We found a match
Your institution may have access to this item. Find your institution then sign in to continue.
- Title
Activation of lysosomal Ca<sup>2 </sup> channels mitigates mitochondrial damage and oxidative stress.
- Authors
Xinghua Feng; Weijie Cai; Qian Li; Liding Zhao; Yaping Meng; Haoxing Xu
- Abstract
Elevated levels of plasma-free fatty acids and oxidative stress have been identified as putative primary pathogenic factors in endothelial dysfunction etiology, though their roles are unclear. In human endothelial cells, we found that saturated fatty acids (SFAs)--including the plasma-predominant palmitic acid (PA)--cause mitochondrial fragmentation and elevation of intracellular reactive oxygen species (ROS) levels. TRPML1 is a lysosomal ROS-sensitive Ca2 channel that regulates lysosomal trafficking and biogenesis. Small-molecule agonists of TRPML1 prevented PA-induced mitochondrial damage and ROS elevation through activation of transcriptional factor EB (TFEB), which boosts lysosome biogenesis and mitophagy. Whereas genetically silencing TRPML1 abolished the protective effects of TRPML1 agonism, TRPML1 overexpression conferred a full resistance to PA-induced oxidative damage. Pharmacologically activating the TRPML1-TFEB pathway was sufficient to restore mitochondrial and redox homeostasis in SFA-damaged endothelial cells. The present results suggest that lysosome activation represents a viable strategy for alleviating oxidative damage, a common pathogenic mechanism of metabolic and age-related diseases.
- Subjects
REACTIVE oxygen species; ENDOTHELIAL cells; OXIDATIVE stress; FATTY acids; ENDOTHELIUM diseases; LYSOSOMES; PALMITIC acid
- Publication
Journal of Cell Biology, 2025, Vol 224, Issue 1, p1
- ISSN
0021-9525
- Publication type
Academic Journal
- DOI
10.1083/jcb.202403104