Glucose feeds the TCA cycle via circulating lactate

Abstract

Mammalian tissues are fuelled by circulating nutrients, including glucose, amino acids, and various intermediary metabolites. Under aerobic conditions, glucose is generally assumed to be burned fully by tissues via the tricarboxylic acid cycle (TCA cycle) to carbon dioxide. Alternatively, glucose can be catabolized anaerobically via glycolysis to lactate, which is itself also a potential nutrient for tissues1 and tumours2–5. The quantitative relevance of circulating lactate or other metabolic intermediates as fuels remains unclear. Here we systematically examine the fluxes of circulating metabolites in mice, and find that lactate can be a primary source of carbon for the TCA cycle and thus of energy. Intravenous infusions of 13C-labelled nutrients reveal that, on a molar basis, the circulatory turnover flux of lactate is the highest of all metabolites and exceeds that of glucose by 1.1-fold in fed mice and 2.5-fold in fasting mice; lactate is made primarily from glucose but also from other sources. In both fed and fasted mice, 13C-lactate extensively labels TCA cycle intermediates in all tissues. Quantitative analysis reveals that during the fasted state, the contribution of glucose to tissue TCA metabolism is primarily indirect (via circulating lactate) in all tissues except the brain. In genetically engineered lung and pancreatic cancer tumours in fasted mice, the contribution of circulating lactate to TCA cycle intermediates exceeds that of glucose, with glutamine making a larger contribution than lactate in pancreatic cancer. Thus, glycolysis and the TCA cycle are uncoupled at the level of lactate, which is a primary circulating TCA substrate in most tissues and tumours.

The plasticity of pancreatic cancer metabolism in tumor progression and therapeutic resistance

“…Taken together, these data provide some insight into maintenance of the glycolytic phenotype found in PDA tumors. In agreement with the proclivity of PDA to utilize pyruvate fermentation over oxidative phosphorylation, in vivo tracing of labeled glucose carbon makes very little contribution to TCA cycle metabolites in PDA [55]. It has been reported, however, that lactate excreted by hypoxic pancreatic cancer cells can provide an alternative fuel source for those PDA cells that are well oxygenated [56].…”

“…It has been reported, however, that lactate excreted by hypoxic pancreatic cancer cells can provide an alternative fuel source for those PDA cells that are well oxygenated [56]. Interestingly, labeled lactate carbon contributes to the labeling of TCA cycle metabolites in PDA as well as in other types of cancer [55, 57]. Once thought to be a waste product of glycolysis, it is now becoming clear that lactate excretion by PDA cells has various roles within the TME, including providing nutrients to neighboring cells and contributing to an immunosuppressive phenotype [58].…”

Glia-neuron energy metabolism in health and diseases: New insights into the role of nervous system metabolic transporters

“…Though it was proposed over twenty years ago (Magistretti et al, 1993; Pellerin and Magistretti, 1994), ANLSH remains controversial and not fully accepted. A recent study claims that during fasting conditions, glucose contributes indirectly (via circulating lactate) to tissue TCA metabolism in all tissues except the brain (Hui et al, 2017). Additionally, a study modeling the kinetic characteristics and cellular concentrations of the neuronal glucose and lactate transporters opposes the ANLSH primarily due to the fact that neuronal glucose transporter, GLUT3, has higher affinity for glucose than the astrocytic counterpart, GLUT1, an, indicating that glucose may be primarily transported to and consumed by neurons (Simpson et al, 2007).…”

Lactate is oxidized outside of the mitochondrial matrix in rodent brain

“…The centrality of lactate to neuroenergetics (Schurr 2017), and to metabolic physiology in general (Hui et al 2017), is undeniable. The experimental freedoms conferred by the permeabilized brain methodology permit evaluation of lactate oxidation in this tissue, and adds to the techniques with which mitochondrial function in brain can be explored to investigate pathologies, test various applications, and describe the phenotypic outcomes of transgenic animal models.…”