COX15 encodes cytochrome c oxidase assembly factor COX15, which catalyzes heme A synthase activity in mitochondrial complex IV biogenesis 1. The protein functions as an oxidoreductase that converts heme O to heme A through successive hydroxylations, essential for cytochrome c oxidase assembly and mitochondrial respiratory chain function 1. COX15 deficiency causes severe mitochondrial complex IV deficiency, manifesting as Leigh syndrome with infantile cardioencephalomyopathy characterized by hypertrophic cardiomyopathy, encephalopathy, microcephaly, and persistent lactic acidosis 23. The R217W mutation represents a hotspot mutation associated with variable phenotypic expression, including progressive quadriparesis, convulsions, and pseudobulbar palsy 4. Recent studies reveal expanded COX15 roles beyond classical mitochondrial disorders. In reproductive biology, COX15 variants cause female infertility through oocyte ferroptosis, where impaired Fe2+ and reactive oxygen species homeostasis sensitizes oocytes to cell death 5. In cancer biology, COX15 functions as an oncogene promoting lung cancer cell proliferation, with Nrf2-mediated transcriptional upregulation 6. COX15 also contributes to vascular calcification in chr10 kidney disease through enhanced oxidative phosphorylation 7. Therapeutically, COX15 represents a potential target, with antagonistic microRNAs (Opantimirs) showing promise in correcting mitochondrial ultrastructure in disease models 8.