Cysteine oxidation is required for brain metastasis in lung cancer

Most cysteine residues are believed to require a reduced state for activity and their oxidation by reactive oxygen species (ROS) is traditionally viewed as damaging to proteins. However, it stands that some cysteines that must be oxidized for protein function, yet their identity remains largely unknown. To answer this question, we lowered ROS levels in 55 lung cancer cell lines and analyzed the cellular consequences using cysteine-focused chemical proteomics paired with functional CRISPR screens. This integrated approach revealed hundreds of impacted cysteines required for proliferation. We focused on NDUFA10•C253 in mitochondrial complex I, which we find exists in a more oxidized state in some human brain metastases. This cysteine is dynamically regulated by antioxidant pathways and its oxidation is required for complex I stability and supports metastasis to the brain. Collectively, we demarcate oxidized cysteines essential for cell fitness and disease states including metastasis.