{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nMT‐CO2 is one of the three mitochondrially encoded core subunits of cytochrome c oxidase (complex IV), the enzyme catalyzing the final step in the electron transport chain. By mediating the transfer of electrons from cytochrome c to molecular oxygen and contributing to the proton gradient needed for ATP synthesis, MT‐CO2 plays an essential role in cellular energy metabolism and homeostasis. Its expression is dynamically modulated in response to cellular stress and growth factor signals, as alterations in MT‐CO2 levels have been observed in aging muscle and in cells exposed to heregulin‐mediated pathways, thereby linking mitochondrial performance to apoptosis and adaptive metabolic reprogramming."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "3"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nThe synthesis and proper assembly of MT‐CO2 into complex IV is finely controlled by a host of mitochondrial assembly factors. Proteins such as SCO2, SCO1, COA6, and SURF1 assist in the incorporation of copper into the CuA center and help stabilize intermediate complexes containing MT‐CO2, ensuring the formation of a fully functional enzyme. Disruption of these interactions—whether by mutations in assembly factor genes or by aberrant post‐translational modifications—can compromise MT‐CO2 maturation, leading to assembly defects with subsequent impairments in respiratory chain activity."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "4", "end_ref": "7"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nMT‐CO2 dysfunction, arising from point mutations, deletions, epigenetic modifications, or aberrant regulation, has been implicated in a diverse array of human disorders. Pathogenic variants in MT‐CO2 cause isolated reductions in cytochrome c oxidase activity, contributing to mitochondrial myopathies, multisystem disorders, and even sensorineural defects such as nonsyndromic deafness and retinopathy in maternally inherited diabetes. In addition, studies in HIV‐infected T cells, acute myeloid leukemia, multiple sclerosis, and colorectal polyposis have linked MT‐CO2 alterations to enhanced apoptosis, impaired energy production, and tumorigenic processes. Epigenetic modifications (for example, promoter hypermethylation) further suggest that disrupted MT‐CO2 expression may accelerate cellular senescence in tissues such as the heart and impact reproductive performance, underscoring its critical role in both health and disease."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "8", "end_ref": "18"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Guillemette Fayet, Monica Jansson, Damien Sternberg, et al. 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