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.

中文翻译：

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溶酶体 Ca2+ 通道的激活可减轻线粒体损伤和氧化应激。


无血浆脂肪酸水平升高和氧化应激已被确定为内皮功能障碍病因学中推定的主要致病因素，尽管它们的作用尚不清楚。在人内皮细胞中，我们发现饱和脂肪酸 （SFA） - 包括血浆为主的棕榈酸 （PA） - 导致线粒体碎裂和细胞内活性氧 （ROS） 水平升高。TRPML1 是一种溶酶体 ROS 敏感的 Ca2+ 通道，可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） 来阻止 PA 诱导的线粒体损伤和 ROS 升高，从而促进溶酶体生物发生和线粒体自噬。虽然遗传沉默 TRPML1 消除了 TRPML1 激动剂的保护作用，但 TRPML1 过表达赋予了对 PA 诱导的氧化损伤的完全抵抗力。药理学激活 TRPML1-TFEB 通路足以恢复 SFA 损伤的内皮细胞中的线粒体和氧化还原稳态。目前的结果表明，溶酶体激活代表了减轻氧化损伤的可行策略，氧化损伤是代谢和年龄相关疾病的常见致病机制。