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

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