COX16 is a mitochondrial inner membrane protein essential for assembling cytochrome c oxidase (complex IV), the terminal enzyme of the respiratory chain 12. As a conserved assembly factor, COX16 specifically interacts with newly synthesized COX2 subunit and copper-coordinating metallochaperones (SCO1, SCO2, COA6) to promote copper insertion into COX2's active site 2. COX16 facilitates the critical merger of independent COX1 and COX2 assembly modules into the functional MITRAC intermediate 2. The protein is localized to the intermembrane space with its C-terminus facing outward 3. COX16 deficiency causes severe mitochondrial disease. Homozygous loss-of-function mutations result in complete complex IV dysfunction, manifesting as neonatal lactic acidosis, encephalopathy, cardiomyopathy, and hepatic dysfunction 4. Notably, COX16 knockout cells retain partial COX activity, suggesting functional redundancy in some contexts 1. Beyond its canonical assembly role, COX16 expression is upregulated in oral squamous cell carcinoma and breast cancer, where it promotes mitochondrial respiration and supports tumor progression 56. COX16 is also identified as part of cancer-associated membrane signatures predicting prognosis in lung adenocarcinoma 7, indicating disease relevance beyond mitochondrial dysfunction.