Cell-surface F1Fo ATP synthase (F1Fo-ATPase)

Cell-surface F1Fo ATP synthase, also known as ectopic ATP synthase, is a multi-subunit enzyme complex traditionally found in the inner mitochondrial membrane but also expressed on the plasma membrane of various cell types, including endothelial cells, hepatocytes, and cancer cells [3, 9]. On the cell surface, it functions as a rotary motor that can either synthesize ATP from extracellular ADP and inorganic phosphate or hydrolyze ATP to pump protons, thereby regulating the extracellular and intracellular pH microenvironments [3, 5]. It plays a critical role in diverse physiological processes such as angiogenesis, high-density lipoprotein (HDL) endocytosis via the P2Y13 receptor, and immune response [3]. In disease states, its overexpression on tumor cells and vascular endothelium promotes tumor growth and survival by maintaining an alkaline intracellular pH in acidic tumor environments [3, 5]. Consequently, it has emerged as a promising therapeutic target; inhibitors like angiostatin and various small molecules or antibodies can block its activity to suppress tumor angiogenesis or modulate lipid metabolism [3, 5]. However, a major challenge in targeting this enzyme is achieving selectivity to avoid disrupting the vital energy-producing functions of its mitochondrial counterpart [1, 2].

Other names

Ectopic ATP synthaseEcto-ATP synthaseEcto-F1Fo-ATPaseCell-surface ATP synthaseExtracellular ATP synthase

Inhibition of the catalytic activity (ATP synthesis or hydrolysis) or proton translocation of the F1Fo ATP synthase complex located on the plasma membrane, thereby disrupting extracellular ATP/ADP levels and intracellular pH homeostasis [3, 5, 11].