{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\n ATP5IF1 (also known as IF1) is a critical physiological inhibitor of the mitochondrial H⁺-ATP synthase that modulates cellular energy metabolism and survival under stress. By binding to and inhibiting the ATP synthase, ATP5IF1 prevents the reversal of the enzyme’s activity during conditions of limited oxygen or substrate availability, thereby preserving cellular ATP levels and stabilizing the mitochondrial membrane potential."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": " In cancer cells, increased expression of ATP5IF1 shifts metabolism away from oxidative phosphorylation toward enhanced aerobic glycolysis, a reprogramming that not only supports rapid proliferation and epithelial–mesenchymal transition but also promotes angiogenesis and metastasis via activation of pro‐survival signaling pathways such as NF‑κB and the transcriptional up‑regulation of factors like Snai1 and VEGF."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "3"}]}, {"type": "t", "text": " In neuronal and other vulnerable cell types, ATP5IF1 activity offers cytoprotection by curtailing unnecessary ATP hydrolysis during ischemic or hypoxic episodes and by facilitating the induction of mitophagy through the stabilization of PINK1 and recruitment of PARK2, thereby promoting mitochondrial quality control."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "5"}]}, {"type": "t", "text": " Furthermore, ATP5IF1 has been implicated in the regulation of mitochondrial pH and redox balance, which in turn influences key biosynthetic processes such as haem production important for red blood cell development."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "7"}]}, {"type": "t", "text": " In addition, aberrant ATP5IF1 levels can affect cell cycle progression, as demonstrated in bladder cancer cells where its overexpression is linked to enhanced proliferation and migration through modulation of cyclin and cyclin‐dependent kinase expression."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "8"}]}, {"type": "t", "text": " Finally, environmental factors—such as exposure to carcinogenic polycyclic aromatic hydrocarbons—can upregulate ATP5IF1 expression, thereby contributing to a glycolytic shift that supports cell survival in hepatocytes."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "9"}]}, {"type": "t", "text": " Collectively, these studies underscore the multifaceted role of ATP5IF1 in controlling mitochondrial bioenergetics, orchestrating metabolic reprogramming, and influencing cell fate decisions in both normal physiology and disease.\n "}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Laura Sánchez-Cenizo, Laura Formentini, Marcos Aldea, et al. 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