{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nMT‐CO3 encodes cytochrome c oxidase subunit III, a core component of complex IV in the mitochondrial respiratory chain that mediates electron transfer from cytochrome c to molecular oxygen, thereby contributing to the proton gradient essential for ATP synthesis. In some contexts, interactions with other proteins (for example, binding of pathological proteins such as α‐synuclein to complex IV components) have also been observed, hinting at additional roles in modulating mitochondrial function. Moreover, proper processing and polyadenylation of the mRNA including MT‐CO3 are critical for maintaining its steady-state levels, ensuring an adequate supply of this subunit for respiration."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nMutations in MT‐CO3 or its transcript have been implicated in a spectrum of clinical disorders. Heteroplasmic missense mutations and deletions in the MT‐CO3 gene have been linked to disorders such as Leigh syndrome, MELAS, presbycusis, and severe metabolic or neuromuscular conditions. These mutations often alter protein hydropathy, disrupt proper folding or translation, and compromise complex IV assembly and activity. As a result, mitochondrial ATP production is reduced, leading to energy deficits observed in affected individuals."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "3", "end_ref": "9"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nMT‐CO3 is also essential for the correct assembly and stability of respiratory chain supercomplexes. Disruptions, whether by mutations per se or by interference with assembly factors (such as HIGD2A), result in incomplete or unstable complex IV formation—a defect that can be further exacerbated by pathological protein–protein interactions (for instance with the hepatitis B virus X protein). In addition, specific mitochondrial DNA deletions or polymorphisms affecting MT‐CO3 in sperm have been associated with male infertility, underscoring its significance in tissue‐specific functions."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "10", "end_ref": "14"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nFurthermore, comprehensive mitochondrial gene profiling in various disorders—including ocular conditions such as keratoconus—suggests that MT‐CO3, alongside other mitochondrial genes, may contribute to broader aspects of mitochondrial pathology and cellular energy homeostasis. This reinforces the central role of MT‐CO3 not only in energy production but also in diverse cellular processes that, when disrupted, contribute to disease phenotypes."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "15"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Hanock Elkon, Jermy Don, Eldad Melamed, et al. 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