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

Dengqin Zhong, Ruiyun Wang, Hongjing Zhang, Mengmeng Wang, Xuxia Zhang and Honghong Chen ()
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Dengqin Zhong: Fudan University
Ruiyun Wang: Fudan University
Hongjing Zhang: Fudan University
Mengmeng Wang: Fudan University
Xuxia Zhang: Fudan University
Honghong Chen: Fudan University

Nature Communications, 2023, vol. 14, issue 1, 1-18

Abstract: 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 Ca2+ 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.

Date: 2023
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DOI: 10.1038/s41467-023-39716-7

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