Short-term methionine deprivation inhibits TCA cycle and regulates macrophage polarization through uncharged tRNA and PDHA1 phosphorylation

Methionine restriction diet has been extensively studied for its beneficial effects on metabolic health and aging. However, the impact of methionine deprivation on glucose metabolism per se and macrophage functions remains incompletely understood. In this study, we analyzed the functional roles of methionine deprivation on glucose flux and macrophage polarization. We used metabolic flux to investigate how methionine deprivation affected glucose metabolism. The functions of methionine deficiency on macrophage polarization and the underlying mechanisms were studied at both the cellular and animal levels. We found that short-term methionine deprivation represses the tricarboxylic acid (TCA) cycle in mitochondria, accompanied by rapid phosphorylation of the E1 subunit of pyruvate dehydrogenase (PDH) complex, PDHA1. This phosphorylation by methionine deprivation is dependent on increased levels of uncharged tRNA but is independent of GCN2. Furthermore, methionine deprivation promotes M1-like polarization of macrophages, consistent with metabolic reprogramming. Notably, the proinflammatory effect of methionine deprivation on macrophages is also mediated by PDHA1 phosphorylation and increases in uncharged tRNA, but independent of GCN2. Our study not only elucidates a direct regulatory role of methionine depletion on the TCA cycle but also reveals that such a regulation is tightly linked to the modulation of macrophage polarization.