Mitochondria, hexokinase and pyruvate kinase isozymes in the aerobic glycolysis of tumor cells

Al 9mM glucose, experimental results show that mitochondrial phosphate depletion (induced by glucose phosphorylation, catalyzed by mitochondrial hexokinase) reduces the activities of the respiratory chain, oxidative phosphorylation and glutaminase. Consequently, the C-14-lactate oxidation to (CO2)-C-14 is lowered in the presence of glucose. The fall of ATP level triggers a high aerobic glycolysis by deinhibiting fructose-6-P kinase. NADH, generated by enhanced glyceraldehyde-3-P dehydrogenase activity, increases the reducing power. Moreover, the lactate dehydrogenase (LDH) system is shifted toward lactate formation, while NAD(+) is regenerated and the oligomycin-inhibited ATP production is replaced by the iodoacetate-inhibited ATP production. From (CO2)-C-14 production and lactate accumulation it is calculated that about 60% of C-14-glucose which disappears is channelled into extraglycolytic reactions. On the contrary, 82% of glucose below 1mM is metabolized through non-glycolytic reactions. The pyruvate kinase-M-2 (PK-M-2) inhibition does not limit the glycolytic now from 9mM glucose, but it may cause sustained gluconeogenesis.