Pharmacologic intervention in macrophage metabolism: Mitochondrial pyruvate carrier inhibition by Mitoglitazone modulates inflammation

Abstract

Upon Toll-like receptor (TLR) activation, macrophages rapidly change their transcriptional- and translational network and rewire their metabolism. Mitochondrial pyruvate import via the mitochondrial pyruvate carrier (MPC) is essential to the metabolic changes controlling inflammatory responses. Thus, the MPC is a promising target to pharmacologically intervene in inflammatory diseases. Mitoglitazone is an MPC inhibitor currently under clinical investigation for insulin sensitization and amelioration of neurodegeneration. Yet, its effects on macrophage metabolism and inflammation remain undescribed. <br /> Here, it is reported that Mitoglitazone inhibits the MPC in macrophages and decreases their inflammatory response following TLR4- or TLR7/8 activation. Metabolic analyses showed rerouting of glucose metabolism and, concomitantly, inhibition of the glycolytic switch and maximal respiration of inflammatory macrophages. Accordingly, Mitoglitazone decreased inflammatory cytokine transcription and release as well as nitric oxide production. Sustained effects of Mitoglitazone under pharmacologic inhibition or in the absence of the nuclear receptor PPARγ emphasize its mode of action via MPC inhibition. In an acute sepsis mouse model Mitoglitazone decreased LPS-induced cytokines, demonstrating its immunomodulatory effect also in vivo. <br /> These findings give new insights into the integrative network of macrophage metabolism and their inflammatory response, and highlight the potential of MPC inhibition by Mitoglitazone as a strategy to ameliorate erroneous inflammation.