Mitochondrial pyruvate carrier-mediated metabolism is dispensable for the classical activation of macrophages
NATURE METABOLISM(2023)
摘要
Glycolysis is essential for the classical activation of macrophages (M1), but how glycolytic pathway metabolites engage in this process remains to be elucidated. Glycolysis leads to production of pyruvate, which can be transported into the mitochondria by the mitochondrial pyruvate carrier (MPC) followed by utilization in the tricarboxylic acid cycle. Based on studies that used the MPC inhibitor UK5099, the mitochondrial route has been considered to be of significance for M1 activation. Using genetic approaches, here we show that the MPC is dispensable for metabolic reprogramming and activation of M1 macrophages. In addition, MPC depletion in myeloid cells has no impact on inflammatory responses and macrophage polarization toward the M1 phenotype in a mouse model of endotoxemia. While UK5099 reaches maximal MPC inhibitory capacity at approximately 2-5 mu M, higher concentrations are required to inhibit inflammatory cytokine production in M1 and this is independent of MPC expression. Taken together, MPC-mediated metabolism is dispensable for the classical activation of macrophages and UK5099 inhibits inflammatory responses in M1 macrophages due to effects other than MPC inhibition. Previous work using chemical inhibitors has reported the need for the mitochondrial pyruvate carrier for the classical activation of macrophages. In this study, Ran, Zhang et al. use a genetic approach to show that LPS-stimulated macrophage activation does not require the import of pyruvate into mitochondria.
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关键词
macrophages,metabolism,carrier-mediated
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