Reciprocal Regulation of V-ATPase and Glycolytic Pathway Elements in Health and Disease

The ability of cells to adapt to fluctuations in glucose availability is crucial for their survival and involves the vacuolar proton-translocating ATPase (V-ATPase), a proton pump found in all eukaryotes. V-ATPase hydrolyzes ATP via its V₁ domain and uses the energy released to transport protons across membranes via its V_o domain. This activity is critical for pH homeostasis and generation of a membrane potential that drives cellular metabolism. A number of stimuli have been reported to alter V-ATPase assembly in yeast and higher eukaryotes. Glucose flux is one of the strongest and best-characterized regulators of V-ATPase; this review highlights current models explaining how glycolysis and V-ATPase are coordinated in both the Saccharomyces cerevisiae model fungus and in mammalian systems. Glucose-dependent assembly and trafficking of V-ATPase, V-ATPase-dependent modulations in glycolysis, and the recent discovery that glucose signaling through V-ATPase acts as a molecular switch to dictate anabolic versus catabolic metabolism are discussed. Notably, metabolic plasticity and altered glycolytic flux are critical drivers of numerous human pathologies, and the expression and activity of V-ATPase is often altered in disease states or can be pharmacologically manipulated as treatment. This overview will specifically discuss connections between V-ATPase and glycolysis in cancer.