Induction of Lysosomal Exocytosis and Biogenesis Via TRPML1 Activation for the Treatment of Uranium-induced Nephrotoxicity

Overview

Journal Nat Commun

Specialty Biology

Date 2023 Jul 6

PMID 37414766

Authors

Dengqin Zhong

Ruiyun Wang

Hongjing Zhang

Mengmeng Wang

Xuxia Zhang

Honghong Chen

Affiliations

Soon will be listed here.

Abstract

Uranium (U) is a well-known nephrotoxicant which forms precipitates in the lysosomes of renal proximal tubular epithelial cells (PTECs) after U-exposure at a cytotoxic dose. However, the roles of lysosomes in U decorporation and detoxification remain to be elucidated. Mucolipin transient receptor potential channel 1 (TRPML1) is a major lysosomal Ca channel regulating lysosomal exocytosis. We herein demonstrate that the delayed administration of the specific TRPML1 agonist ML-SA1 significantly decreases U accumulation in the kidney, mitigates renal proximal tubular injury, increases apical exocytosis of lysosomes and reduces lysosomal membrane permeabilization (LMP) in renal PTECs of male mice with single-dose U poisoning or multiple-dose U exposure. Mechanistic studies reveal that ML-SA1 stimulates intracellular U removal and reduces U-induced LMP and cell death through activating the positive TRPML1-TFEB feedback loop and consequent lysosomal exocytosis and biogenesis in U-loaded PTECs in vitro. Together, our studies demonstrate that TRPML1 activation is an attractive therapeutic strategy for the treatment of U-induced nephrotoxicity.

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References

Boya P, Kroemer G . Lysosomal membrane permeabilization in cell death. Oncogene. 2008; 27(50):6434-51. DOI: 10.1038/onc.2008.310. View

Medina D, Fraldi A, Bouche V, Annunziata F, Mansueto G, Spampanato C . Transcriptional activation of lysosomal exocytosis promotes cellular clearance. Dev Cell. 2011; 21(3):421-30. PMC: 3173716. DOI: 10.1016/j.devcel.2011.07.016. View

Pierrefite-Carle V, Santucci-Darmanin S, Breuil V, Gritsaenko T, Vidaud C, Creff G . Effect of natural uranium on the UMR-106 osteoblastic cell line: impairment of the autophagic process as an underlying mechanism of uranium toxicity. Arch Toxicol. 2016; 91(4):1903-1914. DOI: 10.1007/s00204-016-1833-5. View

Kumar P, Nagarajan A, Uchil P . Analysis of Cell Viability by the Lactate Dehydrogenase Assay. Cold Spring Harb Protoc. 2018; 2018(6). DOI: 10.1101/pdb.prot095497. View

Thompson E, Schaheen L, Dang H, Fares H . Lysosomal trafficking functions of mucolipin-1 in murine macrophages. BMC Cell Biol. 2007; 8:54. PMC: 2254603. DOI: 10.1186/1471-2121-8-54. View

Milgram S, Carriere M, Malaval L, Gouget B . Cellular accumulation and distribution of uranium and lead in osteoblastic cells as a function of their speciation. Toxicology. 2008; 252(1-3):26-32. DOI: 10.1016/j.tox.2008.07.054. View

Ali Samie M, Xu H . Lysosomal exocytosis and lipid storage disorders. J Lipid Res. 2014; 55(6):995-1009. PMC: 4031951. DOI: 10.1194/jlr.R046896. View

Goodwin J, Walkup 4th W, Hooper K, Li T, Kishi-Itakura C, Ng A . GABARAP sequesters the FLCN-FNIP tumor suppressor complex to couple autophagy with lysosomal biogenesis. Sci Adv. 2021; 7(40):eabj2485. PMC: 10938568. DOI: 10.1126/sciadv.abj2485. View

Liu Q, Kirubakaran S, Hur W, Niepel M, Westover K, Thoreen C . Kinome-wide selectivity profiling of ATP-competitive mammalian target of rapamycin (mTOR) inhibitors and characterization of their binding kinetics. J Biol Chem. 2012; 287(13):9742-9752. PMC: 3322972. DOI: 10.1074/jbc.M111.304485. View

10.

Sardiello M, Palmieri M, di Ronza A, Medina D, Valenza M, Gennarino V . A gene network regulating lysosomal biogenesis and function. Science. 2009; 325(5939):473-7. DOI: 10.1126/science.1174447. View

11.

Roczniak-Ferguson A, Petit C, Froehlich F, Qian S, Ky J, Angarola B . The transcription factor TFEB links mTORC1 signaling to transcriptional control of lysosome homeostasis. Sci Signal. 2012; 5(228):ra42. PMC: 3437338. DOI: 10.1126/scisignal.2002790. View

12.

Zhou J, Tan S, Nicolas V, Bauvy C, Yang N, Zhang J . Activation of lysosomal function in the course of autophagy via mTORC1 suppression and autophagosome-lysosome fusion. Cell Res. 2013; 23(4):508-23. PMC: 3616426. DOI: 10.1038/cr.2013.11. View

13.

Vaidya V, Ozer J, Dieterle F, Collings F, Ramirez V, Troth S . Kidney injury molecule-1 outperforms traditional biomarkers of kidney injury in preclinical biomarker qualification studies. Nat Biotechnol. 2010; 28(5):478-85. PMC: 2885849. DOI: 10.1038/nbt.1623. View

14.

Aits S, Jaattela M . Lysosomal cell death at a glance. J Cell Sci. 2013; 126(Pt 9):1905-12. DOI: 10.1242/jcs.091181. View

15.

LaPlante J, Sun M, Falardeau J, Dai D, Brown E, Slaugenhaupt S . Lysosomal exocytosis is impaired in mucolipidosis type IV. Mol Genet Metab. 2006; 89(4):339-48. DOI: 10.1016/j.ymgme.2006.05.016. View

16.

Kim E, Goraksha-Hicks P, Li L, Neufeld T, Guan K . Regulation of TORC1 by Rag GTPases in nutrient response. Nat Cell Biol. 2008; 10(8):935-45. PMC: 2711503. DOI: 10.1038/ncb1753. View

17.

Li D, Shao R, Wang N, Zhou N, Du K, Shi J . Sulforaphane Activates a lysosome-dependent transcriptional program to mitigate oxidative stress. Autophagy. 2020; 17(4):872-887. PMC: 8078734. DOI: 10.1080/15548627.2020.1739442. View

18.

Leist M, Jaattela M . Triggering of apoptosis by cathepsins. Cell Death Differ. 2001; 8(4):324-6. DOI: 10.1038/sj.cdd.4400859. View

19.

Napolitano G, Esposito A, Choi H, Matarese M, Benedetti V, Di Malta C . mTOR-dependent phosphorylation controls TFEB nuclear export. Nat Commun. 2018; 9(1):3312. PMC: 6098152. DOI: 10.1038/s41467-018-05862-6. View

20.

Napolitano G, Di Malta C, Esposito A, de Araujo M, Pece S, Bertalot G . A substrate-specific mTORC1 pathway underlies Birt-Hogg-Dubé syndrome. Nature. 2020; 585(7826):597-602. PMC: 7610377. DOI: 10.1038/s41586-020-2444-0. View