A Spatiotemporally Controlled and Mitochondria-Targeted Prodrug of Hydrogen Sulfide Enables Mild Mitochondrial Uncoupling for the Prevention of Lipid Deposition

作者：Xian Zhang, Mengjie Ye, Yuxin Ge, Can Xiao, Keni Cui, Qidong You, Zhengyu Jiang, Xiaoke Guo · 发表于：Journal of Medicinal Chemistry · 年份：2024 · DOI：10.1021/acs.jmedchem.4c01599 · 被引用次数：5 · 研究领域：Sulfur Compounds in Biology、Metabolomics and Mass Spectrometry Studies、Fatty Acid Research and Health

Mild mitochondrial uncoupling offers therapeutic benefits for various diseases like obesity by regulating cellular energy metabolism. However, effective chemical intervention tools for inducing mild mitochondria-targeted uncoupling are limited. Herein, we have developed a mitochondria-targeted H 2 S prodrug M1 with a unique property of on-demand photoactivated generation of H 2 S accompanied by self-reporting fluorescence for real-time tracking. Upon photoirradiation, M1 decomposes in mitochondria to generate H 2 S and a turn-on fluorescent coumarin derivative for the visualization and quantification of H 2 S. M1 is confirmed to induce reactive oxygen species (ROS)-dependent mild mitochondrial uncoupling, activating mitochondria-associated adenosine monophosphate-activated protein kinase (AMPK) to suppress palmitic acid (PA)-induced lipid deposition in hepatocytes. The uncoupling functions induced by M1 are strictly controlled in mitochondria, representing a fresh strategy to prevent lipid deposition and improve metabolic syndrome by increasing cellular energy expenditure.