Subcellular Delivery of Hydrogen Sulfide Using Small Molecule Donors Impacts Organelle Stress

Hydrogen sulfide (H₂S) is an endogenously produced gaseous signaling molecule with important roles in regulating organelle function and stress. Because of its high reactivity, targeted delivery of H₂S using small molecule H₂S donors has garnered significant interest to minimize off-target effects. Although mitochondrially targeted H₂S donors, such as AP39, have been reported previously and exhibit significantly higher potency than nontargeted donors, the expansion of targeted H₂S delivery to other subcellular organelles remains largely absent. To fill this key unmet need, we report a library of organelle-targeted H₂S donors that localize H₂S delivery to specific subcellular organelles, including the Golgi apparatus, lysosome, endoplasmic reticulum, and mitochondria. We measured H₂S production in vitro from each donor, confirmed the localization of H₂S delivery using organelle-specific H₂S responsive fluorescent probes, and demonstrated enhanced potency of these targeted H₂S donors in providing protection against organelle-specific stress. We anticipate this class of targeted H₂S donors will enable future studies of subcellular roles of H₂S and the pathways by which H₂S alleviates subcellular organelle stress.