Inflamed macrophages sans mitochondrial pyruvate carrier?

Abstract

Glycolysis provides building blocks for the proinflammatory activation of macrophages and simultaneously generates pyruvate. In this issue of Nature Metabolism, Ran et al. provide evidence that the transport of pyruvate to fuel the Krebs cycle in the mitochondria is not required in the inflammatory response.

Fig. 1 |. Metabolic rewiring upon macrophage activation.

a, A hallmark of classical proinflammatory activation of macrophages is enhanced glycolysis, which provides the necessary building blocks for rapid energy production. This often occurs through Warburg metabolism, which involves aerobic glycolysis with pyruvate (an end product of glycolysis) to produce lactate or, alternatively, pyruvate being transported by the action of MPC into the mitochondria (to fuel the Krebs cycle via anaplerotic reactions). Pyruvate can be converted by PC to produce OAA or by PDH to promote acetyl-CoA production and histone acetylation of inflammatory genes. These mechanisms were proposed to occur within only a few hours of inflammatory triggers such as LPS (‘early response’). The accumulation of citrate, itaconate and succinate are considered to be the result of a broken Krebs cycle, due to a decline in Idh1 and an increase in Acod1 mRNA expression, and decreased SDH activity. Together with enhanced glutaminolysis, this promotes citrate accumulation for lipogenesis and succinate accumulation for ROS regulation and modulation of shared metabolite intermediates of the urea cycle, a process that eliminates nitrogen arising from amino acid catabolism. Nitric oxide (NO) production generated through the urea cycle competes with oxygen to inhibit complex II of the electron transport chain. The glutamine-dependent accumulation of succinate and ROS stabilizes HIF1α and boosts the specific expression of IL-1β that occurs after the first inflammatory wave (‘late response’). Altogether, these mechanisms shape classical macrophage activation. b, The absence of MPC owing to Mpc1 deficiency inhibited respiration driven by pyruvate without affecting glycolysis or lactate production. In these specific Mpc1-deficient macrophages, pyruvate import to the mitochondria was uncoupled from both inflammation and global histone acetylation, although locus specificity remains to be investigated. It is unclear whether this is related to a compensatory metabolic rewiring linked to a raise of carbon flux from glutaminolysis. Ac, acetyl; aco, aconitate; CXCL1, chemokine ligand 1; GABA, γ-aminobutyric acid; GLS, glutaminase; GOT, glutamic oxaloacetic transaminase; HAT, histone acetyltransferase; IDHs, isocitrate dehydrogenases; KDM, histone lysine demethylase; LDH, lactate dehydrogenase; LPS (M1), LPSmediated macrophage M1 activation; me, methyl; NOS, NO synthase; TET, ten-eleven translocation enzymes; TF, transcription factor; TNF, tumour necrosis factor-α.