| Cytochrome c oxidase subunit VIc (COX6C) is a small nuclear‑encoded 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 driving oxidative phosphorylation. The protein is an integral inner mitochondrial membrane subunit that associates peripherally with the catalytic core formed by mitochondrially encoded COX1–3 and other nuclear subunits, and adopts a short transmembrane helix with matrix and intermembrane space extensions that help stabilize complex IV assembly and its interaction with neighboring respiratory complexes. COX6C participates in shaping the local environment of the catalytic center by affecting subunit packing and complex IV conformational dynamics, which influences the efficiency of electron transfer from cytochrome c to the binuclear heme a3–CuB center and the coupling of this redox chemistry to proton translocation across the inner membrane. Through its role in the intact holoenzyme, COX6C supports maintenance of mitochondrial membrane potential, ATP synthesis rates, and reactive oxygen species levels that are characteristic of high‑demand tissues, and its expression is enriched in heart, skeletal muscle, brain, and other metabolically active organs according to transcript and proteomic surveys. Altered COX6C expression has been reported in multiple disease states, including chronic kidney disease, diabetes, and several cancers, where up‑ or down‑regulation correlates with changes in oxidative phosphorylation markers and clinical parameters. |
