Effect of lonidamine on the aerobic glycolysis of normal and phytohemagglutinin-stimulated human peripheral blood lymphocytes

Abstract

The effect of lonidamine on the aerobic glycolysis and on the ultrastructure of normal and phytohemagglutinin-stimulated human peripheral blood lymphocytes has been investigated. In quiescent lymphocytes lonidamine does not affect aerobic lactate production and does not induce ultrastructural modifications. On the contrary, lymphocytes stimulated with phytohemagglutinin become susceptible to lonidamine inhibition. The rate of lactate production is decreased by 50% and mitochondria appear swollen with rarified matrix and disrupted cristae. The different effect of lonidamine can be ascribed both to the biochemical modifications induced by phytohemagglutinin and to the mechanism of lonidamine itself. Phytohemagglutinin increases the activity of hexokinase and phosphofructokinase and determines a shift of cytoplasmatic hexokinase toward the mitochondria-bound form which is responsible for the increased lactate production. This interpretation is supported by the finding that lonidamine, which specifically inhibits mitochondria-bound hexokinase only when mitochondria are in a condensed state, decreases lactate production to a value similar to that found in unstimulated cells. the inability of lonidamine to affect the aerobic glycolysis of quiescent lymphocytes can be interpreted along the same line. On this basis it is suggested that the inhibition of mitochondria-bound hexokinase might be ascribed to marked changes in membrane conformation that affect the activity of membrane-associated enzymes, rather than to a direct effect of the enzyme itself.