| COX6B1, encoded by a nuclear gene for cytochrome c oxidase subunit VIb1, is a structural component of cytochrome c oxidase (complex IV), the terminal enzyme of the mitochondrial respiratory chain that catalyzes electron transfer from reduced cytochrome c to molecular oxygen and contributes to the proton motive force used for oxidative phosphorylation. The protein is synthesized in the cytosol and imported into mitochondria, where it localizes to the intermembrane space–facing region of complex IV and occupies a position between the two catalytic monomers, functioning as a bridging subunit that supports dimer formation and higher‑order organization of the holoenzyme. COX6B1 participates in both early and late steps of complex IV assembly; absence or mutation of this subunit leads to a marked loss of assembled complex IV, indicating that COX6B1 is required for redox‑sensitive early assembly events as well as for subsequent stabilization of the mature enzyme. Through this architectural role, COX6B1 influences the efficiency of electron flow from cytochrome c to the binuclear heme–copper center where oxygen reduction occurs and maintains the structural context in which proton translocation by the core subunits contributes to the mitochondrial membrane potential. COX6B1 expression is detectable in multiple tissues and is relatively enriched in organs with high oxidative demands, such as heart and skeletal muscle, where intact complex IV function is essential for sustained ATP generation through oxidative phosphorylation. Increased COX6B1 levels are associated with enhanced formation of complex IV–containing respiratory supercomplexes and with higher cytochrome c oxidase activity and ATP content under calorie restriction, linking COX6B1 abundance to adjustments in mitochondrial respiratory capacity and energy output. Pathogenic variants in COX6B1 cause primary complex IV deficiency with severe infantile encephalomyopathy, lactic acidosis, cardiomyopathy, and multi‑organ dysfunction, and affected cells show reduced complex IV activity and impaired assembly of the enzyme. |
