COXFA4 is a subunit of cytochrome c oxidase (Complex IV), the terminal enzyme of the mitochondrial electron transport chain that catalyzes oxygen reduction to water 1. As a component of this critical respiratory complex, COXFA4 participates in electron transfer from reduced cytochrome c to molecular oxygen, establishing the electrochemical gradient necessary for ATP synthesis 1. COXFA4 is required for Complex IV maintenance and structural integrity 1. Biallelic COXFA4 mutations cause mitochondrial Complex IV deficiency (nuclear type 21), presenting clinically as Leigh or Leigh-like syndrome with variable manifestations including cardiomyopathy, feeding difficulties, poor growth, and neurodevelopmental delay 2. The pathogenic mechanism involves impaired oxidative phosphorylation, reducing cellular ATP production 3. Recent mechanistic studies using animal models revealed that COXFA4 loss dysregulates polyamine metabolism, specifically impairing the ornithine decarboxylase pathway, which contributes to tissue-specific disease manifestations including cardiac dysfunction 2. Modulating polyamine metabolism ameliorates disease phenotypes, suggesting therapeutic potential 2. COXFA4 has isoforms, with Coxfa4l3 expressed during spermatogenesis in a mutually exclusive pattern, indicating specialized Complex IV composition in different tissues 4.