Affinage

PARL

Presenilin-associated rhomboid-like protein, mitochondrial · UniProt Q9H300

Length
379 aa
Mass
42.2 kDa
Annotated
2026-06-10
63 papers in source corpus 25 papers cited in narrative 25 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

PARL is a serine rhomboid intramembrane protease of the mitochondrial inner membrane that controls mitochondrial quality control, cristae integrity, and apoptosis by regulated cleavage of multiple membrane-embedded substrates (PMID:21115803, PMID:33556373). Its central role in mitophagy lies in PINK1 processing: in healthy mitochondria with intact membrane potential, PARL cleaves PINK1 within its transmembrane anchor between Ala103 and Phe104 to generate a truncated form destined for degradation, whereas membrane potential dissipation blocks this cleavage, allowing full-length PINK1 to accumulate on the outer membrane and recruit Parkin to drive mitophagy (PMID:21115803, PMID:21138942, PMID:21426348, PMID:26101826). Loss of PARL catalytic activity impairs PINK1 processing and Parkin recruitment, and PARL-resistant PD-associated PINK1 mutants show reduced kinase activity and defective mitophagy (PMID:21355049, PMID:26101826). PARL operates as a stress-responsive substrate switch, dissociating from PINK1 and reciprocally engaging PGAM5 upon membrane potential loss, with PGAM5 cleavage further gated by its oligomeric state and transmembrane architecture (PMID:22915595, PMID:35921890). Beyond mitophagy, PARL generates the soluble IMS form of OPA1 that restrains apoptotic cristae remodeling and cytochrome c release (PMID:16839884), and it cleaves Smac/DIABLO to expose its IAP-binding motif required for XIAP engagement and apoptosis (PMID:28288130), and STARD7 to partition this lipid-transfer protein and sustain inner-membrane phosphatidylcholine, respiration, and cristae morphogenesis (PMID:29301859). PARL activity is set by N-terminal autocatalytic beta-cleavage—which yields a more active enzyme—modulated by cardiolipin and by PDK2-dependent phosphorylation of the Pbeta domain (PMID:28178523, PMID:33556373, PMID:17116872). PARL functions within the SPY complex with SLP2 and YME1L, which coordinates substrate selection and restricts competing OMA1 activity (PMID:27737933). In mouse nervous system, PARL is additionally required for Complex III function and coenzyme Q biosynthesis through stable expression of TTC19 and COQ4, independent of PINK1 or PGAM5 (PMID:30578322).

Mechanistic history

Synthesis pass · year-by-year structured walk · 23 steps
  1. 2004 Medium

    Established that PARL is itself a substrate of its own protease activity, undergoing autocatalytic N-terminal processing that liberates a nuclear-targeted peptide, setting up the idea that PARL activity is self-regulated.

    Evidence Site-directed mutagenesis of alpha/beta cleavage sites, in vitro cleavage, and fractionation tracking the Pbeta peptide

    PMID:14732705

    Open questions at the time
    • Functional consequence of nuclear Pbeta not established
    • How beta-cleavage alters protease activity on substrates not yet defined
  2. 2006 High

    Defined PARL's first physiological substrate axis by showing it generates soluble IMS-OPA1 to oppose apoptotic cristae remodeling, placing PARL upstream of intrinsic apoptosis.

    Evidence Parl-/- cells, OPA1 fractionation, cytochrome c release assay, IMS-OPA1 complementation rescue

    PMID:16839884

    Open questions at the time
    • Cleavage site within OPA1 by PARL not mapped here
    • Relationship to other OPA1-processing proteases unresolved
  3. 2006 Medium

    Showed PARL activity is regulated by phosphorylation of its vertebrate-specific Pbeta domain, linking beta-cleavage to control of mitochondrial morphology.

    Evidence Phosphomimetic/phospho-ablative PARL mutagenesis with mitochondrial morphology imaging and in-cell cleavage assay

    PMID:17116872

    Open questions at the time
    • Kinase responsible not identified in this study
    • Direct biochemical link between morphology and specific substrate cleavage not shown
  4. 2008 Medium

    Proposed PARL processes HtrA2 in an HAX1-presented manner to suppress apoptosis, extending PARL substrates to a pro-apoptotic serine protease.

    Evidence Co-IP, Hax1 and Parl knockout mice, lymphocyte/neuronal apoptosis and HtrA2 processing assays

    PMID:18288109

    Open questions at the time
    • HAX1-PARL interaction contested as artifactual by a later study
    • Direct catalytic cleavage of HtrA2 by PARL not reconstituted
  5. 2009 Medium

    Challenged the HAX1-PARL model by showing the two proteins occupy distinct compartments and interact only artifactually in vitro, qualifying the proposed coupling.

    Evidence Subcellular fractionation, in vivo Co-IP, and sequence/structure analysis as contradictory evidence

    PMID:19680265

    Open questions at the time
    • Does not exclude PARL-HtrA2 interaction independent of HAX1
    • Single-lab negative result
  6. 2010 High

    Identified PINK1 as a membrane-potential-gated PARL substrate, providing the molecular switch that couples mitochondrial health to PINK1 stability and Parkin recruitment.

    Evidence PARL knockdown/KO, CCCP depolarization, PINK1 Western blot, fractionation, and Parkin recruitment; cleavage site mapped at Ala103-Phe104 by N-terminal sequencing

    PMID:21115803 PMID:21138942

    Open questions at the time
    • Fate of cleaved PINK1 fragment and its degradation route only partially defined
    • How depolarization mechanistically blocks cleavage not fully resolved
  7. 2011 High

    Confirmed PARL cleaves PINK1 within its transmembrane anchor and that catalytic activity is required for proper PINK1 localization and Parkin recruitment, with PD mutations impinging on this processing.

    Evidence Catalytically dead PARL mutant, in-cell cleavage assays, PINK1 localization fractionation, Parkin recruitment, and human PD missense mutation analysis

    PMID:21355049 PMID:21426348

    Open questions at the time
    • Disease causality of the PARL missense variant not established beyond functional assay
    • Precise topology of mature PINK1 after release not fully defined
  8. 2012 High

    Revealed stress-dependent substrate switching: PARL dissociates from PINK1 and engages PGAM5 upon depolarization, showing the protease redirects its activity according to mitochondrial state.

    Evidence PARL knockdown, CCCP, reciprocal Co-IP of PARL with PINK1 and PGAM5, PGAM5 cleavage Western blot

    PMID:22915595

    Open questions at the time
    • Molecular trigger for the switch not defined here
    • Downstream signaling from cleaved PGAM5 not addressed
  9. 2012 Medium

    Extended the OPA1/PARL cristae-remodeling pathway to adaptive stress, showing it is required for heat-shock-induced apoptotic resistance.

    Evidence Parl-/- cells, OPA1 oligomer analysis, heat-shock conditioning, cytochrome c release assay

    PMID:22579715

    Open questions at the time
    • Signal linking heat shock to PARL/OPA1 not identified
    • Single-lab mechanism
  10. 2013 Medium

    Linked PARL-HtrA2 processing to neuronal survival after ischemia, where PARL loss disrupts HtrA2 processing and worsens injury.

    Evidence Co-IP, fractionation, PARL siRNA, and global cerebral ischemia mouse neuronal injury model

    PMID:23921894

    Open questions at the time
    • Does not resolve the HAX1-PARL controversy
    • Direct catalytic cleavage versus correlative association not distinguished
  11. 2015 High

    Clarified the mitophagy mechanism by showing PARL ablation causes retrograde translocation of a PINK1 import intermediate to the outer membrane, phenocopying uncoupler-induced mitophagy.

    Evidence PARL KO, PINK1 localization fractionation, Parkin recruitment, and PINK1 mutant kinase/mitophagy analysis

    PMID:26101826

    Open questions at the time
    • Machinery driving retrograde translocation not identified
    • Quantitative contribution of PARL versus other proteases unresolved
  12. 2016 High

    Placed PARL within a defined inner-membrane protease assembly, the SLP2-PARL-YME1L SPY complex, establishing that complex membership regulates PARL substrate processing and restrains OMA1.

    Evidence Co-IP, Blue Native PAGE, PARL/SLP2 knockdown, and PINK1/PGAM5/OPA1 processing Western blots

    PMID:27737933

    Open questions at the time
    • Stoichiometry and architecture of the SPY complex not structurally defined
    • How SLP2 mechanistically tunes PARL activity not resolved
  13. 2017 High

    Identified Smac/DIABLO as a PARL substrate whose intramembrane cleavage generates the IAP-binding motif required for apoptosis, broadening PARL's role in cell death.

    Evidence PARL substrate proteomics, KO cells, in vitro cleavage, XIAP binding assay, and apoptosis rescue

    PMID:28288130

    Open questions at the time
    • Regulation of Smac cleavage relative to PINK1/PGAM5 not defined
    • In vivo apoptotic contribution not quantified
  14. 2017 Medium

    Connected metabolic state to PARL activity by showing PDK2 phosphorylates PARL to regulate autocatalytic beta-cleavage and negatively control PINK1/Parkin mitophagy.

    Evidence PDK2 kinase assay, phospho-PARL detection, mitophagy reporter, PARL beta-cleavage Western blot

    PMID:28178523

    Open questions at the time
    • Direct phosphosite-to-activity mapping incomplete
    • Single-lab finding
  15. 2018 High

    Established STARD7 as a PARL substrate whose cleavage governs phosphatidylcholine homeostasis, respiration, and cristae morphogenesis, linking PARL to membrane lipid biology.

    Evidence PARL KO cells, STARD7 fractionation, lipid analysis, cristae EM, respiration assays, sorting-signal mutagenesis

    PMID:29301859

    Open questions at the time
    • Regulation of STARD7 cleavage by membrane potential not addressed
    • Quantitative lipid flux not measured
  16. 2018 High

    Uncovered a PINK1/PGAM5-independent neurological function of PARL in supporting Complex III activity and coenzyme Q biosynthesis via stable TTC19 and COQ4 expression.

    Evidence Nervous-system conditional Parl KO mouse, respiratory enzyme assays, CoQ HPLC, TTC19/COQ4 Western blot, EM, and PINK1/PGAM5 epistasis

    PMID:30578322

    Open questions at the time
    • Whether TTC19/COQ4 are direct PARL substrates not established
    • Mechanism of their destabilization in PARL loss unknown
  17. 2019 Medium

    Defined a PHB2-PARL-PGAM5-PINK1 axis in which PHB2 binds and restrains PARL, connecting prohibitin signaling to PARL-dependent mitophagy.

    Evidence Co-IP, PARL activity assay upon PHB2 depletion, PINK1 stability, Parkin recruitment, PGAM5 processing

    PMID:31177901

    Open questions at the time
    • Mechanism by which PHB2 inhibits PARL not defined
    • Single-lab finding
  18. 2021 High

    Reconstituted PARL biochemically to define intrinsic substrate specificity and cofactor dependence, showing beta-cleaved PARL is more active, cardiolipin enhances activity, and PARL prefers bulky P1 residues.

    Evidence Recombinant PARL in proteoliposomes, FRET kinetics, cardiolipin supplementation, 228-peptide substrate profiling, full-length versus beta-cleaved comparison

    PMID:33556373

    Open questions at the time
    • Membrane potential gating not recapitulated in vitro
    • Structural basis of substrate selection not resolved
  19. 2022 High

    Resolved how PGAM5 substrate features and oligomeric state dictate PARL cleavage, defining transmembrane determinants and depolarization-triggered monomerization.

    Evidence NMR of PGAM5 TM domain, polar-residue mutagenesis, membrane-potential dissipation, oligomeric-state analysis, PARL cleavage assay

    PMID:35921890

    Open questions at the time
    • Structure of the PARL-PGAM5 enzyme-substrate complex not solved
    • Generality of oligomer-gating to other substrates unknown
  20. 2022 Medium

    Demonstrated that acute pharmacological PARL inhibition robustly activates PINK1/Parkin mitophagy without major mitochondrial side effects, validating PARL as a druggable mitophagy target.

    Evidence Ketoamide inhibitor synthesis, cellular PARL inhibition, PINK1 intermediate accumulation, Parkin activation assay

    PMID:36540942

    Open questions at the time
    • Selectivity over other rhomboids not fully characterized
    • In vivo efficacy not tested
  21. 2023 Medium

    Identified CHCHD10 as a direct PARL-suppressing interactor whose ALS/FTD mutations derepress PARL to lower PINK1 and impair mitophagy, linking PARL regulation to neurodegenerative disease.

    Evidence Co-IP, PINK1 level and Parkin recruitment assays, mouse models, and human FTD brain tissue

    PMID:38132101

    Open questions at the time
    • Mechanism by which CHCHD10 suppresses PARL activity not defined
    • Single-lab finding
  22. 2025 Low

    Proposed a non-proteolytic anti-apoptotic role for PARL in stabilizing Nur77-BCL-2 complexes at mitochondria via a defined alpha-helix interface.

    Evidence Co-IP of PARL-Nur77-BCL-2, AlphaFold2 modeling, PARL knockdown/Nur77 overexpression in MPTP mouse model

    PMID:41052999

    Open questions at the time
    • Structural interface is computational prediction only, not experimentally solved
    • Not independently replicated
    • Whether the role is protease-independent not biochemically confirmed
  23. 2025 Low

    Suggested PARL indirectly modulates mitochondrial calcium uptake by altering MICU1/MICU2 levels without direct binding to uniporter components.

    Evidence PARL overexpression/silencing, calcium imaging, Co-IP negative for MICU1/MICU2/MCU/EMRE, Western blot of regulator levels

    PMID:40484322

    Open questions at the time
    • Mechanism linking PARL to MICU level changes not defined
    • No direct interaction; indirect inference only
    • Not independently replicated

Open questions

Synthesis pass · forward-looking unresolved questions
  • How PARL's membrane-potential gating of substrate selection is mechanistically transduced—and whether its emerging non-proteolytic roles (Nur77-BCL-2 scaffolding, calcium modulation) are bona fide functions—remains unresolved.
  • No structure of PARL bound to any substrate or partner
  • Sensor coupling membrane potential to PARL activity unidentified
  • Non-proteolytic functions rest on single low-confidence studies

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 6 GO:0016787 hydrolase activity 3
Localization
GO:0005739 mitochondrion 5
Pathway
R-HSA-392499 Metabolism of proteins 5 R-HSA-9612973 Autophagy 4 R-HSA-5357801 Programmed Cell Death 3 R-HSA-1852241 Organelle biogenesis and maintenance 2
Partners
CHCHD10HTRA2PGAM5PHB2PINK1SLP2STARD7YME1L
Complex memberships
SPY complex (SLP2-PARL-YME1L)

Evidence

Reading pass · 25 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2006 PARL, an inner mitochondrial membrane rhomboid protease, is required for the generation of a soluble intermembrane space (IMS) form of OPA1; loss of PARL results in reduced IMS-OPA1, faster apoptotic cristae remodeling, and increased cytochrome c release, placing PARL upstream of OPA1-dependent cristae remodeling in the intrinsic apoptosis pathway. Parl knockout mouse (Parl-/- cells), OPA1 fractionation, cytochrome c release assay, complementation with IMS-targeted OPA1 Cell High 16839884
2004 PARL undergoes autocatalytic cleavage at two N-terminal sites (alpha-site at positions 52-53 and beta-site at positions 77-78); beta-cleavage is developmentally controlled, dependent on PARL I-CliP activity supplied in trans, and releases a nuclear-targeted peptide called Pbeta. Site-directed mutagenesis of cleavage sites, in vitro cleavage assay, subcellular fractionation, nuclear localization tracking of Pbeta The Journal of biological chemistry Medium 14732705
2006 Phosphorylation of three residues in the vertebrate-specific Pbeta domain of PARL (Ser-65, Thr-69, Ser-70) impairs beta-cleavage at position Ser77-Ala78 that is required for PARL-induced mitochondrial fragmentation; thus phosphorylation state of the Pbeta domain regulates PARL proteolytic activity and mitochondrial morphology. Phosphomimetic and phospho-ablative mutagenesis of PARL, mitochondrial morphology imaging, in-cell cleavage assay Proceedings of the National Academy of Sciences of the United States of America Medium 17116872
2008 PARL forms a complex with HAX1 and HtrA2; HAX1 presents HtrA2 to PARL, which cleaves/processes HtrA2 to its active form in the mitochondrial intermembrane space, and processed HtrA2 prevents Bax-dependent apoptosis in lymphocytes and neurons. Co-immunoprecipitation, Hax1 and Parl knockout mice, lymphocyte and neuronal apoptosis assays, HtrA2 processing Western blot Nature Medium 18288109
2010 PARL mediates cleavage of PINK1 in a mitochondrial membrane potential-dependent manner; in healthy mitochondria with intact potential, PARL cleaves PINK1 to generate a ~60 kDa form inside mitochondria; upon membrane potential dissipation, PARL-mediated cleavage is blocked and full-length PINK1 (63 kDa) accumulates on the outer mitochondrial membrane where it recruits Parkin. PARL knockdown (siRNA/KO cells), membrane potential dissipation (CCCP), PINK1 Western blot, mitochondrial fractionation, Parkin recruitment assay The Journal of cell biology High 21115803
2010 PINK1 is cleaved by PARL between amino acids Ala-103 and Phe-104 to generate ΔN-PINK1; PINK1 physically interacts with PARL; loss of PARL results in aberrant PINK1 cleavage; N-terminal PD-associated PINK1 mutations alter the ratio of full-length to ΔN-PINK1. N-terminal sequencing of cleavage products, PARL knockdown, Co-immunoprecipitation of PINK1 and PARL, PD mutant analysis Human molecular genetics High 21138942
2011 PARL cleaves PINK1 within its conserved transmembrane membrane anchor, releasing mature PINK1 into the cytosol or IMS; depolarization blocks canonical PINK1 import and PARL-catalyzed processing; two PD-causing PINK1 mutations decrease PARL-mediated processing. In-cell cleavage assay, membrane potential dissipation, PARL KO/knockdown, PINK1 localization imaging Journal of neurochemistry High 21426348
2011 PARL's catalytic activity is required for normal PINK1 proteolytic processing and localization; PARL deficiency impairs PARKIN recruitment to mitochondria; a novel PARL missense mutation found in PD patients in a functional domain of the PARL N-terminus is insufficient to rescue PARKIN recruitment. Catalytically dead PARL mutant, PARL knockdown, PARKIN recruitment assay, PINK1 localization fractionation Human molecular genetics High 21355049
2012 PARL cleaves PGAM5 in its N-terminal transmembrane domain in response to mitochondrial membrane potential loss; PARL dissociates from PINK1 and reciprocally associates with PGAM5 upon membrane potential loss, demonstrating stress-dependent substrate switching. PARL knockdown, membrane potential dissipation (CCCP), Co-immunoprecipitation of PARL with PINK1 and PGAM5, PGAM5 cleavage Western blot The Journal of biological chemistry High 22915595
2015 Ablation of PARL causes retrograde translocation of a PINK1 import intermediate from the IMS; this intermediate is rerouted to the outer mitochondrial membrane to recruit PARK2/Parkin, phenocopying mitophagy induction by uncoupling agents; pathogenic PINK1 mutants not cleaved by PARL show reduced kinase activity and impaired PARK2-mediated mitophagy. PARL knockout, PINK1 localization fractionation, Parkin recruitment assay, PINK1 mutant analysis Autophagy High 26101826
2016 SLP2 anchors a large protease complex (SPY complex: SLP2-PARL-YME1L) at the mitochondrial inner membrane; association with SLP2 regulates PARL-mediated processing of PINK1 and PGAM5; SLP2 also restricts OMA1 activity, preventing OMA1-mediated PGAM5 and OPA1 cleavage under non-stress conditions. Co-immunoprecipitation, Blue Native PAGE, PARL/SLP2 knockdown, PINK1/PGAM5/OPA1 processing Western blot EMBO reports High 27737933
2017 PARL cleaves the pro-apoptotic protein Smac/DIABLO by intramembrane proteolysis, generating an N-terminal IAP-binding motif required for Smac's apoptotic activity; loss of PARL impairs Smac proteolytic maturation and prevents Smac from binding XIAP, reducing apoptosis. PARL-based proteomics/substrate screen, PARL KO cells, in vitro cleavage assay, XIAP binding assay, apoptosis rescue with Smac peptidomimetics or cytosolic cleaved Smac Nature cell biology High 28288130
2017 PDK2 phosphorylates PARL and regulates its N-terminal autocatalytic beta-cleavage in response to mitochondrial ATP depletion; beta-cleavage produces a less active PARL form (PACT), and PDK2-mediated phosphorylation negatively regulates PINK1/PARKIN-dependent mitophagy through this mechanism. PDK2 kinase assay with PARL substrate, phospho-PARL detection, mitophagy reporter assay, PARL beta-cleavage Western blot Cell reports Medium 28178523
2018 PARL cleaves the lipid transfer protein STARD7 during mitochondrial import; cleavage partitions STARD7 between the cytosol and the mitochondrial IMS; negatively charged residues in STARD7 serve as a sorting signal; mitochondrial STARD7 is necessary for phosphatidylcholine accumulation in the inner membrane and for maintenance of respiration and cristae morphogenesis. PARL KO cells, STARD7 fractionation, phosphatidylcholine lipid analysis, cristae morphology EM, respiratory chain assay, STARD7 sorting signal mutagenesis The EMBO journal High 29301859
2018 PARL deficiency in mouse causes defects in Complex III activity and coenzyme Q biosynthesis in the nervous system; PARL is required for stable expression of TTC19 (required for Complex III activity) and COQ4 (essential for CoQ biosynthesis); genetic modification of PINK1 or PGAM5 does not rescue this neurological phenotype. Conditional Parl KO mouse (nervous system-specific), respiratory chain enzyme activity assay, CoQ HPLC measurement, TTC19/COQ4 protein levels by Western blot, electron microscopy Proceedings of the National Academy of Sciences of the United States of America High 30578322
2019 PHB2-mediated mitophagy is dependent on PARL; PHB2 physically interacts with PARL; PHB2 depletion activates PARL, which processes PGAM5; the PHB2-PARL-PGAM5-PINK1 axis constitutes a novel pathway for PHB2-mediated mitophagy. Co-immunoprecipitation of PHB2 and PARL, PARL activity assay upon PHB2 depletion, PINK1 stability assay, Parkin recruitment, PGAM5 processing Western blot Autophagy Medium 31177901
2021 Purified recombinant human PARL in proteoliposomes cleaves PINK1, PGAM5, and Smac/DIABLO; PARL activity is enhanced by cardiolipin; the beta-cleavage truncated form of PARL is more active than full-length for all three substrates; PARL prefers substrates with a bulky side chain (Phe) at the P1 position, distinct from bacterial rhomboids. In vitro reconstitution of PARL in proteoliposomes, FRET-based kinetic assay, cardiolipin supplementation, multiplex peptide substrate profiling (228 peptides), comparison of full-length vs beta-cleaved PARL The Journal of biological chemistry High 33556373
2022 PGAM5 cleavage by PARL is governed by polar transmembrane residues distant from the cleavage site; an N-terminal amphipathic helix followed by a kink and C-terminal transmembrane helix harboring the scissile bond are key for productive PARL interaction; membrane potential uncoupling triggers PGAM5 disassembly from oligomers to monomers, which are then cleaved by PARL. NMR structural analysis of PGAM5 transmembrane domain, site-directed mutagenesis of polar residues, membrane potential dissipation, PGAM5 oligomeric state analysis, PARL cleavage assay The Journal of biological chemistry High 35921890
2022 Pharmacological inhibition of PARL using novel ketoamide inhibitors leads to robust activation of the PINK1/Parkin pathway without major secondary effects on mitochondrial properties, demonstrating that acute PARL inhibition (as opposed to genetic deficiency) is sufficient to boost PINK1/Parkin-dependent mitophagy. Ketoamide inhibitor synthesis, PARL inhibition in cells, PINK1 intermediate accumulation Western blot, Parkin activation assay Journal of medicinal chemistry Medium 36540942
2023 CHCHD10 wild-type suppresses PARL activity through direct interaction with PARL, stabilizing PINK1 levels; ALS/FTD-linked CHCHD10 mutations (R15L and S59L) reduce PINK1 levels by increasing PARL activity; CHCHD10 mutations impair mitophagy flux and mitochondrial Parkin recruitment. Co-immunoprecipitation of CHCHD10 and PARL, PINK1 level assay, Parkin recruitment assay, in vivo mouse models, human FTD brain tissue analysis Cells Medium 38132101
2009 In vivo, HAX1 and PARL are confined to distinct cellular compartments, and their in vitro interaction is artifactual; the mechanistic coupling of HAX1 to PARL as proposed by Chao et al. is not supported by in vivo evidence. Subcellular fractionation, in vivo co-immunoprecipitation, sequence/secondary structure analysis Cell death and differentiation Medium 19680265
2013 PARL binds HtrA2 in mitochondria of normal neurons; after cerebral ischemia, PARL expression decreases, PARL-HtrA2 binding is lost, processed HtrA2 is reduced in mitochondria and released into cytosol where it binds XIAP; PARL siRNA inhibits HtrA2 processing and worsens ischemic neuronal injury. Co-immunoprecipitation of PARL and HtrA2, subcellular fractionation, siRNA knockdown, neuronal injury assay in global cerebral ischemia mouse model Journal of cerebral blood flow and metabolism Medium 23921894
2012 In Parl-/- cells, accumulation of IMS-OPA1 upon mild heat shock conditioning is blunted, preventing the increase in OPA1 oligomers and the acquisition of cellular resistance to subsequent apoptotic stimuli; the OPA1/PARL-dependent pathway of cristae remodeling is required for the heat shock adaptive response. Parl-/- cells, OPA1 fractionation, OPA1 oligomer analysis, heat shock conditioning protocol, cytochrome c release assay Biochimica et biophysica acta Medium 22579715
2025 PARL interacts with the orphan nuclear receptor Nur77 at the mitochondria; Nur77 stabilizes PARL-BCL-2 complexes to suppress apoptosis; AlphaFold2 structural modeling identified a PARL alpha-helix essential for Nur77 binding; disrupting this interface abolishes BCL-2 stabilization and promotes neuronal death. Co-immunoprecipitation of PARL-Nur77-BCL-2, AlphaFold2 structural modeling, PARL knockdown and Nur77 overexpression in MPTP mouse model, subcellular tracking of Nur77 Cell death & disease Low 41052999
2025 PARL modulation (overexpression or silencing) significantly affects mitochondrial calcium uptake without influencing cytosolic calcium transients or mitochondrial membrane potential; PARL does not directly interact with MICU1 or MICU2 (mtCU regulators), but alters their protein levels in monomeric or dimeric forms, suggesting indirect modulation of the mitochondrial calcium uniporter complex. PARL overexpression and silencing, mitochondrial and cytosolic calcium imaging, Co-immunoprecipitation for MICU1/MICU2/MCU/EMRE interaction, Western blot for protein levels Biochimica et biophysica acta. Molecular cell research Low 40484322

Source papers

Stage 0 corpus · 63 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2010 Mitochondrial membrane potential regulates PINK1 import and proteolytic destabilization by PARL. The Journal of cell biology 1105 21115803
2006 Mitochondrial rhomboid PARL regulates cytochrome c release during apoptosis via OPA1-dependent cristae remodeling. Cell 604 16839884
2010 PINK1 cleavage at position A103 by the mitochondrial protease PARL. Human molecular genetics 410 21138942
2019 PHB2 (prohibitin 2) promotes PINK1-PRKN/Parkin-dependent mitophagy by the PARL-PGAM5-PINK1 axis. Autophagy 342 31177901
2011 The mitochondrial intramembrane protease PARL cleaves human Pink1 to regulate Pink1 trafficking. Journal of neurochemistry 318 21426348
2008 Hax1-mediated processing of HtrA2 by Parl allows survival of lymphocytes and neurons. Nature 218 18288109
2016 The membrane scaffold SLP2 anchors a proteolytic hub in mitochondria containing PARL and the i-AAA protease YME1L. EMBO reports 155 27737933
2012 Rhomboid protease PARL mediates the mitochondrial membrane potential loss-induced cleavage of PGAM5. The Journal of biological chemistry 150 22915595
2011 Functional alteration of PARL contributes to mitochondrial dysregulation in Parkinson's disease. Human molecular genetics 139 21355049
2017 PARL mediates Smac proteolytic maturation in mitochondria to promote apoptosis. Nature cell biology 125 28288130
2007 A cut short to death: Parl and Opa1 in the regulation of mitochondrial morphology and apoptosis. Cell death and differentiation 119 17464328
2015 Intramembrane protease PARL defines a negative regulator of PINK1- and PARK2/Parkin-dependent mitophagy. Autophagy 86 26101826
2018 PARL partitions the lipid transfer protein STARD7 between the cytosol and mitochondria. The EMBO journal 83 29301859
2010 Regulation of skeletal muscle oxidative capacity and insulin signaling by the mitochondrial rhomboid protease PARL. Cell metabolism 76 20444421
2006 Phosphorylation and cleavage of presenilin-associated rhomboid-like protein (PARL) promotes changes in mitochondrial morphology. Proceedings of the National Academy of Sciences of the United States of America 76 17116872
2018 PARL deficiency in mouse causes Complex III defects, coenzyme Q depletion, and Leigh-like syndrome. Proceedings of the National Academy of Sciences of the United States of America 74 30578322
2005 The mitochondrial rhomboid protease PSARL is a new candidate gene for type 2 diabetes. Diabetologia 66 15729572
2017 The Mitochondrial Rhomboid Protease PARL Is Regulated by PDK2 to Integrate Mitochondrial Quality Control and Metabolism. Cell reports 62 28178523
2004 Self-regulated cleavage of the mitochondrial intramembrane-cleaving protease PARL yields Pbeta, a nuclear-targeted peptide. The Journal of biological chemistry 55 14732705
2016 PARL: The mitochondrial rhomboid protease. Seminars in cell & developmental biology 54 27502471
2001 PAMP and PARL, two novel putative metalloproteases interacting with the COOH-terminus of Presenilin-1 and -2. Journal of Alzheimer's disease : JAD 50 12214059
2006 OPA1 and PARL keep a lid on apoptosis. Cell 48 16839872
2023 L-carnitine alleviates cardiac microvascular dysfunction in diabetic cardiomyopathy by enhancing PINK1-Parkin-dependent mitophagy through the CPT1a-PHB2-PARL pathways. Acta physiologica (Oxford, England) 47 37042471
2020 PARL Protease: A Glimpse at Intramembrane Proteolysis in the Inner Mitochondrial Membrane. Journal of molecular biology 42 32320686
2009 Hax1 lacks BH modules and is peripherally associated to heavy membranes: implications for Omi/HtrA2 and PARL activity in the regulation of mitochondrial stress and apoptosis. Cell death and differentiation 42 19680265
2023 STOML2 restricts mitophagy and increases chemosensitivity in pancreatic cancer through stabilizing PARL-induced PINK1 degradation. Cell death & disease 40 36906621
2010 Genome-wide linkage scan and association study of PARL to the expression of LHON families in Thailand. Human genetics 39 20407791
2023 Mitochondrial defects caused by PARL deficiency lead to arrested spermatogenesis and ferroptosis. eLife 31 37505079
2010 The PARL family of mitochondrial rhomboid proteases. Seminars in cell & developmental biology 31 20045481
2021 Insights into the catalytic properties of the mitochondrial rhomboid protease PARL. The Journal of biological chemistry 28 33556373
2012 The antiapoptotic OPA1/Parl couple participates in mitochondrial adaptation to heat shock. Biochimica et biophysica acta 24 22579715
2017 Role of PARL-PINK1-Parkin pathway in adipocyte differentiation. Metabolism: clinical and experimental 23 28641777
1998 Determination of genetic stability in long-term micropropagated shoots of Pinus thunbergii Parl. using RAPD markers. Plant cell reports 23 30744219
2009 The Leu262Val polymorphism of presenilin associated rhomboid like protein (PARL) is associated with earlier onset of type 2 diabetes and increased urinary microalbumin creatinine ratio in an Irish case-control population. Diabetes research and clinical practice 22 19185381
2022 Chemical Blockage of the Mitochondrial Rhomboid Protease PARL by Novel Ketoamide Inhibitors Reveals Its Role in PINK1/Parkin-Dependent Mitophagy. Journal of medicinal chemistry 18 36540942
2010 No association between the SNPs (rs3749446 and rs1402000) in the PARL gene and LHON in Chinese patients with m.11778G>A. Human genetics 18 20711738
2022 Heat Shock Transcription Factor 2 Promotes Mitophagy of Intestinal Epithelial Cells Through PARL/PINK1/Parkin Pathway in Ulcerative Colitis. Frontiers in pharmacology 17 35860016
2009 Genetic variation in PARL influences mitochondrial content. Human genetics 16 19862556
2013 The role of PARL and HtrA2 in striatal neuronal injury after transient global cerebral ischemia. Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism 15 23921894
2013 Identification of the variants in PARL, the nuclear modifier gene, responsible for the expression of LHON patients in Thailand. Experimental eye research 12 23973714
2006 PARL Leu262Val is not associated with fasting insulin levels in UK populations. Diabetologia 12 17019603
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
2023 Disruption of Mitophagy Flux through the PARL-PINK1 Pathway by CHCHD10 Mutations or CHCHD10 Depletion. Cells 10 38132101
2019 Transcriptomic analysis of selenium accumulation in Puccinellia distans (Jacq.) Parl., a boron hyperaccumulator. Chemosphere 10 31877459
2023 Genome-wide Survival Study Identifies PARL as a Novel Locus for Clinical Progression and Neurodegeneration in Alzheimer's Disease. Biological psychiatry 9 36870520
2020 Accumulation of HAX-1 and PARL in brainstem- and cortical-type Lewy bodies in Parkinson's disease and dementia with Lewy bodies. Journal of the neurological sciences 8 32470650
2017 PARL paves the way to apoptosis. Nature cell biology 8 28361942
2023 Resistant and Susceptible Pinus thunbergii ParL. Show Highly Divergent Patterns of Differentially Expressed Genes during the Process of Infection by Bursaphelenchus xylophilus. International journal of molecular sciences 6 37762682
2021 Expression and Purification of Human Mitochondrial Intramembrane Protease PARL. Methods in molecular biology (Clifton, N.J.) 6 33877619
2021 Development of succinimide-based inhibitors for the mitochondrial rhomboid protease PARL. Bioorganic & medicinal chemistry letters 6 34311087
2023 Inhibition of mitochondrial fusion via SIRT1/PDK2/PARL axis breaks mitochondrial metabolic plasticity and sensitizes cancer cells to glucose restriction therapy. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 5 37633053
2016 Extremely high boron tolerance in Puccinellia distans (Jacq.) Parl. related to root boron exclusion and a well-regulated antioxidant system. Zeitschrift fur Naturforschung. C, Journal of biosciences 5 27356235
2008 Association of PARL rs3732581 genetic variant with insulin levels, metabolic syndrome and coronary artery disease. Human genetics 5 18758826
2024 The mitochondrial protease PARL is required for spermatogenesis. Communications biology 4 38182793
2025 Cleaving PINK1 or PGAM5? Involvement of PARL in Methamphetamine-Induced Excessive Mitophagy and Neuronal Necroptosis. CNS neuroscience & therapeutics 3 40013375
2021 Pinus thunbergii Parl. Extracts Reduce Acute Inflammation by Targeting Oxidative Stress. Evidence-based complementary and alternative medicine : eCAM 3 33519946
2025 Impact of PARL-mediated mitochondrial protease activity on calcium regulation. Biochimica et biophysica acta. Molecular cell research 2 40484322
2025 PARL stabilizes mitochondrial BCL-2 via Nur77-mediated scaffolding as a therapeutic strategy for Parkinson's disease. Cell death & disease 2 41052999
2024 Pinus thunbergii Parl. Somatic Plants' Resistance to Bursaphelenchus xylophilus Depends on Pathogen-Induced Differential Transcriptomic Responses. International journal of molecular sciences 2 38791195
2025 PARL regulates porcine oocyte meiotic maturation by mediating mitochondrial activity. Theriogenology 1 39798391
2014 Common variants of the PINK1 and PARL genes do not confer genetic susceptibility to schizophrenia in Han Chinese. Molecular genetics and genomics : MGG 1 25354644
2026 Kinetochore size correlates with chromosome size in Star of Bethlehem (Ornithogalum kochii Parl., Asparagaceae). Plant biology (Stuttgart, Germany) 0 41978920
2024 Establishment of embryogenic Pinus thunbergii Parl. suspension cultures: growth parameters, dynamic analysis, and plant regenerative capacities. BMC plant biology 0 39702005

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