A Spatiotemporally\nControlled and Mitochondria-Targeted\nProdrug of Hydrogen Sulfide Enables Mild Mitochondrial Uncoupling\nfor the Prevention of Lipid Deposition

Mild mitochondrial uncoupling offers therapeutic benefits\nfor various\ndiseases like obesity by regulating cellular energy metabolism. However,\neffective chemical intervention tools for inducing mild mitochondria-targeted\nuncoupling are limited. Herein, we have developed a mitochondria-targeted\nH<sub>2</sub>S prodrug <b>M1</b> with a unique property of on-demand\nphotoactivated generation of H<sub>2</sub>S accompanied by self-reporting\nfluorescence for real-time tracking. Upon photoirradiation, <b>M1</b> decomposes in mitochondria to generate H<sub>2</sub>S and\na turn-on fluorescent coumarin derivative for the visualization and\nquantification of H<sub>2</sub>S. <b>M1</b> is confirmed to\ninduce reactive oxygen species (ROS)-dependent mild mitochondrial\nuncoupling, activating mitochondria-associated adenosine monophosphate-activated\nprotein kinase (AMPK) to suppress palmitic acid (PA)-induced lipid\ndeposition in hepatocytes. The uncoupling functions induced by <b>M1</b> are strictly controlled in mitochondria, representing a\nfresh strategy to prevent lipid deposition and improve metabolic syndrome\nby increasing cellular energy expenditure.