Glucose feeds the TCA cycle via circulating lactate

By Sheng Hui, J. Ghergurovich, Raphael J. Morscher, Cholsoon Jang, Xin Teng, Wenyun Lu, L. Esparza, T. Reya, L. Zhan, J. Y. Guo and 2 more. Nature, 2017

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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 tissues and tumours. 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.

Subfields: Cancer Research, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/723e2408b71bcc7c64163e18fa4dc59dfd2c3028

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Citations in the corpus

Metabolic reprogramming and epigenetic modifications on the path to cancer (2021, background): “Lactic acid has long been considered a waste product of glycolytic metabolism; however, in 2017, two independent groups recently found that it can be reused as the primary carbon source for the mitochondrial TCA cycle in normal tissues and tumors (Faubert et al., 2017; Hui et al., 2017; Sun et al., ”
The Science and Translation of Lactate Shuttle Theory. (2018, background): “For instance, using isotope tracer technology onmice, investigators (Hui et al., 2017) recently stated that ‘‘intravenous infusions of (13)C-labeled 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.”
Class I histone deacetylases (HDAC1–3) are histone lysine delactylases (2021, background): “The sequence requirements of HDAC1/2 were different than those of HDAC3: HDAC1/2 showed lower activity at the H3K23 (8) and H4K12 (10) sites than HDAC3, relative to other peptides, while the H3K9 (6), H3K18 (7), and H4K8 (9) substrates were converted to a larger extent by all three enzymes (Fig.”
Metabolomics and isotope tracing (2018, background): “TCA carbon sources [U-(13)C]nutrients Succinate Malate Citrate a-ketoglutarate Carbon enrichment (number of (13)C atoms versus total carbon atoms) reflects carbon contribution from the nutrient; useful in vivowith correction for circulating nutrient enrichment (Davidson et al., 2016; Faubert et al.,”
Revisiting the Warburg effect: historical dogma versus current understanding (2020, background): “An alternative (respiratory) substrate is circulating lactate (serum level: 1–2 mmol/l) as evidenced by Hui et al. (2017) and Faubert et al. (2017).”