Modulation of Subcellular Redox Homeostasis with Trialkylphosphines

Redox homeostasis is essential for cell function and its disruption is associated with multiple pathologies. Redox balance is largely regulated by the relative concentrations of reduced (GSH) and oxidized (GSSG) glutathione. In eukaryotic cells, this ratio is different in each cell compartment. There is a lack of chemical probes able to modulate GSH/GSSG to study the impact of redox stress in an organelle specific manner. Here, we highlight the importance of trialkylphosphines to induce reductive stress and how it can be targeted to a specific organelle. Our probe is selectively activated by endogenous nitroreductases, and releases tributylphosphine to trigger redox stress in mitochondria. Mechanistic studies revealed that the induced stress activates a cellular response orchestrated by transcription factor ATF4, which upregulates genes involved in glutathione catabolism.