Glucose feeds the TCA cycle via circulating lactate.

TitleGlucose feeds the TCA cycle via circulating lactate.
Publication TypeJournal Article
Year of Publication2017
AuthorsHui, S, Ghergurovich, JM, Morscher, RJ, Jang, C, Teng, X, Lu, W, Esparza, LA, Reya, T, Guo, JYanxiang, White, E, Rabinowitz, JD
JournalNature
Volume551
Issue7678
Pagination115-118
Date Published2017 11 02
ISSN1476-4687
KeywordsAnimals, Blood Glucose, Brain, Carbon, Citric Acid Cycle, Fasting, Glucose, Glutamine, Glycolysis, Lactic Acid, Mice, Muscles, Pancreatic Neoplasms
Abstract

<p>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 C-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, C-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.</p>

DOI10.1038/nature24057
Alternate JournalNature
PubMed ID29045397
PubMed Central IDPMC5898814
Grant ListDP1 DK113643 / DK / NIDDK NIH HHS / United States
P30 CA072720 / CA / NCI NIH HHS / United States
K22 CA190521 / CA / NCI NIH HHS / United States
R01 CA186043 / CA / NCI NIH HHS / United States
5P30 DK019525 / NH / NIH HHS / United States
R01 CA163591 / CA / NCI NIH HHS / United States
R50 CA211437 / CA / NCI NIH HHS / United States
R35 CA197699 / CA / NCI NIH HHS / United States
P30 DK019525 / DK / NIDDK NIH HHS / United States
R01 CA130893 / CA / NCI NIH HHS / United States