COX10 encodes heme A:farnesyltransferase, a mitochondrial enzyme that catalyzes the conversion of protoheme IX and farnesyl diphosphate to heme O, an essential prosthetic group for cytochrome c oxidase (Complex IV) assembly 1. This enzyme is critical for respiratory chain function, with highest expression in metabolically demanding tissues including heart, skeletal muscle, and testis 1. Mechanistically, COX10 functions in the early steps of heme A biosynthesis within mitochondrial oxidative phosphorylation. Impaired COX10 activity compromises Complex IV assembly and function, directly reducing cellular ATP production capacity. Loss of endothelial COX10 prevents metabolic shifts toward oxidative phosphorylation and can suppress angiogenic responses 2. Conversely, endothelial COX10 deficiency triggers mitochondrial dysfunction that activates ALK5-SMAD2 signaling, resulting in retarded vessel growth and arteriovenous malformations 3. Clinically, COX10 mutations cause Leigh Syndrome and mitochondrial complex IV deficiency, nuclear type 3, typically manifesting in infancy 4. Whole-exome sequencing studies identify COX10 among genes frequently mutated in pediatric mitochondrial disorders 5. Functional assessment of variants reveals substantial phenotypic heterogeneity, with some variants retaining approximately 50% of reference enzyme activity while others show severe functional impairment 4. These findings highlight COX10's essential role in mitochondrial energetics and highlight its potential as a therapeutic target in mitochondrial and metabolic diseases.