Mammalian tissues engage in specialized physiology that is regulated by post-translational protein modification. A major mode of protein regulation is initiated by reactive oxygen species (ROS) that reversibly modify protein cysteine residues. ROS regulate a myriad of biological processes and ROS dysregulation has long been implicated in driving age-related dysfunction. However, the protein targets of ROS modification that drive tissue-specific function in vivo are largely unknown. Here we develop a mass spectrometric technology for the first comprehensive and quantitative mapping of the mouse cysteine redox proteome in vivo. We report the cysteine redox landscape across 10 tissues in young and old mice and establish several unexpected and fundamental paradigms of redox signaling. We define and validate cysteine redox networks within each tissue that are highly tissue-selective and underlie tissue-specific biology. We determine a common mechanism for encoding cysteine redox sensitivity by local electrostatic gating. Finally, we comprehensively identify redox-modified disease networks that remodel in aged mice, providing a systemic molecular basis for the longstanding proposed links between redox dysregulation and tissue aging. We provide the Oximouse compendium as a framework for understanding mechanisms of redox regulation in physiology and aging.

The OxiMouse web application was developed by Devin Schweppe (Gygi Lab, HMS) and Haopeng Xiao (Chouchani Lab, DFCI/HMS).

Please Cite: Haopeng Xiao, et al.