New Cornerstone Science Laboratory and Liangzhu Laboratory, The Second Affiliated Hospital and School of Basic Medical Sciences, Zhejiang University, Hangzhou, China.
Collaborative Innovation Center of Yangtze River Delta Region Green Pharmaceuticals, Zhejiang University of Technology, Hangzhou, China.
J Cell Biol. 2025 Jan 6;224(1). doi: 10.1083/jcb.202403104. Epub 2024 Nov 5.
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.
血浆游离脂肪酸水平升高和氧化应激被认为是内皮功能障碍发病机制中的潜在主要致病因素，但其作用尚不清楚。在人内皮细胞中，我们发现饱和脂肪酸（SFAs）-包括血浆中主要的棕榈酸（PA）-导致线粒体碎片化和细胞内活性氧（ROS）水平升高。TRPML1 是溶酶体 ROS 敏感的 Ca2+通道，调节溶酶体运输和生物发生。TRPML1 的小分子激动剂通过激活转录因子 EB（TFEB）防止 PA 诱导的线粒体损伤和 ROS 升高，TFEB 促进溶酶体生物发生和线粒体自噬。然而，TRPML1 的基因沉默消除了 TRPML1 激动剂的保护作用，而过表达 TRPML1 则使内皮细胞完全抵抗 PA 诱导的氧化损伤。药理学上激活 TRPML1-TFEB 途径足以恢复 SFA 损伤的内皮细胞中的线粒体和氧化还原稳态。这些结果表明，溶酶体激活代表了一种缓解氧化损伤的可行策略，氧化损伤是代谢和与年龄相关疾病的常见致病机制。
