolactinoma cells. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 31 30611988
2019 PGAM5 is a key driver of mitochondrial dysfunction in experimental lung fibrosis. Cellular and molecular life sciences : CMLS 30 31168659
2022 NR4A1 Promotes LPS-Induced Acute Lung Injury through Inhibition of Opa1-Mediated Mitochondrial Fusion and Activation of PGAM5-Related Necroptosis. Oxidative medicine and cellular longevity 29 35222801
2021 Mitochondrial Protein PGAM5 Emerges as a New Regulator in Neurological Diseases. Frontiers in molecular neuroscience 28 34630036
2016 The Ablation of Mitochondrial Protein Phosphatase Pgam5 Confers Resistance Against Metabolic Stress. EBioMedicine 27 27077115
2024 RIPK3 causes mitochondrial dysfunction and albuminuria in diabetic podocytopathy through PGAM5-Drp1 signaling. Metabolism: clinical and experimental 26 39089491
2018 Butylphthalide ameliorates experimental autoimmune encephalomyelitis by suppressing PGAM5-induced necroptosis and inflammation in microglia. Biochemical and biophysical research communications 26 29407174
2024 Ponicidin Promotes Hepatocellular Carcinoma Mitochondrial Apoptosis by Stabilizing Keap1-PGAM5 Complex. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 23 39116422
2022 Mitochondrion-Localized SND1 Promotes Mitophagy and Liver Cancer Progression Through PGAM5. Frontiers in oncology 22 35433434
2019 Bufalin engages in RIP1-dependent and ROS-dependent programmed necroptosis in breast cancer cells by targeting the RIP1/RIP3/PGAM5 pathway. Anti-cancer drugs 22 30829654
2022 Morin offsets PTZ-induced neuronal degeneration and cognitive decrements in rats: The modulation of TNF-α/TNFR-1/RIPK1,3/MLKL/PGAM5/Drp-1, IL-6/JAK2/STAT3/GFAP and Keap-1/Nrf-2/HO-1 trajectories. European journal of pharmacology 21 35981604
2020 miR-330 regulates Drp-1 mediated mitophagy by targeting PGAM5 in a rat model of permanent focal cerebral ischemia. European journal of pharmacology 21 32360974
2017 The phosphatase Pgam5 antagonizes Wnt/β-Catenin signaling in embryonic anterior-posterior axis patterning. Development (Cambridge, England) 21 28506997
2024 ZBP1 promotes hepatocyte pyroptosis in acute liver injury by regulating the PGAM5/ROS pathway. Annals of hepatology 20 38331384
2023 PGAM5 degrades PDCoV N protein and activates type I interferon to antagonize viral replication. Journal of virology 20 37882521
2023 TIPE3 represses head and neck squamous cell carcinoma progression via triggering PGAM5 mediated mitochondria dysfunction. Cell death & disease 19 37024453
2022 PGAM5 regulates DRP1-mediated mitochondrial fission/mitophagy flux in lipid overload-induced renal tubular epithelial cell necroptosis. Toxicology letters 19 36273635
2020 PGAM5-MAVS interaction regulates TBK1/ IRF3 dependent antiviral responses. Scientific reports 19 32433485
2016 RIPK1 and PGAM5 Control Leishmania Replication through Distinct Mechanisms. Journal of immunology (Baltimore, Md. : 1950) 19 27183605
2012 Prevention of apoptosis by mitochondrial phosphatase PGAM5 in the mushroom body is crucial for heat shock resistance in Drosophila melanogaster. PloS one 19 22347370
2025 ROS-induced cytosolic release of mitochondrial PGAM5 promotes colorectal cancer progression by interacting with MST3. Nature communications 18 39915446
2023 Pgam5-mediated PHB2 dephosphorylation contributes to endotoxemia-induced myocardial dysfunction by inhibiting mitophagy and the mitochondrial unfolded protein response. International journal of biological sciences 18 37781037
2021 The expression of IFN-β is suppressed by the viral 3D polymerase via its impact on PGAM5 expression during enterovirus D68 infection. Virus research 18 34425164
2019 Cleaved PGAM5 is released from mitochondria depending on proteasome-mediated rupture of the outer mitochondrial membrane during mitophagy. Journal of biochemistry 18 30247576
2024 The necroptosis-mediated imbalance of mitochondrial dynamics is involved in DEHP-induced toxicity to immature testes via the PGAM5-DRP1 interaction. Environmental pollution (Barking, Essex : 1987) 17 38367692
2023 PGAM5 deacetylation mediated by SIRT2 facilitates lipid metabolism and liver cancer proliferation. Acta biochimica et biophysica Sinica 17 37580952
2020 LPS induces cardiomyocyte necroptosis through the Ripk3/Pgam5 signaling pathway. Journal of receptor and signal transduction research 17 32580628
2018 PGAM5 expression and macrophage signatures in non-small cell lung cancer associated with chronic obstructive pulmonary disease (COPD). BMC cancer 17 30526542
2024 PGAM5 interacts with and maintains BNIP3 to license cancer-associated muscle wasting. Autophagy 16 38919131
2023 PGAM5 promotes tumorigenesis of gastric cancer cells through PI3K/AKT pathway. Pathology, research and practice 16 36889176
2023 Mitochondrial PGAM5-Drp1 signaling regulates the metabolic reprogramming of macrophages and regulates the induction of inflammatory responses. Frontiers in immunology 16 37771598
2022 The inhibition of PGAM5 suppresses seizures in a kainate-induced epilepsy model via mitophagy reduction. Frontiers in molecular neuroscience 16 36618822
2020 miR-21-5p Suppresses Mitophagy to Alleviate Hyperoxia-Induced Acute Lung Injury by Directly Targeting PGAM5. BioMed research international 16 33681349
2025 Disruption of tumor-intrinsic PGAM5 increases anti-PD-1 efficacy through the CCL2 signaling pathway. Journal for immunotherapy of cancer 15 39773565
2022 Negative feedback system to maintain cell ROS homeostasis: KEAP1-PGAM5 complex senses mitochondrially generated ROS to induce mitophagy. Autophagy 15 35090371
2025 The dual role of PGAM5 in inflammation. Experimental & molecular medicine 14 39930129
2024 PGAM5 promotes RIPK1-PANoptosome activity by phosphorylating and activating RIPK1 to mediate PANoptosis after subarachnoid hemorrhage in rats. Experimental neurology 13 39603487
2024 Physiological and pathological roles of PGAM5: An update and future trend. iScience 13 39911348
2019 Lipin-1 is a novel substrate of protein phosphatase PGAM5. Biochemical and biophysical research communications 13 30642635
2023 Timely expression of PGAM5 and its cleavage control mitochondrial homeostasis during neurite re-growth after traumatic brain injury. Cell & bioscience 12 37221611
2021 Cleaved PGAM5 dephosphorylates nuclear serine/arginine-rich proteins during mitophagy. Biochimica et biophysica acta. Molecular cell research 12 33872670
2020 The mitochondrial protein PGAM5 suppresses energy consumption in brown adipocytes by repressing expression of uncoupling protein 1. The Journal of biological chemistry 12 32144202
2022 Cleavage of mitochondrial homeostasis regulator PGAM5 by the intramembrane protease PARL is governed by transmembrane helix dynamics and oligomeric state. The Journal of biological chemistry 11 35921890
2024 Mechanisms involved in the regulation of mitochondrial quality control by PGAM5 in heart failure. Cell stress & chaperones 10 38821173
2024 SIRT6 prevent chronic cerebral hypoperfusion induced cognitive impairment by remodeling mitochondrial dynamics in a STAT5-PGAM5-Drp1 dependent manner. Journal of translational medicine 10 39183280
2024 METTL3-mediated m6A modification of OTUD1 aggravates press overload induced myocardial hypertrophy by deubiquitinating PGAM5. International journal of biological sciences 10 39309432
2024 The KEAP1/PGAM5/AIFM1-Mediated oxeiptosis pathway in Alzheimer's disease. Brain research 9 39168265
2023 Deletion of PGAM5 Downregulates FABP1 and Attenuates Long-Chain Fatty Acid Uptake in Hepatocellular Carcinoma. Cancers 9 37835490
2022 PGAM5 interacts with Bcl-rambo and regulates apoptosis and mitophagy. Experimental cell research 9 36075447
2024 The deubiquitinating enzyme USP11 regulates breast cancer progression by stabilizing PGAM5. Breast cancer research : BCR 8 39300548
2025 PGAM5 aggravated doxorubicin-induced cardiotoxicity by disturbing mitochondrial dynamics and exacerbating cardiomyocytes apoptosis. Free radical biology & medicine 7 40280314
2025 Metalloplastic interaction triggers renal oxeiptosis: Novel insights into KEAP1/PGAM5/AIFM1 pathway in snakeheaded fish Channa punctatus. Environmental toxicology and pharmacology 7 40681132
2023 Differential effects of PGAM5 knockout on high fat high fructose diet and methionine choline-deficient diet induced non-alcoholic steatohepatitis (NASH) in mice. Cell & bioscience 7 37605246
2023 Prunetin in a GPR30-dependent manner mitigates renal ischemia/reperfusion injury in rats via interrupting indoxyl sulfate/TLR4/TRIF, RIPK1/RIPK3/MLKL, and RIPK3/PGAM5/DRP-1 crosstalk. Saudi pharmaceutical journal : SPJ : the official publication of the Saudi Pharmaceutical Society 7 37868646
2023 Role of the RIP3-PGAM5-Drp1 pathway in aluminum-induced PC12 cells necroptosis. Ecotoxicology and environmental safety 7 38142589
2024 Unveiling a novel signalling pathway involving NRF2 and PGAM5 in regulating the mitochondrial unfolded protein response in stressed cardiomyocytes. The international journal of biochemistry & cell biology 6 39608747
2024 EGCG Alleviates Skeletal Muscle Oxidative Damage in Heat-Stressed Pigs via Keap1/PGAM5 Complex-Mediated Mitophagy. Journal of agricultural and food chemistry 6 39693506
2023 The Effect of PGAM5 on Regulating Mitochondrial Dysfunction in Ischemic Stroke. Discovery medicine 6 38058078
2018 Assembly of PGAM5 into Multimeric Complexes Provides a Mechanism for Allosteric Regulation of Phosphatase Activity. Methods in enzymology 6 30149865
2022 DHEA restores mitochondrial dynamics of cumulus cells by regulating PGAM5 expression in poor ovarian responders. Taiwanese journal of obstetrics & gynecology 5 35361380
2025 PGAM5 Modulates Macrophage Polarization, Aggravating Inflammation in COPD via the NF-κB Pathway. International journal of chronic obstructive pulmonary disease 4 40078929
2024 Melatonin attenuates liver ischemia-reperfusion injury via inhibiting the PGAM5-mPTP pathway. PloS one 4 39471139

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