{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nSLC25A5, also known as adenine nucleotide translocator‐2 (ANT2), encodes a mitochondrial inner membrane protein that mediates the exchange of ADP and ATP between the mitochondrial matrix and the cytosol—a key process linking oxidative phosphorylation to cellular energy homeostasis. Differentially expressed among the ANT isoforms, SLC25A5 is predominantly found in proliferative and glycolytic cells, where its activity supports high metabolic turnover and rapid cell division."}, {"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": "\nIn the context of cancer, elevated SLC25A5/ANT2 expression is closely linked to metabolic reprogramming. By facilitating the import of glycolytically generated ATP into mitochondria under conditions where oxidative phosphorylation is compromised, ANT2 helps maintain mitochondrial membrane potential and promotes cell survival. The overexpression of ANT2 not only correlates with enhanced tumor cell proliferation and resistance to apoptosis but also contributes to chemo‐ and targeted therapy resistance. Moreover, pharmacologic agents such as apigenin that bind to and inhibit ANT2 can upregulate pro‐apoptotic receptors and resensitize cancer cells to apoptotic signals."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "4", "end_ref": "9"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond its role in sustaining tumor metabolism, SLC25A5 expression is intricately regulated in response to stress and inflammatory signals. Under conditions such as hypoxia or cytokine exposure, transcriptional repressors and microRNAs (mediated by NF1/Smad complexes) modulate ANT2 levels—linking its dysregulation with enhanced reactive oxygen species production, DNA damage responses, and the induction of cellular senescence. These modulatory pathways underscore ANT2’s contribution to both survival and programmed growth arrest."}, {"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": "\nGenetic studies have further expanded the significance of SLC25A5 beyond energy metabolism. Microdeletions at Xq24 that disrupt SLC25A5 have been identified in patients with non‐syndromic intellectual disability, pointing to a crucial role for this gene in brain regions such as the cortex and hippocampus, and implicating mitochondrial ATP exchange in normal cognitive function and memory formation."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "15"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn addition, alterations in SLC25A5/ANT2 expression influence the response of cancer cells to therapeutic agents. Upregulation of ANT2 in tumors such as non‐small cell lung carcinoma confers resistance to EGFR tyrosine kinase inhibitors, while its suppression can restore drug sensitivity and enhance apoptotic responses to agents like TRAIL. Moreover, in metabolic disorders like obesity, increased ANT2 expression in adipose tissue macrophages promotes proinflammatory activation via mitochondrial permeability transition and ROS production."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "16", "end_ref": "19"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nThe broader mitochondrial impact of SLC25A5 is highlighted by its dynamic regulation in response to metabolic stress. Altered ANT2 levels are associated with decreased oxidative phosphorylation activity, modified apoptotic responses, and shifts in substrate metabolism—findings that may render SLC25A5 a promising biomarker and therapeutic target in diseases such as kidney cancer and conditions characterized by altered glucose uptake."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "11"}, {"type": "fg_fs", "start_ref": "20", "end_ref": "22"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nFinally, emerging data on inflammatory skin disorders such as psoriasis suggest a complex interplay between mitochondrial bioenergetics and systemic inflammation, although the direct involvement of SLC25A5/ANT2 in these processes remains to be fully elucidated."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "23"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Arnaud Chevrollier, Dominique Loiseau, Pascal Reynier, et al. 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