ROMO1 overexpression protects the mitochondrial cysteinome from oxidations in aging

Reactive thiols of proteinaceous cysteines are vital to cell biology by serving as sensor, effector and buffer of environmental redox fluctuations. Being the major source, as well as the prime target, of reactive oxygen species (ROS), mitochondria confront great challenges in preserving their thiol pool. Here we show that ROS modulator 1 (ROMO1), a small inner mitochondrial membrane protein, plays a role in protecting the mitochondrial cysteinome. ROMO1 is redox sensitive and reactive and overexpression can prevent deleterious oxidation of proteinaceous thiols. ROMO1 upregulation leads to a reductive shift of the mitochondrial cysteinome, exerting beneficial effects on mitochondria, such as promoting energy metabolism and Ca²⁺ uniport while inhibiting vicious membrane permeability transition. Importantly, ROMO1 overexpression reverses mitochondrial cysteinome oxidations in multiple organs and slows functional decline in aged male mice. These findings unravel a redox regulatory mechanism of the mitochondrial cysteinome and mark ROMO1 as a potential target for combating oxidative stress and improving healthspan.