Effects of alterations in energy supply on gluconeogenesis from L-lactate.

1. We have examined effects, on gluconeogenesis from lactate, of altering energy metabolism in two ways: (a) by primarily lowering cytosolic ATP levels with the use of atractyloside or 2,5 anhydromannose; and (b) by decreasing mitochondrial energy generation with the use of the classical uncoupler, dinitrophenol. 2. Agents which lower cytosolic ATP inhibit gluconeogenesis and increase pyruvate kinase flux (PK) correspondingly, while pyruvate carboxylase and P-enolpyruvate carboxykinase fluxes are unchanged, at least until gluconeogenesis is inhibited by more than 50%. 3. Dinitrophenol, on the other hand, although it also induces a (smaller) increase in PK, primarily decreases gluconeogenesis by an effect on a mitochondrial step in the gluconeogenic pathway. 4. Low concentrations of dinitrophenol increase Krebs cycle oxidation by at least 50% before significant inhibition of gluconeogenesis from lactate occurs.