Subcellular organelles maintain distinct redox environments to carry out their normal physiol. functions. Disruption of redox homeostasis, either in the oxidative or reductive direction, is linked to disease. We recently showed that trialkylphosphine-based chem. probes can induce intracellular reductive stress through their reaction with oxidized glutathione to increase the levels of its monomeric, reduced form. Employing this general strategy, we developed an organelle-targeted probe and explored the effects of reductive stress in mitochondria using a combination of live-cell fluorescence microscopy and mRNA sequencing. These expts. have established a link between mitochondrial reductive stress and glutathione catabolism, mediated by superoxide and the transcription factor ATF4.