Glucose feeds the TCA cycle via circulating lactate
Open accessAbstract
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 13 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, 13 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.
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Recent studies in vivo have demonstrated that cells import lactate from the circulation via monocarboxylate transporter 1 and subsequently oxidize lactate to form pyruvate, resulting in a large fraction of pyruvate and downstream TCA cycle intermediates being derived from circulating lactate.
“However, recent studies in vivo have demonstrated that cells import lactate from the circulation via monocarboxylate transporter 1 and subsequently oxidize lactate to form pyruvate, resulting in a large fraction of pyruvate and downstream TCA cycle intermediates being derived from circulating lactate (46, 47).”
From Regulation and function of the mammalian tricarboxylic acid cycle (2023) · cites this paper as [47]
In cultured cells, pyruvate is largely produced from glucose via glycolysis; in vivo, circulating lactate provides an additional major source of tissue pyruvate.
“In cultured cells, pyruvate is largely produced from glucose via glycolysis; in vivo, circulating lactate provides an additional major source of tissue pyruvate (46, 47, 48).”
From Regulation and function of the mammalian tricarboxylic acid cycle (2023) · cites this paper as [47]
In most tissues and some tumors, the contribution of circulating lactate to TCA cycle intermediates exceeds that of glucose, supporting the idea that lactate is a fundamental TCA cycle substrate in living organisms.
“In most tissues and some tumors, the contribution of circulating lactate to TCA cycle intermediates exceeds that of glucose, supporting the idea that lactate is a fundamental TCA cycle substrate in living organisms (46, 47).”
From Regulation and function of the mammalian tricarboxylic acid cycle (2023) · cites this paper as [47]
The contribution of circulating lactate to TCA cycle intermediates exceeds that of glucose in most tissues and tumors.
“As described previously, the contribution of circulating lactate to TCA cycle intermediates exceeds that of glucose in most tissues and tumors (46, 47).”
From Regulation and function of the mammalian tricarboxylic acid cycle (2023) · cites this paper as [47]
Other organs readily export lactate derived from glucose metabolism and readily use circulating lactate for oxidative metabolism.
“Other organs readily export the lactate they derive from glucose metabolism, and they readily use circulating lactate for their oxidative metabolism.”
From Fueling thought: Management of glycolysis and oxidative phosphorylation in neuronal metabolism (2018) · cites this paper as Hui et al., 2017
The brain's TCA cycle is fed mainly by metabolites derived from circulating glucose, with relatively little intermediate mixing of lactate from the circulation.
“In contrast, the brain’s tricarboxylic acid (TCA) cycle is fed mainly by metabolites derived from circulating glucose, with relatively little intermediate mixing of lactate from the circulation.”
From Fueling thought: Management of glycolysis and oxidative phosphorylation in neuronal metabolism (2018) · cites this paper as Hui et al., 2017
Uncoupling between glycolysis and oxidative metabolism is the norm for all organs except the brain.
“Recent work on in vivo metabolite fluxes argues that uncoupling between glycolysis and oxidative metabolism is the norm for all organs except the brain (Hui et al., 2017).”
From Fueling thought: Management of glycolysis and oxidative phosphorylation in neuronal metabolism (2018) · cites this paper as Hui et al., 2017
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“However, of note, utilization of glucose in the TCA cycle can be attributed to experimental conditions, as multiple studies now demonstrate that both mouse and human tumors oxidize glucose and lactate in the TCA cycle, independent of their mutational driver [20, 21, 25, 28].”
Background
- Authors
- Hui, S., Ghergurovich, J. M., Morscher, R. J., Jang, C., Teng, X., Lu, W., Esparza, L. A., Reya, T., Zhan, L., Yanxiang Guo, J., White, E., & Rabinowitz, J. D.
- Affiliations
- Princeton University (US)
- University of California San Diego (US)
- Rutgers, The State University of New Jersey (US)
- Corresponding author
- Rabinowitz, Joshua D.
- ORCID
- Venue
- Nature
- Published
- 2017-10-18
- Volume
- 551
- Issue
- 7678
- Pages
- 115-118
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC5898814
- OpenAlex
- W2765303057
- Cited by
- 1,721
- References
- 37
- Citations by year
- 2026: 172 · 2025: 234 · 2024: 219 · 2023: 239 · 2022: 227 · 2021: 201 · 2020: 182 · 2019: 142 · 2018: 93 · 2017: 10
- FWCI
- 38.97
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- Zurich Open Repository and Archive (University of Zurich) (acceptedVersion, other-oa)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Zurich Open Repository and Archive (University of Zurich) (submittedVersion, other-oa)
- Zurich Open Repository and Archive (University of Zurich)
- Funders
- American Diabetes Association (1DP1DK113643)
- Rutgers Cancer Institute of New Jersey (P30 CA072720, K22 CA190521)
- Life Sciences Research Foundation
- Cancer Research UK
- National Institutes of Health (CA072720, DK019525)
- Stand Up To Cancer (SU2C-AACR-DT-20-16)
- National Cancer Institute (R01CA186043, K22CA190521, R01CA130893, P30CA072720, R50CA211437, R01CA163591, R35CA197699)
- National Institute of Diabetes and Digestive and Kidney Diseases (DP1DK113643, P30DK019525)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolomics and Mass Spectrometry Studies
- Keywords
- lactate, TCA cycle, glucose metabolism, circulating metabolites, metabolic flux, cancer metabolism, fasting, glycolysis, glutamine, pancreatic cancer, lung cancer, energy metabolism
- MeSH terms
- Animals, Blood Glucose, Brain, Carbon, Citric Acid Cycle, Fasting, Glucose, Glutamine, Glycolysis, Muscles, Pancreatic Neoplasms, Lactic Acid, Mice
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