Search

Lactate has long been considered a cellular waste product. However, we found that as extracellular lactate accumulates, it also enters the mitochondrial matrix and stimulates mitochondrial electron transport chain (ETC) activity. The resulting increase in mitochondrial ATP synthesis suppresses glycolysis and increases the utilization of pyruvate and/or alternative respiratory substrates. The ability of lactate to increase oxidative phosphorylation does not depend on its metabolism. Both L- and D-lactate are effective at enhancing ETC activity and suppressing glycolysis. Furthermore, the selective induction of mitochondrial oxidative phosphorylation by unmetabolized D-lactate reversibly suppressed aerobic glycolysis in both cancer cell lines and proliferating primary cells in an ATP-dependent manner and enabled cell growth on respiratory-dependent bioenergetic substrates. In primary T cells, D-lactate enhanced cell proliferation and effector function. Together, these findings demonstrate that lactate is a critical regulator of the ability of mitochondrial oxidative phosphorylation to suppress glucose fermentation. [Display omitted] • Lactate is a mitochondrial messenger that shifts ATP production to the mitochondria • It activates the electron transport chain (ETC) without being metabolized • Lactate-induced ETC activation increases pyruvate oxidation and lactate utilization • Mitochondrial ETC can sense the availability of lactate as a nutrient Cai et al. found that lactate serves as a mitochondrial messenger that stimulates the electron transport chain independent of its metabolism. Lactate shifts ATP production from glycolysis to oxidative phosphorylation, allowing cells to conserve glucose while using lactate-derived pyruvate as their preferential substrate to support cellular ATP production. [ABSTRACT FROM AUTHOR]

Targeting glycolysis has been considered therapeutically intractable owing to its essential housekeeping role. However, the context-dependent requirement for individual glycolytic steps has not been fully explored. We show that CRISPR-mediated targeting of glycolysis in T cells in mice results in global loss of Th17 cells, whereas deficiency of the glycolytic enzyme glucose phosphate isomerase (Gpi1) selectively eliminates inflammatory encephalitogenic and colitogenic Th17 cells, without substantially affecting homeostatic microbiota-specific Th17 cells. In homeostatic Th17 cells, partial blockade of glycolysis upon Gpi1 inactivation was compensated by pentose phosphate pathway flux and increased mitochondrial respiration. In contrast, inflammatory Th17 cells experience a hypoxic microenvironment known to limit mitochondrial respiration, which is incompatible with loss of Gpi1. Our study suggests that inhibiting glycolysis by targeting Gpi1 could be an effective therapeutic strategy with minimum toxicity for Th17-mediated autoimmune diseases, and, more generally, that metabolic redundancies can be exploited for selective targeting of disease processes. • PPP and OXPHOS compensate for Gpi1 loss in Th17 cells in normoxic environment • Gpi1 is essential in hypoxic inflamed tissue due to reduced OXPHOS compensation • Metabolic redundancy can vary according to the microenvironment • Targeting Gpi1 could be a tolerable approach for therapeutic glycolysis inhibition Metabolic redundancy differs according to microenvironments, making the glycolysis gene Gpi1 dispensable for homeostatic Th17 cells in normal tissue but essential for pathogenic Th17 cells in hypoxic inflamed tissue. [ABSTRACT FROM AUTHOR]

Lymphoid cells that produce interleukin (IL)-17 cytokines protect barrier tissues from pathogenic microbes but are also prominent effectors of inflammation and autoimmune disease. T helper 17 (Th17) cells, defined by RORγt-dependent production of IL-17A and IL-17F, exert homeostatic functions in the gut upon microbiota-directed differentiation from naive CD4+ T cells. In the non-pathogenic setting, their cytokine production is regulated by serum amyloid A proteins (SAA1 and SAA2) secreted by adjacent intestinal epithelial cells. However, Th17 cell behaviors vary markedly according to their environment. Here, we show that SAAs additionally direct a pathogenic pro-inflammatory Th17 cell differentiation program, acting directly on T cells in collaboration with STAT3-activating cytokines. Using loss- and gain-of-function mouse models, we show that SAA1, SAA2, and SAA3 have distinct systemic and local functions in promoting Th17-mediated inflammatory diseases. These studies suggest that T cell signaling pathways modulated by the SAAs may be attractive targets for anti-inflammatory therapies. • SAAs direct a distinct Th17 cell differentiation program independently of TGF-β • Expression of SAAs is associated with inflamed colon of IBD patients • Systemic SAAs in serum promote differentiation of pathogenic Th17 cells • Local SAA expression fuels pathogenicity of activated Th17 cells Serum amyloid A proteins dictate the balance between homeostatic and inflammatory Th17 cells. [ABSTRACT FROM AUTHOR]