The Crabtree effect: a new look at the old problem

Inhibition of respiration by glucose, known as the Crabtree effect, has been observed in several tumours and some other highly glycolytic cells and tissues. Among mechanisms proposed to explain this effect were: competition between glycolysis and respiration for ADP or for inorganic phosphate, change of intracellular pH, change in the permeability of mitochondrial membranes, specific regulatory behavior of glycolytic enzymes, and specific enzyme topography within the cell. None of these proposals alone seems satisfactory. The present article describes the research carried out in the author's laboratory, pointing to the role of Ca2+ in the mechanism of the Crabtree effect. This supposition is based on the following observations: (1) in Ehrlich ascites tumour cells glucose elicits a steady increase of the cytoplasmic concentration of free Ca2+; (2) isolated Ehrlich ascites mitochondria and mitochondria within digitonin-permeabilised cells, preloaded with Ca2+, exhibit a depression of State 3 respiration and lowering of the rate of ATP synthesis; (3) ATPase activity of toluene-permeabilised Ehrlich ascites mitochondria becomes substantially inhibited at micromolar concentrations of Ca2+; (4) Ca2+ potentiates the effect of the inhibitory subunit of F1F0-ATPase. These results allow to hypothesize on the following sequence of events: (1) glucose elevates the cytoplasmic concentration of Ca2+; (2) this elicits an increased accumulation of Ca2+ in mitochondria; (3) loading of mitochondria with Ca2+ leads to an increased association of the inhibitory subunit with F1F0 which results in (4) the inhibition of coupled respiration. The importance of these mechanisms for glycolytic and rapidly proliferating cells is discussed.