Hexokinase-II Enzymatic Activity Requires High Levels of Intracellular K+

High expression levels of mitochondria-associated hexokinase-II (HKII) represent a hallmark of metabolically highly active cells such as fast proliferating cancer cells. Typically, the enzyme provides a crucial metabolic switch towards aerobic glycolysis. Here, we emphasize that HKII binds up to 11 potassium ions (K+), thereby sensitizing cell metabolism for K+. Thus, increased intra- and extracellular K+ levels, as found within the tumor microenvironment, strongly reinforce aberrant glucose catabolism, and accelerate the proliferation of HKII positive cancer cells. Any reduction of intracellular K+ acutely disrupted HKII dependent glycolysis and triggered cellular energy stress pathways. Our findings provide a mechanistic link between the expression and activities of distinct K+ channels, cell metabolism, and proliferation.