Affinage

MCOLN1

Mucolipin-1 · UniProt Q9GZU1

Length
580 aa
Mass
65.0 kDa
Annotated
2026-04-28
100 papers in source corpus 41 papers cited in narrative 40 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

MCOLN1 encodes TRPML1, a lysosomal non-selective cation channel that releases Ca²⁺, Fe²⁺, and Zn²⁺ from late endosomes and lysosomes to regulate membrane trafficking, organelle homeostasis, and cellular signaling. Activated by PI(3,5)P₂ binding to transmembrane helices S1–S3 via an allosteric S4–S5 linker mechanism and by reactive oxygen species, TRPML1 is inhibited by mTORC1-mediated phosphorylation and tonically suppressed by LAMTOR1; its Ca²⁺ release drives calcineurin-dependent TFEB nuclear translocation for autophagy/lysosome biogenesis, CaMKKβ/AMPK/VPS34-dependent autophagosome biogenesis, calmodulin-dependent lysosome fission, ARL8B-dependent lysosomal exocytosis, phagosome–lysosome fusion, SNARE-mediated autophagosome–lysosome fusion, and mitochondrial Ca²⁺ transfer at organelle contact sites (PMID:18794901, PMID:27357649, PMID:30305615, PMID:29460684, PMID:35099830, PMID:31822666, PMID:26010303, PMID:28360104, PMID:38924427, PMID:32703809, PMID:33890549). Cryo-EM structures in multiple gating states reveal that PI(3,5)P₂ induces a π-cation interaction (Y355–R403) that moves the S4–S5 linker to open a lower gate formed by S5/S6/PH1, while a luminal polycation trap and Ca²⁺-blocking acidic residues confer pH- and divalent-cation selectivity (PMID:29019981, PMID:29019983, PMID:30305615, PMID:35131932). Loss-of-function mutations in MCOLN1 cause mucolipidosis type IV, characterized by lysosomal iron and zinc accumulation, over-acidification, defective membrane trafficking, and impaired autophagy (PMID:18794901, PMID:16361256, PMID:20864526, PMID:25119295).

Mechanistic history

Synthesis pass · year-by-year structured walk · 27 steps
  1. 2005 High

    Establishing TRPML1 as an ion channel with lysosomal pH-regulatory function resolved the question of whether the channel contributes to lysosomal acidification and how its loss causes storage disease.

    Evidence Lysosomal pH measurements and H⁺ channel recordings in TRPML1⁻/⁻ patient fibroblasts with ionophore rescue of lipase activity; parallel identification of cathepsin B cleavage at R200-P201 inactivating channel activity

    PMID:16257972 PMID:16361256

    Open questions at the time
    • Whether H⁺ permeation is physiologically relevant versus secondary to other ion fluxes
    • Relative contribution of cleavage-mediated inactivation in vivo
  2. 2006 High

    Demonstration that TRPML1 forms homo- and heteromultimers with TRPML2/3 and dictates lysosomal targeting of the complex resolved how TRPML channel family members achieve compartment-specific localization.

    Evidence Reciprocal co-IP and localization rescue upon disruption of lysosomal targeting signals

    PMID:16606612

    Open questions at the time
    • Stoichiometry and structure of heteromultimeric complexes
    • Functional differences between homo- and heteromultimeric channels
  3. 2008 High

    Identifying TRPML1 as a Fe²⁺-permeable lysosomal channel whose disease mutations impair iron permeation established a direct mechanistic link between channel dysfunction and lysosomal metal accumulation in mucolipidosis IV.

    Evidence Lysosomal patch-clamp electrophysiology, radiolabeled iron uptake, and cytosolic/intralysosomal iron monitoring in TRPML1⁻/⁻ versus control fibroblasts

    PMID:18794901

    Open questions at the time
    • Whether Fe²⁺ transport is direct or facilitated by co-transported ions
    • Molecular determinants of Fe²⁺ selectivity in the pore
  4. 2009 High

    Systematic proline-scanning mutagenesis of TM5 revealed that constitutive TRPML1 activation drives lysosomal exocytosis and plasma membrane trafficking, linking channel gating to membrane fusion events.

    Evidence Gain-of-function mutagenesis with patch-clamp, surface LAMP-1 staining, and subcellular localization in heterologous cells

    PMID:19638346

    Open questions at the time
    • Identity of the Ca²⁺ effector coupling channel opening to exocytic machinery
    • Whether constitutive exocytosis reflects a physiological or pathological state
  5. 2010 High

    Demonstrating lysosomal Zn²⁺ accumulation in TRPML1-deficient cells and mouse brain established TRPML1 as a zinc efflux channel, broadening its role beyond iron to general divalent cation homeostasis.

    Evidence siRNA knockdown, spectrofluorometric zinc quantification in MLIV fibroblasts, ICP-MS on TRPML1⁻/⁻ mouse brain; complemented by parietal cell studies showing TRPML1 palmitoylation-dependent membrane trafficking

    PMID:20864526 PMID:21111738

    Open questions at the time
    • Relative Zn²⁺ versus Fe²⁺ permeability under physiological conditions
    • Structural basis of zinc permeation
  6. 2011 High

    Definitive separation of TRPML1 from the NAADP–TPC signaling axis clarified that TRPML1 and TPC channels are independent lysosomal Ca²⁺ release pathways despite physical colocalization.

    Evidence Patch-clamp recordings showing unchanged NAADP-evoked Ca²⁺ signals in TRPML1⁻/⁻ cells; co-IP confirming proximity without functional coupling

    PMID:21540176

    Open questions at the time
    • Whether TRPML1 and TPCs cooperate under specific physiological stimuli
    • Earlier report of NAADP sensitivity in coronary myocytes remains unreconciled
  7. 2012 High

    Discovery that acute TRPML1 loss causes cathepsin B leakage and Bax-dependent apoptosis revealed TRPML1 as essential for lysosomal membrane integrity and connected its dysfunction to cell death pathways.

    Evidence siRNA knockdown with epistatic pharmacological dissection (CatB inhibitor, Bax inhibitor) ordering CatB leak upstream of Bax activation

    PMID:22262857

    Open questions at the time
    • Whether lysosomal membrane permeabilization is a direct consequence of ion imbalance or secondary to trafficking defects
  8. 2013 High

    Identification of TMEM163 as a direct TRPML1 interactor that modulates zinc homeostasis, and epistatic analysis of MTF-1/ZnT4 in TRPML1-knockdown cells, built a pathway model for lysosomal zinc efflux.

    Evidence Yeast two-hybrid, co-IP, mass spectrometry, and siRNA co-knockdown epistasis with zinc quantification

    PMID:23368743 PMID:25130899

    Open questions at the time
    • Whether TMEM163 directly conducts Zn²⁺ or modulates TRPML1 pore properties
    • In vivo validation of the TMEM163–TRPML1 partnership
  9. 2014 High

    Characterization of ML-SA1 and PI(3,5)P₂ as direct TRPML1 agonists via lysosomal patch-clamp, and rescue of MLIV patient cell phenotypes with small-molecule activators, established the pharmacological framework for TRPML1 modulation.

    Evidence Whole-lysosome planar patch-clamp with mutant characterization (F465L, F408Δ), zinc accumulation rescue in MLIV fibroblasts

    PMID:25119295

    Open questions at the time
    • In vivo therapeutic efficacy of ML-SA1 class agonists
    • Long-term safety of chronic TRPML1 activation
  10. 2015 High

    Showing that PIKfyve-generated PI(3,5)P₂ activates TRPML1 to drive Ca²⁺-dependent phagosome–lysosome fusion in macrophages placed TRPML1 centrally in innate immune function.

    Evidence TRPML1 siRNA, PIKfyve inhibition, phagosome isolation, lysosomal marker acquisition, ionomycin rescue

    PMID:26010303

    Open questions at the time
    • Whether TRPML1 is the sole PI(3,5)P₂ effector for phagosome maturation
    • Identity of the Ca²⁺-sensitive fusion machinery downstream
  11. 2016 High

    Discovery that ROS directly activate TRPML1 to trigger calcineurin/TFEB-dependent autophagy and lysosome biogenesis established TRPML1 as a lysosomal oxidative stress sensor.

    Evidence Pharmacological ROS manipulation, GCaMP3 lysosomal Ca²⁺ imaging, TFEB nuclear translocation, KO phenotype with defective mitophagy

    PMID:27357649

    Open questions at the time
    • Direct ROS binding site on TRPML1 not identified
    • Whether ROS sensitivity is redox-dependent or mediated by lipid intermediates
  12. 2017 High

    Near-atomic cryo-EM structures of TRPML1 in closed and open states revealed the pore architecture, luminal polycation trap, Ca²⁺-blocking gate, and PI(3,5)P₂ binding site, transforming mechanistic understanding from pharmacology to structure.

    Evidence Cryo-EM of mouse and human TRPML1 at 3.5–3.7 Å in nanodiscs, with mutagenesis and electrophysiology validation

    PMID:29019981 PMID:29019983

    Open questions at the time
    • No structure of a disease-associated mutant
    • Conformational transitions during ion permeation not captured
  13. 2017 High

    Demonstrating that TRPML1-released Ca²⁺ activates calmodulin to promote lysosome fission resolved the mechanism by which TRPML1 controls lysosome size.

    Evidence TRPML1 activation/overexpression with CaM inhibition, Ca²⁺ chelation, and lysosome size quantification

    PMID:28360104

    Open questions at the time
    • Identity of downstream CaM effectors mediating membrane scission
    • How fission is coordinated with fusion events
  14. 2018 High

    Structures with PI(3,5)P₂ and PI(4,5)P₂ bound revealed that both lipids share the S1–S3 binding pocket but PI(3,5)P₂ induces a Y355–R403 π-cation interaction moving the S4–S5 linker to open the channel, while PI(4,5)P₂ inhibits it—explaining compartment-specific gating.

    Evidence Cryo-EM structures of human TRPML1 at pH 5.0 with different phosphoinositides, electrophysiology

    PMID:30305615

    Open questions at the time
    • Dynamics of lipid exchange at the binding site in intact membranes
    • Whether other lysosomal lipids modulate binding
  15. 2018 High

    Identification of mTORC1 as a direct kinase that phosphorylates and inhibits TRPML1, with a starvation-relief/calmodulin-dependent feedback loop, integrated TRPML1 into nutrient-sensing signaling.

    Evidence Phosphorylation site mutagenesis, mTORC1 kinase assays, TRPML1 electrophysiology, calmodulin inhibition

    PMID:26195823 PMID:29460684

    Open questions at the time
    • Specific phosphorylation sites on TRPML1 targeted by mTORC1 not fully mapped
    • Whether other kinases phosphorylate the same sites
  16. 2019 High

    Demonstration that TRPML1 drives autophagosome biogenesis via CaMKKβ/AMPK/ULK1/VPS34 independently of TFEB revealed a second, parallel pro-autophagic signaling arm downstream of lysosomal Ca²⁺.

    Evidence Pharmacological TRPML1 activation/inhibition, AMPK/ULK1/VPS34 biochemical assays, PI3P biosensor imaging, MLIV patient fibroblasts

    PMID:31822666

    Open questions at the time
    • How TFEB-dependent and AMPK-dependent arms are coordinated temporally
    • Whether the AMPK arm operates in all cell types
  17. 2019 High

    Linking TRPML1 to cholesterol egress from endolysosomes and maintenance of plasma membrane HRAS nanoclusters extended TRPML1's role to lipid transport and oncogenic signaling.

    Evidence MCOLN1 knockdown and pharmacological inhibition with cholesterol imaging, HRAS nanoclustering analysis, ERK phosphorylation

    PMID:30787043

    Open questions at the time
    • Whether cholesterol transport is direct or mediated by NPC1/NPC2
    • Generality to other RAS isoforms
  18. 2019 High

    Sphingosine, generated by acid ceramidase, was identified as an endogenous lipid activator of TRPML1 that controls lysosome–MVB interactions and exosome release.

    Evidence Planar patch-clamp with sphingolipids, AC inhibitor carmofur, SIM imaging of lysosome–MVB contacts, nanoparticle tracking

    PMID:31268777

    Open questions at the time
    • Binding site for sphingosine on TRPML1 not determined
    • In vivo relevance for exosome-dependent signaling
  19. 2020 High

    Discovery of nanoscale TRPML1–RyR2 complexes at lysosome–SR junctions in smooth muscle, where TRPML1 initiates Ca²⁺ sparks that activate BK channels, established a non-canonical physiological role causing hypertension and bladder overactivity when lost.

    Evidence Super-resolution microscopy, Ca²⁺ spark imaging, BK electrophysiology, pressure myography, radiotelemetry, and voiding assays in Mcoln1⁻/⁻ mice

    PMID:32576680 PMID:33199609

    Open questions at the time
    • Molecular basis of TRPML1–RyR2 physical coupling
    • Whether this mechanism operates in non-muscle excitable cells
  20. 2020 High

    Demonstration that TRPML1-mediated Ca²⁺ release at mitochondria–lysosome contact sites drives VDAC1/MCU-dependent mitochondrial Ca²⁺ uptake connected TRPML1 to inter-organelle calcium transfer.

    Evidence High-resolution live-cell contact site imaging, organelle-targeted Ca²⁺ indicators, MLIV patient fibroblasts

    PMID:32703809

    Open questions at the time
    • Identity of tethering proteins mediating TRPML1-proximal contacts
    • Quantitative contribution relative to ER-mediated mitochondrial Ca²⁺ supply
  21. 2021 High

    Showing that TRPML1-released Zn²⁺ disrupts STX17–VAMP8 SNARE interaction to block autophagosome–lysosome fusion revealed zinc as a second messenger downstream of TRPML1 that opposes the Ca²⁺-driven pro-fusion arm.

    Evidence Co-IP of STX17/VAMP8, TRPML1 agonist/antagonist, zinc chelation, autophagy flux in vitro and xenograft models

    PMID:33890549

    Open questions at the time
    • How cells resolve the opposing Ca²⁺ (pro-fusion) and Zn²⁺ (anti-fusion) signals from the same channel
    • Zinc concentration thresholds in vivo
  22. 2022 High

    Cryo-EM capture of PI(3,5)P₂ and temsirolimus co-bound states revealed synergistic cooperative gating where two distinct ligand sites must be occupied for full channel opening.

    Evidence Cryo-EM of apo-closed, PI(3,5)P₂-bound closed, and PI(3,5)P₂/temsirolimus-bound open states with electrophysiology

    PMID:35131932

    Open questions at the time
    • Whether endogenous co-agonists occupy the temsirolimus site
    • Structural basis of cooperativity at atomic detail
  23. 2022 High

    Identification of LAMTOR1 as a direct tonic inhibitor of TRPML1 that modulates calcineurin-dependent GluA1 degradation and synaptic plasticity placed TRPML1 in neuronal signaling circuitry.

    Evidence Co-IP, domain mapping, GCaMP3 Ca²⁺ imaging in hippocampal neurons, synaptic plasticity recordings, behavioral assays

    PMID:35099830

    Open questions at the time
    • Whether LAMTOR1 inhibition is regulated by nutrient status independently of mTORC1
    • Specificity for GluA1 versus other synaptic substrates
  24. 2022 High

    Mapping the oxidative-stress-induced TRPML1→CaMK2G→JIP4-pT217 axis for lysosomal retrograde transport distinguished it from the starvation-induced pathway and identified JIP4 phosphorylation as a context-specific switch.

    Evidence JIP4/TRPML1/ALG2 genetic KO and rescue, phospho-site mapping, CaMK2G inhibition, lysosome positioning imaging

    PMID:36394115

    Open questions at the time
    • Whether other kinases can substitute for CaMK2G
    • Integration with TFEB-dependent transcriptional response
  25. 2024 High

    Discovery that AKT phosphorylates TRPML1 at S343 to block ubiquitination and promote ARL8B-dependent lysosomal exocytosis for ferroptosis resistance connected TRPML1 to oncogenic survival signaling.

    Evidence CRISPR screen, kinase inhibitor library, phospho-site mapping, co-IP of TRPML1–ARL8B, ubiquitination and exocytosis assays, in vivo tumor models

    PMID:38924427

    Open questions at the time
    • Identity of the E3 ligase targeting K552
    • Whether AKT-TRPML1 axis operates in non-cancer contexts
  26. 2024 High

    Demonstrating that TRPML1 activation promotes SNARE carrier vesicle delivery (STX7, VAMP7) to lysosomes in a positive feedback with PI(3,5)P₂ generation resolved how TRPML1 rapidly activates lysosomal acidification and hydrolase function.

    Evidence ML-SA1 activation, pH imaging, hydrolase activity assays, SNARE trafficking analysis with kinetic measurements

    PMID:39433126

    Open questions at the time
    • Origin of the SNARE carrier vesicles
    • Whether PI(3,5)P₂ positive feedback is self-limiting
  27. 2025 High

    Identification of a TRPML1→Fe²⁺→PHD→NF-κB axis that suppresses IL-1β transcription in macrophages established an anti-inflammatory role for lysosomal iron release and demonstrated in vivo therapeutic potential in colitis.

    Evidence TRPML1 agonist/antagonist, Fe²⁺ release assays, PHD activity, NF-κB reporter, IL-1β quantification, TRPML1 KO, DSS-colitis mouse model

    PMID:39856099

    Open questions at the time
    • Whether other lysosomal channels contribute to this anti-inflammatory Fe²⁺ release
    • Long-term consequences of modulating lysosomal iron for systemic iron homeostasis

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include the direct ROS-sensing site on TRPML1, how opposing Ca²⁺ (pro-fusion) and Zn²⁺ (anti-fusion) signals from the same channel are decoded by cells, the identity of tethering factors at TRPML1-dependent organelle contact sites, and whether disease-associated mutant structures can inform targeted therapies for mucolipidosis IV.
  • No cryo-EM structure of a disease-causing TRPML1 mutant
  • Direct ROS-binding site unidentified
  • Mechanism coordinating Ca²⁺ and Zn²⁺ dual signaling unknown
  • Tethering partners at lysosome–mitochondria contacts for TRPML1-dependent Ca²⁺ transfer not identified

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0005215 transporter activity 5 GO:0140299 molecular sensor activity 1
Localization
GO:0005764 lysosome 8 GO:0005768 endosome 2
Pathway
R-HSA-5653656 Vesicle-mediated transport 5 R-HSA-9612973 Autophagy 5 R-HSA-162582 Signal Transduction 4 R-HSA-1852241 Organelle biogenesis and maintenance 3 R-HSA-382551 Transport of small molecules 3 R-HSA-168256 Immune System 2
Partners
ALG2ARL8BLAMTOR1RYR2STIM1TMEM163TRPML2TRPML3
Complex memberships
TRPML1 homotetramerTRPML1-RyR2 nanoscale complexTRPML1-TRPML2 heteromultimer

Evidence

Reading pass · 40 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2008 TRPML1 functions as a Fe2+-permeable channel in late endosomes and lysosomes, mediating iron release from these organelles into the cytosol. ML4 disease mutations impair Fe2+ permeation to varying degrees correlating with disease severity. Loss of TRPML1 results in reduced cytosolic Fe2+ and increased intralysosomal Fe2+. Radiolabelled iron uptake, cytosolic/intralysosomal iron monitoring, direct lysosomal patch-clamp electrophysiology, comparison of TRPML1−/− vs. control fibroblasts Nature High 18794901
2016 TRPML1 acts as a ROS sensor on the lysosomal membrane; oxidants directly and specifically activate TRPML1, inducing lysosomal Ca2+ release that triggers calcineurin-dependent TFEB nuclear translocation, autophagy induction, and lysosome biogenesis. Genetic inactivation or pharmacological inhibition of TRPML1 blocks clearance of damaged mitochondria and removal of excess ROS. Pharmacological ROS manipulation, GCaMP3 lysosomal Ca2+ imaging, TFEB nuclear translocation assays, genetic knockout/knockdown with autophagic flux readouts Nature Communications High 27357649
2017 Cryo-EM structure of mouse TRPML1 in nanodiscs reveals that PI(3,5)P2 binds to the N-terminus distal from the pore; an S2-S3 helix-turn-helix extension couples ligand binding to pore opening; the selectivity filter has multiple ion-binding sites; conserved acidic residues form a luminal Ca2+-blocking site conferring pH/Ca2+ modulation; a luminal linker domain forms a fenestrated canopy creating a divalent cation-preferring electrostatic trap. Single-particle cryo-EM in nanodiscs, mutagenesis analysis, electrophysiology Nature High 29019981
2017 Cryo-EM structures of full-length human TRPML1 in apo (closed, pH 7.0) and agonist-bound (open, pH 6.0) states reveal that channel opening involves dilation of a lower gate together with movement of pore helix 1; a hydrophobic cavity formed by S5, S6, and PH1 houses the synthetic agonist, distinct from TRPV1 binding site. Single-particle cryo-EM at 3.49–3.72 Å resolution Nature High 29019983
2018 Structural basis for PI(3,5)P2 and PI(4,5)P2 regulation: both lipids bind to extended helices of S1, S2, and S3. The phosphate group of PI(3,5)P2 induces a Y355–R403 π-cation interaction that moves the S4-S5 linker, allosterically activating the channel. PI(4,5)P2 acts as an inhibitor via the same site. Cryo-EM structures of human TRPML1 at pH 5.0 with PI(3,5)P2, PI(4,5)P2, or ML-SA1+PI(3,5)P2; electrophysiology Nature Communications High 30305615
2022 Cryo-EM structures of mouse TRPML1 in apo-closed, PI(3,5)P2-bound closed, and PI(3,5)P2/temsirolimus-bound open states reveal synergistic activation: PI(3,5)P2 binds N-terminal domain and rapamycin analog binds a distinct site; together they cooperate to fully open the channel. Cryo-EM structural determination in multiple states, patch-clamp electrophysiology Proceedings of the National Academy of Sciences High 35131932
2005 Loss of TRPML1 causes lysosomal over-acidification; TRPML1 can function as a H+ channel providing a proton leak that limits lysosomal acidification. Over-acidification in TRPML1−/− cells reduces lysosomal lipase activity; restoring normal pH with nigericin or chloroquine rescues the lysosomal storage phenotype. Lysosomal pH measurement, H+ channel recording, lipase activity assay in TRPML1−/− patient cells, rescue experiments with ionophores Journal of Biological Chemistry High 16361256
2005 TRPML1 is a lysosomal monovalent cation channel that undergoes proteolytic cleavage by cathepsin B at Arg200-Pro201; cleavage inactivates channel activity. N- and C-terminal fragments co-immunoprecipitate and co-elute, indicating they remain associated after cleavage. Planar patch-clamp electrophysiology, N-terminal sequencing, co-immunoprecipitation, expression in cathepsin B-deficient cells, inhibitor studies Journal of Biological Chemistry High 16257972
2009 Proline-scanning mutagenesis of the TM5 region identifies gain-of-function (GOF) mutations causing constitutive Ca2+ permeability. GOF TRPML1 channels traffic beyond late endosomes/lysosomes to the plasma membrane because constitutive intralysosomal Ca2+ release triggers lysosomal exocytosis. TRPML1 is an inwardly rectifying, proton-impermeable, Ca2+/Fe2+/Mn2+-permeable channel gated via conformational change at the cytoplasmic face of TM5. Proline scanning mutagenesis, whole-cell and lysosomal patch-clamp, surface LAMP-1 staining, subcellular localization by fluorescence microscopy Journal of Biological Chemistry High 19638346
2006 TRPML proteins form homo- and heteromultimers. TRPML1 and TRPML2 are lysosomal homomultimers and dictate lysosomal localization of TRPML3 (which alone resides in the ER) through heteromultimerization. Co-immunoprecipitation, subcellular localization by fluorescence microscopy, disruption of lysosomal targeting signals Journal of Biological Chemistry High 16606612
2019 TRPML1 activation triggers autophagosome biogenesis via lysosomal Ca2+ release activating CaMKKβ and AMPK, which increase activation of ULK1 and VPS34 autophagic complexes and PI3P generation, independently of TFEB. MLIV patient cells show reduced recruitment of PI3P-binding proteins to the phagophore. Pharmacological activation/inhibition of TRPML1, CaMKKβ/AMPK/ULK1/VPS34 biochemical assays, PI3P biosensor imaging, MLIV patient fibroblast analysis Nature Communications High 31822666
2020 TRPML1-mediated lysosomal Ca2+ release at mitochondria-lysosome contact sites promotes calcium transfer to mitochondria, dependent on tethering of contact sites and requiring VDAC1 and the mitochondrial calcium uniporter. MLIV patient fibroblasts show altered contact dynamics and defective contact-dependent mitochondrial calcium uptake. High-resolution live-cell microscopy, organelle Ca2+ imaging, contact site analysis, MLIV patient fibroblast studies Proceedings of the National Academy of Sciences High 32703809
2015 TRPML1 is a PI(3,5)P2-gated lysosomal Ca2+ channel required for phagosome-lysosome fusion in macrophages. PIKfyve synthesizes PI(3,5)P2 to activate TRPML1, and the resulting Ca2+ release drives membrane fusion. Silencing TRPML1 causes lysosomes to dock but not fuse with phagosomes; forcible Ca2+ release rescues maturation. TRPML1 siRNA knockdown, PIKfyve pharmacological inhibition, phagosome isolation, lysosomal marker acquisition assays, ionomycin rescue, cytosolic Ca2+ measurement Traffic High 26010303
2018 mTORC1 (TOR kinase) directly phosphorylates TRPML1 to inactivate the channel. Mutating TOR phosphorylation sites to unphosphorylatable residues blocks TOR-mediated TRPML1 regulation. Conversely, starvation relieves mTORC1-mediated inhibition of TRPML1, and activated TRPML1 then reactivates mTORC1 via calmodulin in a negative feedback loop. Phosphorylation site mutagenesis, kinase inhibition, mTORC1 activity assays, TRPML1 channel electrophysiology, calmodulin inhibition Autophagy High 26195823 29460684
2021 TRPML1 mediates lysosomal Zn2+ release into the cytosol. Activation of TRPML1 by agonists blocks autophagosome-lysosome fusion by disrupting interaction of STX17 (autophagosome SNARE) with VAMP8 (lysosome SNARE), thereby arresting autophagic flux. This zinc-dependent block of SNARE-mediated fusion is replicated by extracellular zinc, confirming zinc as the effector. TRPML1 agonist/antagonist pharmacology, zinc chelation, co-immunoprecipitation of STX17/VAMP8, autophagy flux assays, xenograft tumor models Autophagy High 33890549
2019 TRPML1 maintains oncogenic HRAS in signaling-competent nanoclusters at the plasma membrane by mediating cholesterol de-esterification and transport from endolysosomes to the plasma membrane. TRPML1 inhibition causes cholesterol accumulation in endolysosomes, loss of HRAS from the plasma membrane, and reduced ERK phosphorylation. MCOLN1 knockdown and pharmacological inhibition, cholesterol localization imaging, HRAS nanoclustering analysis, ERK phosphorylation assays EMBO Reports High 30787043
2024 AKT directly phosphorylates TRPML1 at Ser343, which inhibits K552 ubiquitination and proteasomal degradation of TRPML1, thereby promoting TRPML1 binding to ARL8B and triggering lysosomal exocytosis. This TRPML1-mediated exocytosis reduces intracellular ferrous iron and enhances membrane repair, protecting AKT-hyperactivated cancer cells from ferroptosis. Genome-wide CRISPR-Cas9 screen, kinase inhibitor library screen, phosphorylation site mapping, co-IP of TRPML1-ARL8B, ubiquitination assays, lysosomal exocytosis assays, in vivo tumor models Science Translational Medicine High 38924427
2010 Loss of TRPML1 causes intracellular chelatable zinc dyshomeostasis with zinc accumulation in lysosomes and elevated brain zinc in TRPML1−/− mice, establishing a role for TRPML1 in zinc efflux from lysosomes. siRNA knockdown in HEK-293 cells, spectrofluorometric zinc quantification in MLIV patient fibroblasts, ICP-MS on TRPML1−/− mouse brain tissue Journal of Biological Chemistry High 20864526
2013 TRPML1 interacts with TMEM163 (a putative zinc transporter) as demonstrated by yeast two-hybrid, co-immunoprecipitation, mass spectrometry, and confocal colocalization. This interaction modulates cellular zinc homeostasis; TMEM163 plasma membrane levels decrease when co-expressed with TRPML1, and knockdown of TMEM163 or combined TMEM163/TRPML1 knockdown elevates intracellular zinc. Yeast two-hybrid, co-immunoprecipitation, mass spectrometry, confocal microscopy, siRNA knockdown, zinc quantification Traffic High 25130899
2010 TRPML1 is required for parietal cell membrane trafficking: it is dynamically palmitoylated and dephosphorylated following histamine stimulation of acid secretion. Loss of TRPML1 reduces levels and mislocalizes the gastric proton pump, alters secretory canaliculi, and causes hypochlorhydria; this indicates TRPML1 functions in tubulovesicle formation and trafficking. Trpml1−/− mouse model, histology, ultrastructural analysis, biochemical analyses of proton pump levels and localization, palmitoylation/phosphorylation assays, gastric acid secretion measurements Gastroenterology High 21111738
2012 Acute siRNA-mediated loss of TRPML1 causes cathepsin B (CatB) leak from lysosomes into the cytoplasm, triggering Bax-dependent apoptosis. CatB inhibition prevents apoptosis; Bax inhibition prevents apoptosis but not CatB leak, placing CatB leak upstream of Bax activation. siRNA knockdown, cathepsin B activity/localization assays, apoptosis assays, CatB inhibitor pharmacology, Bax inhibition Journal of Biological Chemistry High 22262857
2020 TRPML1 channels in late endosomes/lysosomes of vascular smooth muscle cells form stable nanoscale complexes with type 2 ryanodine receptors (RyR2) on the sarcoplasmic reticulum. TRPML1-mediated Ca2+ release initiates RyR2-dependent Ca2+ sparks that activate BK channels; loss of TRPML1 abolishes Ca2+ sparks, renders arteries hypercontractile, and causes spontaneous hypertension in Mcoln1−/− mice. TRPML1-KO mice, super-resolution microscopy (nanoscale colocalization), live-cell confocal Ca2+ imaging, ex vivo pressure myography, in vivo radiotelemetry Science Signaling High 32576680
2017 TRPML1-mediated lysosomal Ca2+ release activates calmodulin (CaM) to promote lysosome fission/size regulation. Activation of TRPML1 suppresses vacuolin-1- or P2X4-induced lysosomal enlargement; this effect requires Ca2+ and CaM, not the lysosomal Na+ channel TPC2. TRPML1 overexpression/activation, vacuolin-1 and P2X4 treatment, Ca2+ chelation, CaM inhibition, lysosome size quantification Journal of Biological Chemistry High 28360104
2011 Although TRPML1 and TPC2 co-immunoprecipitate and colocalize, they function as independent ion channels: TPC1/TPC2 do not affect TRPML1 channel activity, and TRPML1 does not mediate NAADP-evoked Ca2+ signals (NAADP-Ca2+ responses are identical in wild-type and TRPML1−/− cells). TPCs, not TRPMLs, are the NAADP targets. Co-immunoprecipitation, colocalization, patch-clamp of TRPML1 and TPC channels, NAADP-Ca2+ measurement in TRPML1−/− cells and pancreatic acinar cells Journal of Biological Chemistry High 21540176
2011 CUP-5, the C. elegans ortholog of TRPML1, localizes to lysosomes (not gut granules) and is required for lysosome biogenesis and proteolytic degradation in autolysosomes. cup-5 mutations cause enlarged autolysosomes with defective degradation; reduced autophagy activity partially suppresses cup-5 mutant phenotypes. C. elegans genetics, autophagy substrate accumulation assays, organelle marker colocalization, genetic epistasis with autophagy mutants Autophagy High 21997367
2022 LAMTOR1 (Ragulator subunit) directly interacts with TRPML1 through its N-terminal domain and tonically inhibits TRPML1 activity independently of mTORC1. Disrupting LAMTOR1-TRPML1 binding increases TRPML1-mediated Ca2+ release, activates calcineurin-dependent GluA1 dephosphorylation, promotes lysosomal degradation of GluA1, and impairs synaptic plasticity and memory in mice. Co-immunoprecipitation, LAMTOR1 deletion/domain mapping, GCaMP3 Ca2+ imaging in hippocampal neurons, dendritic lysosome trafficking imaging, synaptic plasticity recordings, behavioral assays EMBO Journal High 35099830
2021 Cryo-EM structure of human TRPML1 with antagonist ML-SI3 at 2.9-Å resolution reveals that ML-SI3 binds to the same hydrophobic S5/S6/PH1 cavity as agonist ML-SA1. ML-SI3 competes with ML-SA1 but does not block PI(3,5)P2-dependent activation, demonstrating two functionally distinct activation pathways. Cryo-EM, whole-lysosome electrophysiology, competitive binding studies Structure High 34171299
2014 TRPML1 mediates lysosomal Ca2+ release in response to the synthetic agonist ML-SA1 and the endogenous ligand PI(3,5)P2. F465L mutation renders TRPML1 pH-insensitive; F408Δ impacts synthetic ligand binding. Small-molecule activators can restore TRPML1 mutant channel function and rescue trafficking defects and lysosomal zinc accumulation in MLIV patient fibroblasts. Whole-lysosome planar patch-clamp, MLIV patient fibroblast studies, zinc accumulation assays, trafficking assays Nature Communications High 25119295
2022 Oxidative stress-induced phosphorylation of JIP4 at T217 by CaMK2G in response to TRPML1-mediated Ca2+ fluxes regulates lysosomal retrograde transport and clustering. TRPML1-ALG2 pathway operates downstream, and the phosphorylation status of JIP4 acts as a switch between oxidative-stress-induced versus starvation-induced lysosomal retrograde transport. JIP4/TRPML1/ALG2 genetic KO and rescue, acrolein/H2O2 treatment, phosphorylation site mapping (T217), CaMK2G inhibition, lysosome positioning imaging EMBO Journal High 36394115
2019 Acid ceramidase (AC) product sphingosine activates TRPML1 channel-mediated Ca2+ release; ceramide and sphingomyelin have different modulatory effects on TRPML1 in podocytes. AC inhibition attenuates TRPML1 activity. TRPML1-mediated Ca2+ release controls lysosome-multivesicular body interaction and suppresses exosome release. Port-a-Patch planar patch-clamp, GCaMP3 Ca2+ imaging, AC inhibitor carmofur, structured illumination microscopy of lysosome-MVB interactions, nanoparticle tracking for exosomes American Journal of Physiology – Cell Physiology High 31268777
2025 TRPML1 is activated secondarily to ROS elevation upon inflammatory stimuli, mediating release of lysosomal Fe2+ into the cytosol. Released Fe2+ activates prolyl hydroxylase domain enzymes (PHDs), which then suppress NF-κB transcriptional activity, resulting in inhibited IL-1β (IL1B) transcription in macrophages. In vivo TRPML1 stimulation ameliorates colitis. TRPML1 agonist/antagonist pharmacology, Fe2+ release assays, PHD activity measurement, NF-κB reporter assays, IL-1β quantification, TRPML1 KO and siRNA, DSS-colitis mouse model Nature Communications High 39856099
2024 TRPML1 activation promotes autophagosome-lysosome fusion through Ca2+-dependent delivery of lysosomal SNARE proteins (syntaxin 7, VAMP7) via SNARE carrier vesicles, thereby activating lysosomal acidification and hydrolase activity within 10–20 min of TRPML1 activation. Incoming vesicle fusion is a prerequisite that generates PI(3,5)P2 to activate TRPML1 in a positive feedback. Pharmacological TRPML1 activation (ML-SA1), pH imaging, hydrolase activity assays, SNARE trafficking analysis, autophagy flux measurements Journal of Biological Chemistry High 39433126
2013 siRNA-induced TRPML1 knockdown leads to lysosomal enlargement and zinc accumulation when cells are exposed to high zinc; this is ameliorated by knockdown of zinc-sensitive transcription factor MTF-1 or zinc transporter ZnT4. TRPML1 knockdown delays zinc leak from lysosomes to cytoplasm, and elevated cytoplasmic zinc drives MT2a transcription. siRNA knockdown, zinc staining (LysoTracker/zinc fluorophore), MTF-1 and ZnT4 co-knockdown epistasis, lysosomal secretion assays, mRNA quantification Biochemical Journal High 23368743
2021 TRPML1 co-immunoprecipitates with the ER Ca2+ sensor STIM1 in motor neurons. STIM1 is required for TRPML1-mediated Ca2+ release; loss of STIM1 abolishes ML-SA1 and PI(3,5)P2-induced Ca2+ efflux through TRPML1. TRPML1 co-localizes with ER marker and LAMP1 in motor neurons. Co-immunoprecipitation, GCaMP3-ML1 Ca2+ indicator, siRNA knockdown, confocal colocalization in motor neurons FASEB Journal Medium 33484198
2019 TLR3 activation triggers lysosomal alkalization, which activates TRPML1, leading to lysosomal ATP and acid phosphatase release (lysosomal exocytosis) in astrocytes and RPE cells. TRPML1 agonist ML-SA1 is sufficient to trigger this release; TRPML1-KO cells show blunted poly(I:C)-dependent ATP release. TRPML1-KO cells, ML-SA1 agonist, ATP/acid phosphatase release assays, lysosomal pH measurement, TBK-1 inhibition Scientific Reports Medium 29636491
2020 TRPML1 channels in bladder and urethral smooth muscle cells form nanoscale complexes with RyR2 on the sarcoplasmic reticulum, similar to vascular SMCs. Loss of TRPML1 in Mcoln1−/− mice impairs Ca2+ sparks and BK channel activity, rendering lower urinary tract smooth muscle hypercontractile and causing bladder overactivity. Mcoln1−/− mouse, lattice light-sheet microscopy, super-resolution colocalization, Ca2+ spark imaging, BK channel electrophysiology, ex vivo contractility, voiding assays Proceedings of the National Academy of Sciences High 33199609
2019 TRPML1-mediated lysosomal exocytosis is required for adipogenesis. TRPML1 expression increases during adipogenic differentiation; acute TRPML1 deletion reduces lipid synthesis, marker gene expression, and exosome release from mature adipocytes. TRPML1 deletion in OP9 pre-adipocytes, lipid synthesis assays, differentiation marker gene expression, exosome quantification Biochemical and Biophysical Research Communications Medium 30711251
2017 Lysosomal adenosine accumulation (from ADA deficiency) inhibits TRPML1 channel activity; overexpressing ENT3 (adenosine transporter) rescues TRPML1 activity and lysosomal function. ADA deficiency causes lysosome enlargement, alkalinization, and dysfunction that are rescued by TRPML1 activation. This mechanism links purine metabolism to lysosomal Ca2+ homeostasis. ADA-KO cells, TRPML1 electrophysiology, ENT3 overexpression rescue, lysosomal pH measurement, B-lymphocyte oxidative stress assays Journal of Biological Chemistry Medium 28087698
2014 Loss of TRPML1 promotes ROS production via trapped lysosomal Fe2+; TRPML1-knockdown cells exposed to Fe2+ show mitochondrial fragmentation, loss of mitochondrial membrane potential, ROS buildup, lipid peroxidation, and oxidative stress gene induction—all reversed by the ROS chelator α-tocopherol. siRNA knockdown, Fe2+ treatment, mitochondrial morphology imaging, membrane potential assays, ROS/lipid peroxidation measurement, α-tocopherol rescue Biochemical Journal Medium 24192042
2008 TRPML1 functions as an NAADP-sensitive lysosomal Ca2+ release channel in coronary arterial myocytes; siRNA silencing of TRPML1 reduces NAADP-activated lysosomal Ca2+ channel activity by ~71% in reconstituted lysosomal preparations, and anti-TRPML1 antibodies almost abolish NAADP-induced channel activation. siRNA knockdown, lysosomal channel reconstitution, NAADP pharmacology, FRET, intracellular Ca2+ imaging Journal of Cellular and Molecular Medicine Medium 18754814

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2008 The type IV mucolipidosis-associated protein TRPML1 is an endolysosomal iron release channel. Nature 477 18794901
2016 MCOLN1 is a ROS sensor in lysosomes that regulates autophagy. Nature communications 459 27357649
2020 Mitochondria-lysosome contacts regulate mitochondrial Ca2+ dynamics via lysosomal TRPML1. Proceedings of the National Academy of Sciences of the United States of America 251 32703809
2010 Mucolipins: Intracellular TRPML1-3 channels. FEBS letters 209 20074572
2005 TRP-ML1 regulates lysosomal pH and acidic lysosomal lipid hydrolytic activity. The Journal of biological chemistry 201 16361256
2017 Structure of mammalian endolysosomal TRPML1 channel in nanodiscs. Nature 174 29019981
2019 TRPML1 links lysosomal calcium to autophagosome biogenesis through the activation of the CaMKKβ/VPS34 pathway. Nature communications 156 31822666
2014 A small molecule restores function to TRPML1 mutant isoforms responsible for mucolipidosis type IV. Nature communications 138 25119295
2021 Autophagy inhibition mediated by MCOLN1/TRPML1 suppresses cancer metastasis via regulating a ROS-driven TP53/p53 pathway. Autophagy 129 34878954
2017 Human TRPML1 channel structures in open and closed conformations. Nature 124 29019983
2005 TRP-ML1 is a lysosomal monovalent cation channel that undergoes proteolytic cleavage. The Journal of biological chemistry 124 16257972
2006 Lysosomal localization of TRPML3 depends on TRPML2 and the mucolipidosis-associated protein TRPML1. The Journal of biological chemistry 123 16606612
2017 TRPML1: The Ca(2+)retaker of the lysosome. Cell calcium 119 28689729
2017 The lysosomal Ca2+ release channel TRPML1 regulates lysosome size by activating calmodulin. The Journal of biological chemistry 100 28360104
2014 Activation of TRPML1 clears intraneuronal Aβ in preclinical models of HIV infection. The Journal of neuroscience : the official journal of the Society for Neuroscience 98 25143627
2009 Activating mutations of the TRPML1 channel revealed by proline-scanning mutagenesis. The Journal of biological chemistry 95 19638346
2015 The Phosphoinositide-Gated Lysosomal Ca(2+) Channel, TRPML1, Is Required for Phagosome Maturation. Traffic (Copenhagen, Denmark) 88 26010303
2014 TRPML1: an ion channel in the lysosome. Handbook of experimental pharmacology 88 24756723
2011 Transient receptor potential mucolipin 1 (TRPML1) and two-pore channels are functionally independent organellar ion channels. The Journal of biological chemistry 86 21540176
2008 TRP-ML1 functions as a lysosomal NAADP-sensitive Ca2+ release channel in coronary arterial myocytes. Journal of cellular and molecular medicine 83 18754814
2009 Neuropathology of the Mcoln1(-/-) knockout mouse model of mucolipidosis type IV. Journal of neuropathology and experimental neurology 80 19151629
2018 Structural basis for PtdInsP2-mediated human TRPML1 regulation. Nature communications 79 30305615
2010 Zinc dyshomeostasis is linked with the loss of mucolipidosis IV-associated TRPML1 ion channel. The Journal of biological chemistry 76 20864526
2019 HRAS-driven cancer cells are vulnerable to TRPML1 inhibition. EMBO reports 73 30787043
2018 A negative feedback regulation of MTORC1 activity by the lysosomal Ca2+ channel MCOLN1 (mucolipin 1) using a CALM (calmodulin)-dependent mechanism. Autophagy 68 29460684
2015 The mucolipidosis IV Ca2+ channel TRPML1 (MCOLN1) is regulated by the TOR kinase. The Biochemical journal 67 26195823
2001 Mucolipidosis type IV: novel MCOLN1 mutations in Jewish and non-Jewish patients and the frequency of the disease in the Ashkenazi Jewish population. Human mutation 67 11317355
2021 MCOLN1/TRPML1 finely controls oncogenic autophagy in cancer by mediating zinc influx. Autophagy 65 33890549
2013 Zinc-dependent lysosomal enlargement in TRPML1-deficient cells involves MTF-1 transcription factor and ZnT4 (Slc30a4) transporter. The Biochemical journal 64 23368743
2022 Artemisia Leaf Extract protects against neuron toxicity by TRPML1 activation and promoting autophagy/mitophagy clearance in both in vitro and in vivo models of MPP+/MPTP-induced Parkinson's disease. Phytomedicine : international journal of phytotherapy and phytopharmacology 63 35752074
2009 The tissue-specific expression of TRPML2 (MCOLN-2) gene is influenced by the presence of TRPML1. Pflugers Archiv : European journal of physiology 61 19763610
2004 Transfer of a mitochondrial DNA fragment to MCOLN1 causes an inherited case of mucolipidosis IV. Human mutation 59 15523648
2021 miR-204 silencing reduces mitochondrial autophagy and ROS production in a murine AD model via the TRPML1-activated STAT3 pathway. Molecular therapy. Nucleic acids 58 34026326
2011 CUP-5, the C. elegans ortholog of the mammalian lysosomal channel protein MLN1/TRPML1, is required for proteolytic degradation in autolysosomes. Autophagy 57 21997367
2017 TRPML1 Participates in the Progression of Alzheimer's Disease by Regulating the PPARγ/AMPK/Mtor Signalling Pathway. Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology 56 29131026
2019 The activation of Mucolipin TRP channel 1 (TRPML1) protects motor neurons from L-BMAA neurotoxicity by promoting autophagic clearance. Scientific reports 54 31341250
2010 A role for the Ca2+ channel TRPML1 in gastric acid secretion, based on analysis of knockout mice. Gastroenterology 54 21111738
2024 TRPML1 triggers ferroptosis defense and is a potential therapeutic target in AKT-hyperactivated cancer. Science translational medicine 52 38924427
2014 Cellular zinc levels are modulated by TRPML1-TMEM163 interaction. Traffic (Copenhagen, Denmark) 51 25130899
2010 Shutting down secondary reaction pathways: the essential role of the pyrrolyl ligand in improving silica supported d(0)-ML4 alkene metathesis catalysts from DFT calculations. Journal of the American Chemical Society 50 20481452
2022 Structural mechanism of allosteric activation of TRPML1 by PI(3,5)P2 and rapamycin. Proceedings of the National Academy of Sciences of the United States of America 47 35131932
2012 Loss of lysosomal ion channel transient receptor potential channel mucolipin-1 (TRPML1) leads to cathepsin B-dependent apoptosis. The Journal of biological chemistry 47 22262857
2018 Endolysosomal Ca2+ Signalling and Cancer Hallmarks: Two-Pore Channels on the Move, TRPML1 Lags Behind! Cancers 46 30591696
2019 TRPML1 Promotes Protein Homeostasis in Melanoma Cells by Negatively Regulating MAPK and mTORC1 Signaling. Cell reports 44 31461647
2014 Loss of TRPML1 promotes production of reactive oxygen species: is oxidative damage a factor in mucolipidosis type IV? The Biochemical journal 44 24192042
2023 The synthetic TRPML1 agonist ML-SA1 rescues Alzheimer-related alterations of the endosomal-autophagic-lysosomal system. Journal of cell science 42 36825945
2019 Control of lysosomal TRPML1 channel activity and exosome release by acid ceramidase in mouse podocytes. American journal of physiology. Cell physiology 42 31268777
2011 Reconstitution of lysosomal NAADP-TRP-ML1 signaling pathway and its function in TRP-ML1(-/-) cells. American journal of physiology. Cell physiology 42 21613607
2018 Stimulation of TLR3 triggers release of lysosomal ATP in astrocytes and epithelial cells that requires TRPML1 channels. Scientific reports 40 29636491
2021 Estradiol analogs attenuate autophagy, cell migration and invasion by direct and selective inhibition of TRPML1, independent of estrogen receptors. Scientific reports 38 33859333
2018 Robust lysosomal calcium signaling through channel TRPML1 is impaired by lysosomal lipid accumulation. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 38 29030399
2023 Induction of lysosomal exocytosis and biogenesis via TRPML1 activation for the treatment of uranium-induced nephrotoxicity. Nature communications 36 37414766
2010 Roles of CUP-5, the Caenorhabditis elegans orthologue of human TRPML1, in lysosome and gut granule biogenesis. BMC cell biology 36 20540742
2021 Regulation of TRPML1 channel activity and inflammatory exosome release by endogenously produced reactive oxygen species in mouse podocytes. Redox biology 35 34030116
2019 Exosomal release through TRPML1-mediated lysosomal exocytosis is required for adipogenesis. Biochemical and biophysical research communications 35 30711251
2017 Cryo-EM structures of the mammalian endo-lysosomal TRPML1 channel elucidate the combined regulation mechanism. Protein & cell 34 28936784
2022 TRPML1-induced autophagy inhibition triggers mitochondrial mediated apoptosis. Cancer letters 33 35644286
2020 TRPML1 channels initiate Ca2+ sparks in vascular smooth muscle cells. Science signaling 33 32576680
2015 Mucolipidosis type IV protein TRPML1-dependent lysosome formation. Traffic (Copenhagen, Denmark) 33 25491304
2019 Cyclodextrin triggers MCOLN1-dependent endo-lysosome secretion in Niemann-Pick type C cells. Journal of lipid research 32 30709900
2014 Differential mechanisms of action of the mucolipin synthetic agonist, ML-SA1, on insect TRPML and mammalian TRPML1. Cell calcium 31 25266962
2017 Inhibition of Transient Receptor Potential Channel Mucolipin-1 (TRPML1) by Lysosomal Adenosine Involved in Severe Combined Immunodeficiency Diseases. The Journal of biological chemistry 30 28087698
2021 Atomic insights into ML-SI3 mediated human TRPML1 inhibition. Structure (London, England : 1993) 27 34171299
2024 MCOLN1/TRPML1 in the lysosome: a promising target for autophagy modulation in diverse diseases. Autophagy 25 38522082
2022 LAMTOR1 inhibition of TRPML1-dependent lysosomal calcium release regulates dendritic lysosome trafficking and hippocampal neuronal function. The EMBO journal 25 35099830
2019 Lycorine Attenuates Autophagy in Osteoclasts via an Axis of mROS/TRPML1/TFEB to Reduce LPS-Induced Bone Loss. Oxidative medicine and cellular longevity 25 31687088
2011 TRPML1. Advances in experimental medicine and biology 25 21290297
2023 Blunting ROS/TRPML1 pathway protects AFB1-induced porcine intestinal epithelial cells apoptosis by restoring impaired autophagic flux. Ecotoxicology and environmental safety 24 37086622
2019 PIKfyve accelerates phagosome acidification through activation of TRPML1 while arrests aberrant vacuolation independent of the Ca2+ channel. Journal of biochemistry 24 30295876
2023 LW-213 induces immunogenic tumor cell death via ER stress mediated by lysosomal TRPML1. Cancer letters 23 37806516
2021 Lysosomal calcium is modulated by STIM1/TRPML1 interaction which participates to neuronal survival during ischemic preconditioning. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 23 33484198
2019 TRPML1-/TFEB-Dependent Regulation of Lysosomal Exocytosis. Methods in molecular biology (Clifton, N.J.) 22 30674023
2019 Downregulated MCOLN1 Attenuates The Progression Of Non-Small-Cell Lung Cancer By Inhibiting Lysosome-Autophagy. Cancer management and research 22 31576167
2017 The mucolipin-1 (TRPML1) ion channel, transmembrane-163 (TMEM163) protein, and lysosomal zinc handling. Frontiers in bioscience (Landmark edition) 22 28199205
2005 The frequency of mucolipidosis type IV in the Ashkenazi Jewish population and the identification of 3 novel MCOLN1 mutations. Human mutation 22 16287144
2022 Oxidative stress-induced phosphorylation of JIP4 regulates lysosomal positioning in coordination with TRPML1 and ALG2. The EMBO journal 21 36394115
2020 The intracellular Ca2+ release channel TRPML1 regulates lower urinary tract smooth muscle contractility. Proceedings of the National Academy of Sciences of the United States of America 21 33199609
2022 Targeting MCOLN1/TRPML1 channels to protect against ischemia-reperfusion injury by restoring the inhibited autophagic flux in cardiomyocytes. Autophagy 20 35491864
2020 Multiple facets of TRPML1 in autophagy. Cell calcium 19 32380434
2020 Abnormal podocyte TRPML1 channel activity and exosome release in mice with podocyte-specific Asah1 gene deletion. Biochimica et biophysica acta. Molecular and cell biology of lipids 19 33221496
2013 Intracellular two-phase Ca2+ release and apoptosis controlled by TRP-ML1 channel activity in coronary arterial myocytes. American journal of physiology. Cell physiology 18 23283937
2021 MCOLN1 gene therapy corrects neurologic dysfunction in the mouse model of mucolipidosis IV. Human molecular genetics 17 33822942
2019 TRPML1 and RAS-driven cancers - exploring a link with great therapeutic potential. Channels (Austin, Tex.) 17 31526156
2002 Cloning and characterization of the mouse Mcoln1 gene reveals an alternatively spliced transcript not seen in humans. BMC genomics 17 11897010
2025 Lysosomes finely control macrophage inflammatory function via regulating the release of lysosomal Fe2+ through TRPML1 channel. Nature communications 16 39856099
2022 Doxorubicin Induces Bone Loss by Increasing Autophagy through a Mitochondrial ROS/TRPML1/TFEB Axis in Osteoclasts. Antioxidants (Basel, Switzerland) 16 36009195
2021 Lysosomal TRPML1 Channel: Implications in Cardiovascular and Kidney Diseases. Advances in experimental medicine and biology 15 35138619
2024 Lysosomal TFEB-TRPML1 Axis in Astrocytes Modulates Depressive-like Behaviors. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 14 39264289
2023 The inhibition of TRPML1/TFEB leads to lysosomal biogenesis disorder, contributes to developmental fluoride neurotoxicity. Ecotoxicology and environmental safety 14 36608573
2023 TRPML1-Induced Lysosomal Ca2+ Signals Activate AQP2 Translocation and Water Flux in Renal Collecting Duct Cells. International journal of molecular sciences 14 36675161
2022 Activated Endolysosomal Cation Channel TRPML1 Facilitates Maturation of α-Synuclein-Containing Autophagosomes. Frontiers in cellular neuroscience 14 35875350
2013 Systematic screens for proteins that interact with the mucolipidosis type IV protein TRPML1. PloS one 14 23418601
2024 Qixian granule inhibits ferroptosis in vascular endothelial cells by modulating TRPML1 in the lysosome to prevent postmenopausal atherosclerosis. Journal of ethnopharmacology 13 38521431
2023 Ezrin inhibition alleviates oxidative stress and pyroptosis via regulating TRPML1-calcineurin axis mediated enhancement of autophagy in spinal cord injury. Free radical biology & medicine 13 38142951
2022 Iron-induced cytotoxicity mediated by endolysosomal TRPML1 channels is reverted by TFEB. Cell death & disease 13 36522443
2009 NMR assignments of the DNA binding domain of Ml4 protein from Mesorhizobium loti. Biomolecular NMR assignments 13 20020226
2008 Mucolipidosis type IV in a Turkish boy associated with a novel MCOLN1 mutation. Brain & development 13 19006653
2024 Lysosomal activity depends on TRPML1-mediated Ca2+ release coupled to incoming vesicle fusions. The Journal of biological chemistry 12 39433126
2019 Association of luteal cell degeneration and progesterone deficiency with lysosomal storage disorder mucolipidosis type IV in Mcoln1-/- mouse model†. Biology of reproduction 12 31317194
2012 Cross-talk between TRPML1 channel, lipids and lysosomal storage diseases. Communicative & integrative biology 12 22808310