Cox15, coding for heme A synthase, is essential for the assembly of cytochrome c oxidase, a key enzyme in the mitochondrial electron transport chain. This process is crucial for oxidative phosphorylation, a major energy-generating pathway in cells [5,7,9].

In female reproduction, oocyte-specific deletion of Cox15 in mice led to impaired Fe2+ and reactive oxygen species homeostasis, causing mitochondrial dysfunction and oocyte ferroptosis, ultimately resulting in female infertility [1]. In lung cancer, increased transcription and protein expression levels of Cox15 were observed. Nrf2 binds to the Cox15 promoter to trigger its expression, and Cox15 functions as an oncogene facilitating lung cancer cell proliferation [2].

Mutations in the COX15 gene in humans are associated with various severe disorders. For example, in infants, it can cause hypertrophic cardiomyopathy, encephalopathy, and hyperlacticaemia [3,6]. In Leigh syndrome patients, a homozygous p.R217W mutation in COX15 was identified, highlighting it as a mutation hotspot [4]. In chronic kidney disease, higher expression levels of COX15 were found in patients with aortic arch calcification, and suppressing COX attenuated vascular calcification [8].

In conclusion, Cox15 is vital for cytochrome c oxidase assembly and oxidative phosphorylation. Studies using gene-knockout or mutation models in mice and humans have revealed its significant roles in female infertility, lung cancer, infantile cardioencephalomyopathy, Leigh syndrome, and vascular calcification in chronic kidney disease. These findings enhance our understanding of the biological functions of Cox15 and its implications in various disease conditions.