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Induction of lysosomal exocytosis and biogenesis via TRPML1 activation for the treatment of uranium-induced nephrotoxicity

Zhong, Dengqin, Wang, Ruiyun, Zhang, Hongjing, Wang, Mengmeng, Zhang, Xuxia, Chen, Honghong·2023·Nature Communications
DOI 10.1038/s41467-023-39716-7PMC PMC10326073
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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 2+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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  • Impaired degradation leads to lysosomal stress and could prompt cells to rid themselves of undigested cargo via other mechanisms.

    “Impaired degradation leads to lysosomal stress and could prompt cells to rid themselves of undigested cargo via other mechanisms (Domingues et al. 2024; Wang, Telpoukhovskaia, et al. 2018; Zhong et al. 2023).”

    From The Alzheimer's Disease Gene SORL1 Regulates Lysosome Function in Human Microglia (2025) · cites this paper as Zhong et al. 2023

    The Introduction describes lysosomal exocytosis as a way to release lysosomal contents, and the Results and discussion report that it helps U-loaded HK-2 cells expel uranium and damaged lysosomes. The paper does not establish that impaired degradation causes lysosomal stress or prompts this response; it studies uranium-induced lysosomal damage and exocytosis. (LLM, conf=0.85)

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Metadata

Authors
Zhong, D., Wang, R., Zhang, H., Wang, M., Zhang, X., & Chen, H.
ORCID
Venue
Nature Communications
Publisher
Springer Science and Business Media LLC
Published
2023-07-06
Volume
14
Issue
1
ISSN
2041-1723
DOI
10.1038/s41467-023-39716-7
PMC
PMC10326073
Cited by
52
References
3
Language
en
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