HIF1α Activates Glycolysis to Suppress Mycobacterium tuberculosis Growth in Mouse Bone Marrow-Derived Macrophages

Tuberculosis, caused by Mycobacterium tuberculosis (Mtb), remains a significant global health challenge due to the pathogen's ability to evade host immune responses and persist within macrophages. We investigated the metabolic changes in mouse bone marrow-derived macrophages (BMDMs) upon Mtb infection and identified significant alterations in gene expression related to key metabolic pathways through RNA sequencing analyses. Among them, glycolysis-related genes, including hypoxia-inducible factor 1α as a key regulator of glycolysis, are upregulated in Mtb-infected BMDMs. To investigate whether glycolysis plays a critical role in reducing intracellular Mtb growth, we cultured Mtb-infected BMDMs under high- or low-glucose conditions. We found that high-glucose conditions increased glycolytic enzyme levels, inducible nitric oxide synthase expression and proinflammatory cytokine production, reducing Mtb's intracellular survival. HIF1α agonist treatment increased glycolysis, reactive oxygen species levels and proinflammatory cytokine production, enhancing bactericidal activity against Mtb. In contrast, inhibition of HIF1α by a specific inhibitor FM19G11 leads to decreased glycolysis, reduced proinflammatory cytokine production and increased Mtb survival. Since succinate has been known to increase the stabilisation and activation of HIF1α, we added succinate to Mtb-infected BMDMs to evaluate the function of succinate related to HIF1α activation. As expected, succinate treatment enhanced glycolysis through HIF1α stabilisation and shifted BMDMs to proinflammatory M1-like phenotype. Our findings indicate that Mtb-induced glycolysis plays a central role in the reduction of intracellular Mtb in BMDMs. Succinate is a key factor for HIF1α-mediated glycolysis in Mtb-infected BMDMs.