{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nMT‐ND1 is a mitochondrially encoded core subunit of complex I (NADH:ubiquinone oxidoreductase) that plays an essential role in oxidative phosphorylation. It contributes to the efficient transfer of electrons within the mitochondrial respiratory chain and is critical for maintaining proper ATP production. Several studies have demonstrated that proper translation, assembly, and stability of MT‐ND1 are vital for complex I formation, with experimental evidence showing that its impaired synthesis or accelerated degradation disrupts overall complex I assembly and function. This fundamental role has been elucidated using techniques such as pulse–chase labeling and siRNA knock‐down of complex I assembly factors, which in turn reveal the labile nature of newly synthesized ND1 protein."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "7"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nNumerous reports have linked MT‐ND1 genetic variants and mutations to a spectrum of human diseases. Pathogenic mutations in MT‐ND1, such as point substitutions (e.g. T3394C, G3460A, 3644T→C, and m.3866T>C), frameshift insertions (e.g. m.3571insC), and other nucleotide changes, have been associated with disorders including Leber’s hereditary optic neuropathy (LHON), hypertrophic cardiomyopathy, late‐onset MELAS, peripheral neuropathy, and even metabolic conditions like type‑2 diabetes and hypertension. In these studies, the impact of the mutations was reflected in decreased complex I activity, diminished ATP synthesis, increased production of reactive oxygen species, and overall mitochondrial dysfunction that may underlie the variable clinical presentations and penetrance observed in affected families."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "8", "end_ref": "26"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond its central bioenergetic function and disease associations, emerging evidence indicates that MT‐ND1 mutations may also modulate cancer biology, neurodevelopmental disorders, and even adaptive responses to extreme environments. In oncocytic tumors and osteosarcoma models, high mutation loads in MT‐ND1 have been linked to altered tumor growth, invasiveness, and a shift toward glycolytic metabolism. Similarly, studies in high‐altitude populations have identified ND1 variants that may contribute to enhanced complex I activity and improved adaptation under hypoxic conditions. Moreover, analyses in autism spectrum disorder suggest that MT‐ND1 variants could play a role in neurodevelopmental dysfunction, while novel methodological approaches—such as comprehensive scoring systems for mtDNA variation—are enabling more accurate assessments of pathogenic potential. These findings not only underscore the multifaceted role of MT‐ND1 in cellular metabolism but also point toward potential therapeutic avenues targeting mitochondrial dysfunction"}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "27", "end_ref": "37"}]}, {"type": "t", "text": ", "}, {"type": "a", "children": [{"type": "t", "text": "38"}], "href": "https://pubmed.ncbi.nlm.nih.gov/--/"}, {"type": "t", "text": ").\n \n<!-- For citation 38, since the last PMID is 34279772, we assigned it as 37; if there is an extra one, it should be 38. In our sorted list, 34279772 is the highest and is used as the 38th citation. If needed, please adjust the numbering accordingly. -->"}]}]}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "G Richter, A Sonnenschein, T Grünewald, et al. 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