COX3 (mitochondrial cytochrome c oxidase subunit III) is a critical component of Complex IV, the terminal enzyme of the mitochondrial electron transport chain. COX3 functions as part of the binuclear copper and heme catalytic center that reduces molecular oxygen to water, coupling this reaction to proton pumping across the inner mitochondrial membrane to generate the electrochemical gradient necessary for ATP synthesis via oxidative phosphorylation. Mechanistically, COX3 works in concert with other cytochrome c oxidase subunits to transfer electrons from reduced cytochrome c through copper A centers and heme groups to the active catalytic site, where four electrons and four protons reduce O₂ to two water molecules 1. The protein is polyproline-rich, and its efficient synthesis requires TACO1-mediated relief of ribosomal stalling at polyproline stretches during mitochondrial translation 1. COX3 dysfunction has significant clinical relevance. Mutations in COX3 are associated with Leber hereditary optic neuropathy, mitochondrial complex IV deficiency, and recurrent myoglobinuria. Recent findings indicate that non-synonymous COX3 variants in peripheral blood leukocytes are associated with increased idiopathic pulmonary fibrosis (IPF) risk and poor prognosis, with affected patients showing shorter survival times 2. Additionally, truncating COX3 mutations alter nuclear DNA methylation patterns in ways that predict mortality and cardiovascular disease risk 3, demonstrating broader epigenetic consequences of COX3 dysfunction beyond direct bioenergetic effects.