{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nNicotinamide nucleotide transhydrogenase (NNT) is an integral mitochondrial inner membrane enzyme that catalyzes the hydride transfer from NADH to NADP+, thereby generating NADPH. This reaction is fundamental for maintaining cellular redox homeostasis, since NADPH fuels antioxidant systems—such as the glutathione pathway—to detoxify reactive oxygen species (ROS). NNT is broadly expressed in a variety of tissues including the adrenal gland, heart, brain, and others, and its catalytic activity is pivotal in sustaining the NADPH-dependent GSH/GSSG ratio as well as modulating mitochondrial H₂O₂ levels. These biochemical features underscore its central role in mitochondrial bioenergetics and oxidative stress management."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "5"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nAlterations in NNT—through mutations, posttranslational modifications, or changes in expression—have been implicated in a range of diseases. Loss‐of‐function mutations underlie conditions such as familial glucocorticoid deficiency, where impaired ROS detoxification in adrenocortical cells leads to heightened apoptosis and defective steroidogenesis. Similarly, in heart failure and various cancers (including gastric cancer, non‐small cell lung cancer, and adrenocortical carcinoma), aberrations in NNT activity compromise NADPH production and mitochondrial iron–sulfur cluster maintenance, thereby perturbing metabolic fluxes and promoting oxidative damage and cell death. Moreover, in malignant cells, NNT modulation appears to influence key signaling pathways—including those governed by HIF‑1α and p53 acetylation—to support proliferation, chemoresistance, and even immune evasion."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}, {"type": "fg_fs", "start_ref": "6", "end_ref": "11"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond its canonical role in antioxidant defense, emerging evidence indicates that NNT exerts multifaceted influences on cellular physiology. In addition to its established links with adrenal and cardiac function, dysregulated NNT activity has now been associated with altered pigmentation, thyroid dysgenesis, and disturbances in metabolic as well as reproductive processes. Structural studies have further delineated key motifs essential for NNT’s conformational dynamics and catalytic efficiency, while alterations in its regulation—including acetylation events triggered by inflammatory signals—can modify its interaction with mitochondrial cofactors and even alter the expression of neighboring non‐coding RNAs (for example, NNT‑AS1). Together, these studies highlight the complex, context‐dependent roles of NNT in modulating redox signaling, maintaining mitochondrial integrity, and influencing disease pathogenesis across multiple organ systems."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "12", "end_ref": "23"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Eirini Meimaridou, Julia Kowalczyk, Leonardo Guasti, et al. 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"}, {"type": "b", "children": [{"type": "t", "text": "Downregulation of nicotinamide nucleotide transhydrogenase and its naturally occurring antisense RNA in gastric cancer."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Asia Pac J Clin Oncol (2019)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1111/ajco.13230"}], "href": "https://doi.org/10.1111/ajco.13230"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "31309731"}], "href": "https://pubmed.ncbi.nlm.nih.gov/31309731"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "Maria Favia, Anna Atlante "}, {"type": "b", "children": [{"type": "t", "text": "Cellular Redox State Acts as Switch to Determine the Direction of NNT-Catalyzed Reaction in Cystic Fibrosis Cells."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Int J Mol Sci (2021)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.3390/ijms22020967"}], "href": "https://doi.org/10.3390/ijms22020967"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "33478087"}], "href": "https://pubmed.ncbi.nlm.nih.gov/33478087"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "Hung-Yao Ho, Yu-Ting Lin, Gigin Lin, et al. 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