Phloretin - an uncoupler and an inhibitor of mitochondrial oxidative phosphorylation.

The effect of phloretin on respiration by isolated mitochondria and submitochondrial particles was studied. In submitochondrial particles, both NADH- and succinate-dependent respiration was inhibited by phloretin. 50% maximum inhibition was reached at phloretin concentrations of 0.1 mM (NADH oxidation) and 0.7 mM (succinate oxidation). In isolated mitochondria, phloretin inhibited glutamate oxidation in both State 3 and State 4; 50% maximum inhibition occurred at about 30 microM. Succinate oxidation is inhibited in State 3 by phloretin, inhibition being half its maximum value at 0.5 mM, but in State 4 it is stimulated about 2-fold by phloretin at a concentration of 0.6 mM. Ascorbate oxidation is stimulated in both State 3 and State 4, maximum stimulation being equal to that obtained with an uncoupler of oxidative phosphorylation. Under all circumstances, phloretin lowered the transmembrane electrical potential difference in isolated mitochondria. These results are discussed in terms of mosaic non-equilibrium thermodynamics. We conclude that phloretin is both an uncoupler and an inhibitor of oxidative phosphorylation.