{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nRecent evidence has redefined the role of NDUFA4 in mitochondrial biology. Initially believed to be a subunit of complex I, investigations have demonstrated that NDUFA4 is an integral component of cytochrome c oxidase (complex IV). Loss‐of‐function mutations in NDUFA4 result in the abrogation of its protein product, contributing to cytochrome c oxidase deficiency and severe neurological phenotypes such as Leigh syndrome, thereby establishing its critical role in mitochondrial oxidative phosphorylation (OXPHOS) and energy production."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nDysregulation of NDUFA4 has emerged as an important oncogenic driver in several cancer types. In colorectal cancer, for instance, the long noncoding RNA MAFG‐AS1 acts as a molecular sponge for miR-147b, leading to the de-repression of NDUFA4; this axis enhances cell proliferation, invasion, and glycolysis, contributing to tumorigenesis. Similarly, in gastric cancer, upregulated NDUFA4—as a consequence of imbalances in lncRNA-mediated signaling (e.g., lncMIF‐AS1/miR‐212-5p) and m6A methylation by METTL3—promotes cell proliferation by activating OXPHOS and optimizing mitochondrial metabolism. Comparable oncogenic functions of NDUFA4 have been documented in pancreatic adenocarcinoma, where its elevated expression supports tumor growth through enhanced mitochondrial respiration, and in head and neck paraganglioma, where high NDUFA4 levels sustain cancer cell viability while its depletion sensitizes cells to ferroptosis, especially when combined with metformin treatment."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "2", "end_ref": "6"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond its roles in energy metabolism and tumorigenesis, NDUFA4-related pathways are integral to modulating inflammatory and immune responses. A small open reading frame-encoded peptide, MOCCI—a paralog of NDUFA4—has been shown to replace NDUFA4 in complex IV during inflammatory conditions. This substitution lowers the mitochondrial membrane potential and reduces reactive oxygen species (ROS) production, thereby tempering inflammatory signaling. Furthermore, the MOCCI transcript co-generates miR-147b, which in turn targets NDUFA4 mRNA, contributing to immune dampening while simultaneously enhancing antiviral pathways."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "7"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nGenetic variation within the cis-regulatory region of the NDUFA4 gene has also been implicated in modulating viral susceptibility. Genome-wide association studies in human-induced pluripotent stem cell models have identified specific SNP clusters that, when diminishing NDUFA4 activity, trigger mitochondrial stress and subsequent leakage of mitochondrial DNA. This cascade leads to the upregulation of type I interferon signaling, thereby conferring relative resistance to infections such as Zika virus, Dengue virus, and SARS-CoV-2."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "8"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Robert D S Pitceathly, Shamima Rahman, Yehani Wedatilake, et al. "}, {"type": "b", "children": [{"type": "t", "text": "NDUFA4 mutations underlie dysfunction of a cytochrome c oxidase subunit linked to human neurological disease."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cell Rep (2013)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.celrep.2013.05.005"}], "href": "https://doi.org/10.1016/j.celrep.2013.05.005"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "23746447"}], "href": "https://pubmed.ncbi.nlm.nih.gov/23746447"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Shanshan Cui, Xi Yang, Lihong Zhang, et al. 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"}, {"type": "b", "children": [{"type": "t", "text": "NDUFA4 promotes the progression of head and neck paraganglioma by inhibiting ferroptosis."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Biochem Cell Biol (2023)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1139/bcb-2023-0018"}], "href": "https://doi.org/10.1139/bcb-2023-0018"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "37602474"}], "href": "https://pubmed.ncbi.nlm.nih.gov/37602474"}]}, {"type": "r", "ref": 7, "children": [{"type": "t", "text": "Cheryl Q E Lee, Baptiste Kerouanton, Sonia Chothani, et al. 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