NDUFS4 and mitochondrial disease: Oxygen serves as a substrate for over 200 biochemical reactions, making it essential for human health.1 However, excess oxygen is also toxic.2 We recently demonstrated that mitochondrial diseases reduce whole-body oxygen consumption, leading to an imbalance between oxygen supply and demand.3–5 This imbalance results in tissue hyperoxia, as observed in the leading mouse model of mitochondrial disease, the Ndufs4 knockout (KO) mouse.