COX6B1 encodes a nuclear-encoded subunit of cytochrome c oxidase (complex IV), the terminal enzyme in the mitochondrial electron transport chain that catalyzes oxygen reduction to water during oxidative phosphorylation 1. Despite being classified as a late incorporation subunit, COX6B1 is essential for both redox-sensitive early assembly steps and late stabilization of complex IV, with knockout cells showing complete loss of complex IV 1. The protein is located in the intermembrane space-facing region of complex IV and is indispensable for proper respiratory chain function 1. Pathogenic mutations in COX6B1 cause mitochondrial complex IV deficiency, manifesting as encephalomyopathy, hydrocephalus, and hypertrophic cardiomyopathy, with severely reduced or undetectable COX activity in patient tissues 2. COX6B1 expression is significantly downregulated in Alzheimer's disease patients and correlates with disease pathology 3. The gene shows disease associations across multiple conditions, including potential roles in lung adenocarcinoma where it may be regulated by miR-30b-3p 4, and involvement in pemphigus vulgaris through oxidative phosphorylation pathway activation 5. These findings highlight COX6B1's critical role in mitochondrial bioenergetics and its clinical significance in various pathological conditions.