The Korean Journal of Physiology and Pharmacology

The Korean Society of Pharmacology (대한약리학회)
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Unveiling the impact of lysosomal ion channels: balancing ion signaling and disease pathogenesis

  • Yoona Jung (Department of Physiology, Konkuk University School of Medicine) ;
  • Wonjoon Kim (Division of Future Convergence (HCI Science Major), Dongduk Women's University) ;
  • Na Kyoung Shin (Department of Physiology, Konkuk University School of Medicine) ;
  • Young Min Bae (Department of Physiology, Konkuk University School of Medicine) ;
  • Jinhong Wie (Department of Physiology, Konkuk University School of Medicine)
  • Received : 2023.05.31
  • Accepted : 2023.06.07
  • Published : 2023.07.01
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Abstract

Ion homeostasis, which is regulated by ion channels, is crucial for intracellular signaling. These channels are involved in diverse signaling pathways, including cell proliferation, migration, and intracellular calcium dynamics. Consequently, ion channel dysfunction can lead to various diseases. In addition, these channels are present in the plasma membrane and intracellular organelles. However, our understanding of the function of intracellular organellar ion channels is limited. Recent advancements in electrophysiological techniques have enabled us to record ion channels within intracellular organelles and thus learn more about their functions. Autophagy is a vital process of intracellular protein degradation that facilitates the breakdown of aged, unnecessary, and harmful proteins into their amino acid residues. Lysosomes, which were previously considered protein-degrading garbage boxes, are now recognized as crucial intracellular sensors that play significant roles in normal signaling and disease pathogenesis. Lysosomes participate in various processes, including digestion, recycling, exocytosis, calcium signaling, nutrient sensing, and wound repair, highlighting the importance of ion channels in these signaling pathways. This review focuses on different lysosomal ion channels, including those associated with diseases, and provides insights into their cellular functions. By summarizing the existing knowledge and literature, this review emphasizes the need for further research in this field. Ultimately, this study aims to provide novel perspectives on the regulation of lysosomal ion channels and the significance of ion-associated signaling in intracellular functions to develop innovative therapeutic targets for rare and lysosomal storage diseases.

Keywords

Acknowledgement

Thank you for supporting Wie Lab members.

References

  1. Sterea AM, Almasi S, El Hiani Y. The hidden potential of lysosomal ion channels: a new era of oncogenes. Cell Calcium. 2018;72:91-103.  https://doi.org/10.1016/j.ceca.2018.02.006
  2. Xiong J, Zhu MX. Regulation of lysosomal ion homeostasis by channels and transporters. Sci China Life Sci. 2016;59:777-791.  https://doi.org/10.1007/s11427-016-5090-x
  3. Wang H, Zhu Y, Liu H, Liang T, Wei Y. Advances in drug discovery targeting lysosomal membrane proteins. Pharmaceuticals (Basel). 2023;16:601. 
  4. Parenti G, Medina DL, Ballabio A. The rapidly evolving view of lysosomal storage diseases. EMBO Mol Med. 2021;13:e12836. 
  5. de Duve C, Pressman BC, Gianetto R, Wattiaux R, Appelmans F. Tissue fractionation studies. 6. Intracellular distribution patterns of enzymes in rat-liver tissue. Biochem J. 1955;60:604-617.  https://doi.org/10.1042/bj0600604
  6. de Duve C. The lysosome turns fifty. Nat Cell Biol. 2005;7:847-849.  https://doi.org/10.1038/ncb0905-847
  7. Lubke T, Lobel P, Sleat DE. Proteomics of the lysosome. Biochim Biophys Acta. 2009;1793:625-635.  https://doi.org/10.1016/j.bbamcr.2008.09.018
  8. Yim WW, Mizushima N. Lysosome biology in autophagy. Cell Discov. 2020;6:6. 
  9. Tancini B, Buratta S, Delo F, Sagini K, Chiaradia E, Pellegrino RM, Emiliani C, Urbanelli L. Lysosomal exocytosis: the extracellular role of an intracellular organelle. Membranes (Basel). 2020;10:406. 
  10. Bouhamdani N, Comeau D, Turcotte S. A compendium of information on the lysosome. Front Cell Dev Biol. 2021;9:798262. 
  11. Shin HR, Zoncu R. The lysosome at the intersection of cellular growth and destruction. Dev Cell. 2020;54:226-238.  https://doi.org/10.1016/j.devcel.2020.06.010
  12. Ballabio A, Bonifacino JS. Lysosomes as dynamic regulators of cell and organismal homeostasis. Nat Rev Mol Cell Biol. 2020;21:101-118.  https://doi.org/10.1038/s41580-019-0185-4
  13. Wie J, Liu Z, Song H, Tropea TF, Yang L, Wang H, Liang Y, Cang C, Aranda K, Lohmann J, Yang J, Lu B, Chen-Plotkin AS, Luk KC, Ren D. A growth-factor-activated lysosomal K+ channel regulates Parkinson's pathology. Nature. 2021;591:431-437. Erratum in: Nature. 2021;592:E10. 
  14. Perera RM, Zoncu R. The lysosome as a regulatory hub. Annu Rev Cell Dev Biol. 2016;32:223-253.  https://doi.org/10.1146/annurev-cellbio-111315-125125
  15. Finkbeiner S. The autophagy lysosomal pathway and neurodegeneration. Cold Spring Harb Perspect Biol. 2020;12:a033993. 
  16. de Martin Garrido N, Aylett CHS. Nutrient signaling and lysosome positioning crosstalk through a multifunctional protein, folliculin. Front Cell Dev Biol. 2020;8:108. 
  17. Rabanal-Ruiz Y, Korolchuk VI. mTORC1 and nutrient homeostasis: the central role of the lysosome. Int J Mol Sci. 2018;19:818. 
  18. Yogalingam G, Luu AR, Prill H, Lo MJ, Yip B, Holtzinger J, Christianson T, Aoyagi-Scharber M, Lawrence R, Crawford BE, LeBowitz JH. BMN 250, a fusion of lysosomal alpha-N-acetylglucosaminidase with IGF2, exhibits different patterns of cellular uptake into critical cell types of Sanfilippo syndrome B disease pathogenesis. PLoS One. 2019;14:e0207836. 
  19. Jia R, Bonifacino JS. Lysosome positioning influences mTORC2 and AKT signaling. Mol Cell. 2019;75:26-38.e3.  https://doi.org/10.1016/j.molcel.2019.05.009
  20. Liu B, Palmfeldt J, Lin L, Colaco A, Clemmensen KKB, Huang J, Xu F, Liu X, Maeda K, Luo Y, Jaattela M. STAT3 associates with vacuolar H+-ATPase and regulates cytosolic and lysosomal pH. Cell Res. 2018;28:996-1012.  https://doi.org/10.1038/s41422-018-0080-0
  21. Lloyd-Lewis B, Krueger CC, Sargeant TJ, D'Angelo ME, Deery MJ, Feret R, Howard JA, Lilley KS, Watson CJ. Stat3-mediated alterations in lysosomal membrane protein composition. J Biol Chem. 2018;293:4244-4261.  https://doi.org/10.1074/jbc.RA118.001777
  22. Liu B, Chen R, Zhang Y, Huang J, Luo Y, Rosthoj S, Zhao C, Jaattela M. Cationic amphiphilic antihistamines inhibit STAT3 via Ca2+-dependent lysosomal H+ efflux. Cell Rep. 2023;42:112137. 
  23. Zhang CS, Jiang B, Li M, Zhu M, Peng Y, Zhang YL, Wu YQ, Li TY, Liang Y, Lu Z, Lian G, Liu Q, Guo H, Yin Z, Ye Z, Han J, Wu JW, Yin H, Lin SY, Lin SC. The lysosomal v-ATPase-Ragulator complex is a common activator for AMPK and mTORC1, acting as a switch between catabolism and anabolism. Cell Metab. 2014;20:526-540.  https://doi.org/10.1016/j.cmet.2014.06.014
  24. Wang F, Gomez-Sintes R, Boya P. Lysosomal membrane permeabilization and cell death. Traffic. 2018;19:918-931.  https://doi.org/10.1111/tra.12613
  25. Er EE, Mendoza MC, Mackey AM, Rameh LE, Blenis J. AKT facilitates EGFR trafficking and degradation by phosphorylating and activating PIKfyve. Sci Signal. 2013;6:ra45. 
  26. Chadha R, Meador-Woodruff JH. Downregulated AKT-mTOR signaling pathway proteins in dorsolateral prefrontal cortex in Schizophrenia. Neuropsychopharmacology. 2020;45:1059-1067.  https://doi.org/10.1038/s41386-020-0614-2
  27. Hoeffer CA, Klann E. mTOR signaling: at the crossroads of plasticity, memory and disease. Trends Neurosci. 2010;33:67-75.  https://doi.org/10.1016/j.tins.2009.11.003
  28. Ishizuka Y, Kakiya N, Witters LA, Oshiro N, Shirao T, Nawa H, Takei N. AMP-activated protein kinase counteracts brain-derived neurotrophic factor-induced mammalian target of rapamycin complex 1 signaling in neurons. J Neurochem. 2013;127:66-77.  https://doi.org/10.1111/jnc.12362
  29. Dalle Pezze P, Ruf S, Sonntag AG, Langelaar-Makkinje M, Hall P, Heberle AM, Razquin Navas P, van Eunen K, Tolle RC, Schwarz JJ, Wiese H, Warscheid B, Deitersen J, Stork B, Fassler E, Schauble S, Hahn U, Horvatovich P, Shanley DP, Thedieck K. A systems study reveals concurrent activation of AMPK and mTOR by amino acids. Nat Commun. 2016;7:13254. 
  30. Jeger JL. Endosomes, lysosomes, and the role of endosomal and lysosomal biogenesis in cancer development. Mol Biol Rep. 2020;47:9801-9810.  https://doi.org/10.1007/s11033-020-05993-4
  31. Reggiori F, Gabius HJ, Aureli M, Romer W, Sonnino S, Eskelinen EL. Glycans in autophagy, endocytosis and lysosomal functions. Glycoconj J. 2021;38:625-647.  https://doi.org/10.1007/s10719-021-10007-x
  32. Trivedi PC, Bartlett JJ, Pulinilkunnil T. Lysosomal biology and function: modern view of cellular debris bin. Cells. 2020;9:1131. 
  33. Bonam SR, Wang F, Muller S. Lysosomes as a therapeutic target. Nat Rev Drug Discov. 2019;18:923-948.  https://doi.org/10.1038/s41573-019-0036-1
  34. Bajaj L, Lotfi P, Pal R, Ronza AD, Sharma J, Sardiello M. Lysosome biogenesis in health and disease. J Neurochem. 2019;148:573-589.  https://doi.org/10.1111/jnc.14564
  35. Pfeffer SR. NPC intracellular cholesterol transporter 1 (NPC1)-mediated cholesterol export from lysosomes. J Biol Chem. 2019;294:1706-1709.  https://doi.org/10.1074/jbc.TM118.004165
  36. Altuzar J, Notbohm J, Stein F, Haberkant P, Hempelmann P, Heybrock S, Worsch J, Saftig P, Hoglinger D. Lysosome-targeted multifunctional lipid probes reveal the sterol transporter NPC1 as a sphingosine interactor. Proc Natl Acad Sci U S A. 2023;120:e2213886120. 
  37. Henne WM. How NPC1 loss twists the TORCque of lysosomes. Dev Cell. 2021;56:251-252.  https://doi.org/10.1016/j.devcel.2021.01.007
  38. Patel S, Ramakrishnan L, Rahman T, Hamdoun A, Marchant JS, Taylor CW, Brailoiu E. The endo-lysosomal system as an NAADP-sensitive acidic Ca(2+) store: role for the two-pore channels. Cell Calcium. 2011;50:157-167.  https://doi.org/10.1016/j.ceca.2011.03.011
  39. Yuan Y, Jaslan D, Rahman T, Bolsover SR, Arige V, Wagner LE 2nd, Abrahamian C, Tang R, Keller M, Hartmann J, Rosato AS, Weiden EM, Bracher F, Yule DI, Grimm C, Patel S. Segregated cation flux by TPC2 biases Ca2+ signaling through lysosomes. Nat Commun. 2022;13:4481. 
  40. Lagostena L, Festa M, Pusch M, Carpaneto A. The human two-pore channel 1 is modulated by cytosolic and luminal calcium. Sci Rep. 2017;7:43900. 
  41. Calcraft PJ, Ruas M, Pan Z, Cheng X, Arredouani A, Hao X, Tang J, Rietdorf K, Teboul L, Chuang KT, Lin P, Xiao R, Wang C, Zhu Y, Lin Y, Wyatt CN, Parrington J, Ma J, Evans AM, Galione A, et al. NAADP mobilizes calcium from acidic organelles through two-pore channels. Nature. 2009;459:596-600.  https://doi.org/10.1038/nature08030
  42. Cang C, Zhou Y, Navarro B, Seo YJ, Aranda K, Shi L, Battaglia-Hsu S, Nissim I, Clapham DE, Ren D. mTOR regulates lysosomal ATP-sensitive two-pore Na(+) channels to adapt to metabolic state. Cell. 2013;152:778-790.  https://doi.org/10.1016/j.cell.2013.01.023
  43. Wang X, Zhang X, Dong XP, Samie M, Li X, Cheng X, Goschka A, Shen D, Zhou Y, Harlow J, Zhu MX, Clapham DE, Ren D, Xu H. TPC proteins are phosphoinositide- activated sodium-selective ion channels in endosomes and lysosomes. Cell. 2012;151:372-383.  https://doi.org/10.1016/j.cell.2012.08.036
  44. She J, Guo J, Chen Q, Zeng W, Jiang Y, Bai XC. Structural insights into the voltage and phospholipid activation of the mammalian TPC1 channel. Nature. 2018;556:130-134.  https://doi.org/10.1038/nature26139
  45. Patel S, Yuan Y, Gunaratne GS, Rahman T, Marchant JS. Activation of endo-lysosomal two-pore channels by NAADP and PI(3,5) P2. Five things to know. Cell Calcium. 2022;103:102543. 
  46. Russell T, Gangotia D, Barry G. Assessing the potential of repurposing ion channel inhibitors to treat emerging viral diseases and the role of this host factor in virus replication. Biomed Pharmacother. 2022;156:113850. 
  47. Guo J, Zeng W, Jiang Y. Tuning the ion selectivity of two-pore channels. Proc Natl Acad Sci U S A. 2017;114:1009-1014.  https://doi.org/10.1073/pnas.1616191114
  48. She J, Zeng W, Guo J, Chen Q, Bai XC, Jiang Y. Structural mechanisms of phospholipid activation of the human TPC2 channel. Elife. 2019;8:e45222. 
  49. Castonguay J, Orth JHC, Muller T, Sleman F, Grimm C, Wahl-Schott C, Biel M, Mallmann RT, Bildl W, Schulte U, Klugbauer N. The two-pore channel TPC1 is required for efficient protein processing through early and recycling endosomes. Sci Rep. 2017;7:10038. 
  50. Moccia F, Negri S, Faris P, Perna A, De Luca A, Soda T, Berra-Romani R, Guerra G. Targeting endolysosomal two-pore channels to treat cardiovascular disorders in the novel COronaVIrus Disease 2019. Front Physiol. 2021;12:629119. Erratum in: Front Physiol. 2021;12:690189.  https://doi.org/10.3389/fphys.2021.629119
  51. Penny CJ, Vassileva K, Jha A, Yuan Y, Chee X, Yates E, Mazzon M, Kilpatrick BS, Muallem S, Marsh M, Rahman T, Patel S. Mining of Ebola virus entry inhibitors identifies approved drugs as two-pore channel pore blockers. Biochim Biophys Acta Mol Cell Res. 2019;1866:1151-1161.  https://doi.org/10.1016/j.bbamcr.2018.10.022
  52. Heister PM, Poston RN. Pharmacological hypothesis: TPC2 antagonist tetrandrine as a potential therapeutic agent for COVID-19. Pharmacol Res Perspect. 2020;8:e00653. 
  53. Lin PH, Duann P, Komazaki S, Park KH, Li H, Sun M, Sermersheim M, Gumpper K, Parrington J, Galione A, Evans AM, Zhu MX, Ma J. Lysosomal two-pore channel subtype 2 (TPC2) regulates skeletal muscle autophagic signaling. J Biol Chem. 2015;290:3377-3389.  https://doi.org/10.1074/jbc.M114.608471
  54. Grimm C, Holdt LM, Chen CC, Hassan S, Muller C, Jors S, Cuny H, Kissing S, Schroder B, Butz E, Northoff B, Castonguay J, Luber CA, Moser M, Spahn S, Lullmann-Rauch R, Fendel C, Klugbauer N, Griesbeck O, Haas A, et al. High susceptibility to fatty liver disease in two-pore channel 2-deficient mice. Nat Commun. 2014;5:4699. 
  55. Patel S, Kilpatrick BS. Two-pore channels and disease. Biochim Biophys Acta Mol Cell Res. 2018;1865 (11 Pt B):1678-1686.  https://doi.org/10.1016/j.bbamcr.2018.05.004
  56. Sakurai Y, Kolokoltsov AA, Chen CC, Tidwell MW, Bauta WE, Klugbauer N, Grimm C, Wahl-Schott C, Biel M, Davey RA. Ebola virus. Two-pore channels control Ebola virus host cell entry and are drug targets for disease treatment. Science. 2015;347:995-998.  https://doi.org/10.1126/science.1258758
  57. Gerndt S, Krogsaeter E, Patel S, Bracher F, Grimm C. Discovery of lipophilic two-pore channel agonists. FEBS J. 2020;287:5284-5293.  https://doi.org/10.1111/febs.15432
  58. Chapel A, Kieffer-Jaquinod S, Sagne C, Verdon Q, Ivaldi C, Mellal M, Thirion J, Jadot M, Bruley C, Garin J, Gasnier B, Journet A. An extended proteome map of the lysosomal membrane reveals novel potential transporters. Mol Cell Proteomics. 2013;12:1572-1588.  https://doi.org/10.1074/mcp.M112.021980
  59. Cang C, Aranda K, Seo YJ, Gasnier B, Ren D. TMEM175 is an organelle K(+) channel regulating lysosomal function. Cell. 2015;162:1101-1112.  https://doi.org/10.1016/j.cell.2015.08.002
  60. Chia R, Sabir MS, Bandres-Ciga S, Saez-Atienzar S, Reynolds RH, Gustavsson E, Walton RL, Ahmed S, Viollet C, Ding J, Makarious MB, Diez-Fairen M, Portley MK, Shah Z, Abramzon Y, Hernandez DG, Blauwendraat C, Stone DJ, Eicher J, Parkkinen L, et al. Genome sequencing analysis identifies new loci associated with Lewy body dementia and provides insights into its genetic architecture. Nat Genet. 2021;53:294-303.  https://doi.org/10.1038/s41588-021-00785-3
  61. Jinn S, Drolet RE, Cramer PE, Wong AH, Toolan DM, Gretzula CA, Voleti B, Vassileva G, Disa J, Tadin-Strapps M, Stone DJ. TMEM175 deficiency impairs lysosomal and mitochondrial function and increases α-synuclein aggregation. Proc Natl Acad Sci U S A. 2017;114:2389-2394.  https://doi.org/10.1073/pnas.1616332114
  62. Nalls MA, Pankratz N, Lill CM, Do CB, Hernandez DG, Saad M, DeStefano AL, Kara E, Bras J, Sharma M, Schulte C, Keller MF, Arepalli S, Letson C, Edsall C, Stefansson H, Liu X, Pliner H, Lee JH, Cheng R, et al.; International Parkinson's Disease Genomics Consortium (IPDGC); Parkinson's Study Group (PSG) Parkinson's Research: The Organized GENetics Initiative (PROGENI); 23andMe; GenePD; NeuroGenetics Research Consortium (NGRC); Hussman Institute of Human Genomics (HIHG); Ashkenazi Jewish Dataset Investigator; Cohorts for Health and Aging Research in Genetic Epidemiology (CHARGE); North American Brain Expression Consortium (NABEC); United Kingdom Brain Expression Consortium (UKBEC); Greek Parkinson's Disease Consortium; Alzheimer Genetic Analysis Group. Large-scale meta-analysis of genome-wide association data identifies six new risk loci for Parkinson's disease. Nat Genet. 2014;46:989-993.  https://doi.org/10.1038/ng.3043
  63. Hopfner F, Mueller SH, Szymczak S, Junge O, Tittmann L, May S, Lohmann K, Grallert H, Lieb W, Strauch K, Muller-Nurasyid M, Berger K, Schormair B, Winkelmann J, Mollenhauer B, Trenkwalder C, Maetzler W, Berg D, Kasten M, Klein C, et al. Rare variants in specific lysosomal genes are associated with Parkinson's disease. Mov Disord. 2020;35:1245-1248.  https://doi.org/10.1002/mds.28037
  64. Brunner JD, Jakob RP, Schulze T, Neldner Y, Moroni A, Thiel G, Maier T, Schenck S. Structural basis for ion selectivity in TMEM175 K+ channels. Elife. 2020;9:e53683. 
  65. Iwaki H, Blauwendraat C, Leonard HL, Liu G, Maple-Grodem J, Corvol JC, Pihlstrom L, van Nimwegen M, Hutten SJ, Nguyen KH, Rick J, Eberly S, Faghri F, Auinger P, Scott KM, Wijeyekoon R, Van Deerlin VM, Hernandez DG, Day-Williams AG, Brice A, et al. Genetic risk of Parkinson disease and progression: an analysis of 13 longitudinal cohorts. Neurol Genet. 2019;5:e348. Erratum in: Neurol Genet. 2019;5:e354. 
  66. Ge L, Hoa NT, Wilson Z, Arismendi-Morillo G, Kong XT, Tajhya RB, Beeton C, Jadus MR. Big Potassium (BK) ion channels in biology, disease and possible targets for cancer immunotherapy. Int Immunopharmacol. 2014;22:427-443.  https://doi.org/10.1016/j.intimp.2014.06.040
  67. Cao Q, Zhong XZ, Zou Y, Zhang Z, Toro L, Dong XP. BK channels alleviate lysosomal storage diseases by providing positive feedback regulation of lysosomal Ca2+ release. Dev Cell. 2015;33:427-441.  https://doi.org/10.1016/j.devcel.2015.04.010
  68. Clapham DE, Runnels LW, Strubing C. The TRP ion channel family. Nat Rev Neurosci. 2001;2:387-396.  https://doi.org/10.1038/35077544
  69. Xia Z, Xie L, Li D, Hong X, Qin C. Gene expression of TRPMLs and its regulation by pathogen stimulation. Gene. 2023;864:147291. 
  70. Zeevi DA, Frumkin A, Bach G. TRPML and lysosomal function. Biochim Biophys Acta. 2007;1772:851-858.  https://doi.org/10.1016/j.bbadis.2007.01.004
  71. Falardeau JL, Kennedy JC, Acierno JS Jr, Sun M, Stahl S, Goldin E, Slaugenhaupt SA. Cloning and characterization of the mouse Mcoln1 gene reveals an alternatively spliced transcript not seen in humans. BMC Genomics. 2002;3:3. 
  72. Grimm C, Jors S, Saldanha SA, Obukhov AG, Pan B, Oshima K, Cuajungco MP, Chase P, Hodder P, Heller S. Small molecule activators of TRPML3. Chem Biol. 2010;17:135-148.  https://doi.org/10.1016/j.chembiol.2009.12.016
  73. Santoni G, Morelli MB, Amantini C, Nabissi M, Santoni M, Santoni A. Involvement of the TRPML mucolipin channels in viral infections and anti-viral innate immune responses. Front Immunol. 2020;11:739. 
  74. Li M, Zhang WK, Benvin NM, Zhou X, Su D, Li H, Wang S, Michailidis IE, Tong L, Li X, Yang J. Structural basis of dual Ca2+/pH regulation of the endolysosomal TRPML1 channel. Nat Struct Mol Biol. 2017;24:205-213.  https://doi.org/10.1038/nsmb.3362
  75. Venkatachalam K, Hofmann T, Montell C. Lysosomal localization of TRPML3 depends on TRPML2 and the mucolipidosis-associated protein TRPML1. J Biol Chem. 2006;281:17517-17527.  https://doi.org/10.1074/jbc.M600807200
  76. Di Paola S, Scotto-Rosato A, Medina DL. TRPML1: The Ca(2+)retaker of the lysosome. Cell Calcium. 2018;69:112-121.  https://doi.org/10.1016/j.ceca.2017.06.006
  77. Dong XP, Cheng X, Mills E, Delling M, Wang F, Kurz T, Xu H. The type IV mucolipidosis-associated protein TRPML1 is an endolysosomal iron release channel. Nature. 2008;455:992-996.  https://doi.org/10.1038/nature07311
  78. Dong XP, Shen D, Wang X, Dawson T, Li X, Zhang Q, Cheng X, Zhang Y, Weisman LS, Delling M, Xu H. PI(3,5)P(2) controls membrane trafficking by direct activation of mucolipin Ca(2+) release channels in the endolysosome. Nat Commun. 2010;1:38. 
  79. Soyombo AA, Tjon-Kon-Sang S, Rbaibi Y, Bashllari E, Bisceglia J, Muallem S, Kiselyov K. TRP-ML1 regulates lysosomal pH and acidic lysosomal lipid hydrolytic activity. J Biol Chem. 2006;281:7294-7301.  https://doi.org/10.1074/jbc.M508211200
  80. Samie MA, Grimm C, Evans JA, Curcio-Morelli C, Heller S, Slaugenhaupt SA, Cuajungco MP. The tissue-specific expression of TRPML2 (MCOLN-2) gene is influenced by the presence of TRPML1. Pflugers Arch. 2009;459:79-91.  https://doi.org/10.1007/s00424-009-0716-5
  81. Karacsonyi C, Miguel AS, Puertollano R. Mucolipin-2 localizes to the Arf6-associated pathway and regulates recycling of GPI-APs. Traffic. 2007;8:1404-1414.  https://doi.org/10.1111/j.1600-0854.2007.00619.x
  82. Sun L, Hua Y, Vergarajauregui S, Diab HI, Puertollano R. Novel role of TRPML2 in the regulation of the innate immune response. J Immunol. 2015;195:4922-4932.  https://doi.org/10.4049/jimmunol.1500163
  83. Hirschi M, Herzik MA Jr, Wie J, Suo Y, Borschel WF, Ren D, Lander GC, Lee SY. Cryo-electron microscopy structure of the lysosomal calcium-permeable channel TRPML3. Nature. 2017;550:411-414.  https://doi.org/10.1038/nature24055
  84. Kim HJ, Li Q, Tjon-Kon-Sang S, So I, Kiselyov K, Soyombo AA, Muallem S. A novel mode of TRPML3 regulation by extracytosolic pH absent in the varitint-waddler phenotype. EMBO J. 2008;27:1197-1205.  https://doi.org/10.1038/emboj.2008.56
  85. Venkatachalam K, Wong CO, Zhu MX. The role of TRPMLs in endolysosomal trafficking and function. Cell Calcium. 2015;58:48-56.  https://doi.org/10.1016/j.ceca.2014.10.008
  86. Choi S, Kim HJ. The Ca2+ channel TRPML3 specifically interacts with the mammalian ATG8 homologue GATE16 to regulate autophagy. Biochem Biophys Res Commun. 2014;443:56-61.  https://doi.org/10.1016/j.bbrc.2013.11.044
  87. Kim SW, Kim DH, Park KS, Kim MK, Park YM, Muallem S, So I, Kim HJ. Palmitoylation controls trafficking of the intracellular Ca2+ channel MCOLN3/TRPML3 to regulate autophagy. Autophagy. 2019;15:327-340.  https://doi.org/10.1080/15548627.2018.1518671
  88. Kim HJ, Soyombo AA, Tjon-Kon-Sang S, So I, Muallem S. The Ca(2+) channel TRPML3 regulates membrane trafficking and autophagy. Traffic. 2009;10:1157-1167.  https://doi.org/10.1111/j.1600-0854.2009.00924.x
  89. Grimm C, Cuajungco MP, van Aken AF, Schnee M, Jors S, Kros CJ, Ricci AJ, Heller S. A helix-breaking mutation in TRPML3 leads to constitutive activity underlying deafness in the varitint-waddler mouse. Proc Natl Acad Sci U S A. 2007;104:19583-19588.  https://doi.org/10.1073/pnas.0709846104
  90. Jentsch TJ, Pusch M. CLC chloride channels and transporters: structure, function, physiology, and disease. Physiol Rev. 2018;98:1493-1590.  https://doi.org/10.1152/physrev.00047.2017
  91. Zifarelli G, Pusch M. CLC transport proteins in plants. FEBS Lett. 2010;584:2122-2127.  https://doi.org/10.1016/j.febslet.2009.12.042
  92. Kornak U, Kasper D, Bosl MR, Kaiser E, Schweizer M, Schulz A, Friedrich W, Delling G, Jentsch TJ. Loss of the ClC-7 chloride channel leads to osteopetrosis in mice and man. Cell. 2001;104:205-215.  https://doi.org/10.1016/S0092-8674(01)00206-9
  93. Kasper D, Planells-Cases R, Fuhrmann JC, Scheel O, Zeitz O, Ruether K, Schmitt A, Poet M, Steinfeld R, Schweizer M, Kornak U, Jentsch TJ. Loss of the chloride channel ClC-7 leads to lysosomal storage disease and neurodegeneration. EMBO J. 2005;24:1079-1091.  https://doi.org/10.1038/sj.emboj.7600576
  94. Brandt S, Jentsch TJ. ClC-6 and ClC-7 are two novel broadly expressed members of the CLC chloride channel family. FEBS Lett. 1995;377:15-20.  https://doi.org/10.1016/0014-5793(95)01298-2
  95. Stauber T, Weinert S, Jentsch TJ. Cell biology and physiology of CLC chloride channels and transporters. Compr Physiol. 2012;2:1701-1744.  https://doi.org/10.1002/cphy.c110038
  96. Bergsdorf EY, Zdebik AA, Jentsch TJ. Residues important for nitrate/proton coupling in plant and mammalian CLC transporters. J Biol Chem. 2009;284:11184-11193.  https://doi.org/10.1074/jbc.M901170200
  97. Schrecker M, Korobenko J, Hite RK. Cryo-EM structure of the lysosomal chloride-proton exchanger CLC-7 in complex with OSTM1. Elife. 2020;9:e59555. 
  98. Lange PF, Wartosch L, Jentsch TJ, Fuhrmann JC. ClC-7 requires Ostm1 as a beta-subunit to support bone resorption and lysosomal function. Nature. 2006;440:220-223.  https://doi.org/10.1038/nature04535
  99. Jentsch TJ. Chloride and the endosomal-lysosomal pathway: emerging roles of CLC chloride transporters. J Physiol. 2007;578:633-640.  https://doi.org/10.1113/jphysiol.2006.124719
  100. Chalhoub N, Benachenhou N, Rajapurohitam V, Pata M, Ferron M, Frattini A, Villa A, Vacher J. Grey-lethal mutation induces severe malignant autosomal recessive osteopetrosis in mouse and human. Nat Med. 2003;9:399-406.  https://doi.org/10.1038/nm842
  101. Leisle L, Ludwig CF, Wagner FA, Jentsch TJ, Stauber T. ClC-7 is a slowly voltage-gated 2Cl(-)/1H(+)-exchanger and requires Ostm1 for transport activity. EMBO J. 2011;30:2140-2152.  https://doi.org/10.1038/emboj.2011.137
  102. Wu JZ, Zeziulia M, Kwon W, Jentsch TJ, Grinstein S, Freeman SA. ClC-7 drives intraphagosomal chloride accumulation to support hydrolase activity and phagosome resolution. J Cell Biol. 2023;222:e202208155. 
  103. Leray X, Hilton JK, Nwangwu K, Becerril A, Mikusevic V, Fitzgerald G, Amin A, Weston MR, Mindell JA. Tonic inhibition of the chloride/proton antiporter ClC-7 by PI(3,5)P2 is crucial for lysosomal pH maintenance. Elife. 2022;11:e74136. 
  104. Klaus F, Laufer J, Czarkowski K, Strutz-Seebohm N, Seebohm G, Lang F. PIKfyve-dependent regulation of the Cl- channel ClC-2. Biochem Biophys Res Commun. 2009;381:407-411.  https://doi.org/10.1016/j.bbrc.2009.02.053
  105. Zifarelli G. The role of the lysosomal Cl-/H+ antiporter ClC-7 in osteopetrosis and neurodegeneration. Cells. 2022;11:366. 
  106. Kroemer G, Jaattela M. Lysosomes and autophagy in cell death control. Nat Rev Cancer. 2005;5:886-897.  https://doi.org/10.1038/nrc1738
  107. Hwang J, Estick CM, Ikonne US, Butler D, Pait MC, Elliott LH, Ruiz S, Smith K, Rentschler KM, Mundell C, Almeida MF, Stumbling Bear N, Locklear JP, Abumohsen Y, Ivey CM, Farizatto KLG, Bahr BA. The role of lysosomes in a broad disease-modifying approach evaluated across transgenic mouse models of Alzheimer's disease and Parkinson's disease and models of mild cognitive impairment. Int J Mol Sci. 2019;20:4432. 
  108. Navarro-Romero A, Montpeyo M, Martinez-Vicente M. The emerging role of the lysosome in Parkinson's disease. Cells. 2020;9:2399. 
  109. Wiwatpanit T, Remis NN, Ahmad A, Zhou Y, Clancy JC, Cheatham MA, Garcia-Anoveros J. Codeficiency of lysosomal mucolipins 3 and 1 in cochlear hair cells diminishes outer hair cell longevity and accelerates age-related hearing loss. J Neurosci. 2018;38:3177-3189.  https://doi.org/10.1523/JNEUROSCI.3368-17.2018
  110. Hayashi K, Suzuki Y, Fujimoto C, Kanzaki S. Molecular mechanisms and biological functions of autophagy for genetics of hearing impairment. Genes (Basel). 2020;11:1331. 
  111. Mizunoe Y, Kobayashi M, Tagawa R, Nakagawa Y, Shimano H, Higami Y. Association between lysosomal dysfunction and obesity-related pathology: a key knowledge to prevent metabolic syndrome. Int J Mol Sci. 2019;20:3688. 
  112. Rawnsley DR, Diwan A. Lysosome impairment as a trigger for inflammation in obesity: the proof is in the fat. EBioMedicine. 2020;56:102824. 
  113. Barnett BS, Ziegler K, Doblin R, Carlo AD. Is psychedelic use associated with cancer?: interrogating a half-century-old claim using contemporary population-level data. J Psychopharmacol. 2022;36:1118-1128.  https://doi.org/10.1177/02698811221117536
  114. Ng PY, Ribet ABP, Guo Q, Mullin BH, Tan JWY, Landao-Bassonga E, Stephens S, Chen K, Yuan J, Abudulai L, Bollen M, Nguyen ETTT, Kular J, Papadimitriou JM, Soe K, Teasdale RD, Xu J, Parton RG, Takayanagi H, Pavlos NJ. Sugar transporter Slc37a2 regulates bone metabolism in mice via a tubular lysosomal network in osteoclasts. Nat Commun. 2023;14:906. 
  115. Larsen LE, van den Boogert MAW, Rios-Ocampo WA, Jansen JC, Conlon D, Chong PLE, Levels JHM, Eilers RE, Sachdev VV, Zelcer N, Raabe T, He M, Hand NJ, Drenth JPH, Rader DJ, Stroes ESG, Lefeber DJ, Jonker JW, Holleboom AG. Defective lipid droplet-lysosome interaction causes fatty liver disease as evidenced by human mutations in TMEM199 and CCDC115. Cell Mol Gastroenterol Hepatol. 2022;13:583-597.  https://doi.org/10.1016/j.jcmgh.2021.09.013
  116. Machado ER, Annunziata I, van de Vlekkert D, Grosveld GC, d'Azzo A. Lysosomes and cancer progression: a malignant liaison. Front Cell Dev Biol. 2021;9:642494. 
  117. Zhao Z, Qin P, Huang YW. Lysosomal ion channels involved in cellular entry and uncoating of enveloped viruses: implications for therapeutic strategies against SARS-CoV-2. Cell Calcium. 2021;94:102360. 
  118. Wang X, Melino G, Shi Y. Actively or passively deacidified lysosomes push β-coronavirus egress. Cell Death Dis. 2021;12:235. 
  119. Vardi A, Pri-Or A, Wigoda N, Grishchuk Y, Futerman AH. Proteomics analysis of a human brain sample from a mucolipidosis type IV patient reveals pathophysiological pathways. Orphanet J Rare Dis. 2021;16:39. 
  120. Vacca F, Vossio S, Mercier V, Moreau D, Johnson S, Scott CC, Montoya JP, Moniatte M, Gruenberg J. Cyclodextrin triggers MCOLN1-dependent endo-lysosome secretion in Niemann-Pick type C cells. J Lipid Res. 2019;60:832-843.  https://doi.org/10.1194/jlr.M089979
  121. Gibson PG, Qin L, Puah SH. COVID-19 acute respiratory distress syndrome (ARDS): clinical features and differences from typical pre-COVID-19 ARDS. Med J Aust. 2020;213:54-56.e1.  https://doi.org/10.5694/mja2.50674
  122. Huang C, Wang Y, Li X, Ren L, Zhao J, Hu Y, Zhang L, Fan G, Xu J, Gu X, Cheng Z, Yu T, Xia J, Wei Y, Wu W, Xie X, Yin W, Li H, Liu M, Xiao Y, et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet. 2020;395:497-506. Erratum in: Lancet. 2020 Jan 30.  https://doi.org/10.1016/S0140-6736(20)30183-5
  123. Zhou P, Yang XL, Wang XG, Hu B, Zhang L, Zhang W, Si HR, Zhu Y, Li B, Huang CL, Chen HD, Chen J, Luo Y, Guo H, Jiang RD, Liu MQ, Chen Y, Shen XR, Wang X, Zheng XS, et al. A pneumonia outbreak associated with a new coronavirus of probable bat origin. Nature. 2020;579:270-273. Erratum in: Nature. 2020;588:E6. 
  124. Nishiga M, Wang DW, Han Y, Lewis DB, Wu JC. COVID-19 and cardiovascular disease: from basic mechanisms to clinical perspectives. Nat Rev Cardiol. 2020;17:543-558.  https://doi.org/10.1038/s41569-020-0413-9
  125. Zheng YY, Ma YT, Zhang JY, Xie X. COVID-19 and the cardiovascular system. Nat Rev Cardiol. 2020;17:259-260.  https://doi.org/10.1038/s41569-020-0360-5
  126. Grimm C, Tang R. Could an endo-lysosomal ion channel be the Achilles heel of SARS-CoV2? Cell Calcium. 2020;88:102212. 
  127. Arlt E, Fraticelli M, Tsvilovskyy V, Nadolni W, Breit A, O'Neill TJ, Resenberger S, Wennemuth G, Wahl-Schott C, Biel M, Grimm C, Freichel M, Gudermann T, Klugbauer N, Boekhoff I, Zierler S. TPC1 deficiency or blockade augments systemic anaphylaxis and mast cell activity. Proc Natl Acad Sci U S A. 2020;117:18068-18078.  https://doi.org/10.1073/pnas.1920122117
  128. Scotto Rosato A, Krogsaeter EK, Jaslan D, Abrahamian C, Montefusco S, Soldati C, Spix B, Pizzo MT, Grieco G, Bock J, Wyatt A, Wunkhaus D, Passon M, Stieglitz M, Keller M, Hermey G, Markmann S, Gruber-Schoffnegger D, Cotman S, Johannes L, et al. TPC2 rescues lysosomal storage in mucolipidosis type IV, Niemann-Pick type C1, and Batten disease. EMBO Mol Med. 2022;14:e15377. 
  129. Du X, Carvalho-de-Souza JL, Wei C, Carrasquel-Ursulaez W, Lorenzo Y, Gonzalez N, Kubota T, Staisch J, Hain T, Petrossian N, Xu M, Latorre R, Bezanilla F, Gomez CM. Loss-of-function BK channel mutation causes impaired mitochondria and progressive cerebellar ataxia. Proc Natl Acad Sci U S A. 2020;117:6023-6034.  https://doi.org/10.1073/pnas.1920008117
  130. Gonzalez-Sanabria N, Echeverria F, Segura I, Alvarado-Sanchez R, Latorre R. BK in double-membrane organelles: a biophysical, pharmacological, and functional survey. Front Physiol. 2021;12:761474. 
  131. Park SM, Roache CE, Iffland PH 2nd, Moldenhauer HJ, Matychak KK, Plante AE, Lieberman AG, Crino PB, Meredith A. BK channel properties correlate with neurobehavioral severity in three KCNMA1-linked channelopathy mouse models. Elife. 2022;11:e77953. 
  132. Caldeira da Silva CC, Cerqueira FM, Barbosa LF, Medeiros MH, Kowaltowski AJ. Mild mitochondrial uncoupling in mice affects energy metabolism, redox balance and longevity. Aging Cell. 2008;7:552-560.  https://doi.org/10.1111/j.1474-9726.2008.00407.x
  133. Donida B, Marchetti DP, Biancini GB, Deon M, Manini PR, da Rosa HT, Moura DJ, Saffi J, Bender F, Burin MG, Coitinho AS, Giugliani R, Vargas CR. Oxidative stress and inflammation in mucopolysaccharidosis type IVA patients treated with enzyme replacement therapy. Biochim Biophys Acta. 2015;1852:1012-1019.  https://doi.org/10.1016/j.bbadis.2015.02.004
  134. Teixeira CA, Miranda CO, Sousa VF, Santos TE, Malheiro AR, Solomon M, Maegawa GH, Brites P, Sousa MM. Early axonal loss accompanied by impaired endocytosis, abnormal axonal transport, and decreased microtubule stability occur in the model of Krabbe's disease. Neurobiol Dis. 2014;66:92-103.  https://doi.org/10.1016/j.nbd.2014.02.012
  135. Eldar-Finkelman H, Martinez A. GSK-3 inhibitors: preclinical and clinical focus on CNS. Front Mol Neurosci. 2011;4:32. 
  136. Stepien KM, Cufflin N, Donald A, Jones S, Church H, Hargreaves IP. Secondary mitochondrial dysfunction as a cause of neurodegenerative dysfunction in lysosomal storage diseases and an overview of potential therapies. Int J Mol Sci. 2022;23:10573. 
  137. Zhang X, Chen W, Gao Q, Yang J, Yan X, Zhao H, Su L, Yang M, Gao C, Yao Y, Inoki K, Li D, Shao R, Wang S, Sahoo N, Kudo F, Eguchi T, Ruan B, Xu H. Rapamycin directly activates lysosomal mucolipin TRP channels independent of mTOR. PLoS Biol. 2019;17:e3000252. 
  138. Hooper C, Killick R, Lovestone S. The GSK3 hypothesis of Alzheimer's disease. J Neurochem. 2008;104:1433-1439. https://doi.org/10.1111/j.1471-4159.2007.05194.x