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

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 H₂S prodrug <b>M1</b> with a unique property of on-demand photoactivated generation of H₂S accompanied by self-reporting fluorescence for real-time tracking. Upon photoirradiation, <b>M1</b> decomposes in mitochondria to generate H₂S and a turn-on fluorescent coumarin derivative for the visualization and quantification of H₂S. <b>M1</b> 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 <b>M1</b> are strictly controlled in mitochondria, representing a fresh strategy to prevent lipid deposition and improve metabolic syndrome by increasing cellular energy expenditure.