Glucose feeds the TCA cycle via circulating lactate.

Published on Oct 18, 2017in Nature42.778
· DOI :10.1038/NATURE24057
Sheng Hui12
Estimated H-index: 12
(Princeton University),
Jonathan M. Ghergurovich11
Estimated H-index: 11
(Princeton University)
+ 9 AuthorsJoshua D. Rabinowitz100
Estimated H-index: 100
Metabolic flux analysis in mice reveals that lactate often acts as the primary carbon source for the tricarboxylic acid cycle both in normal tissues and in tumour microenvironments.
📖 Papers frequently viewed together
500 Citations
534 Citations
9,291 Citations
#1Jared R. Mayers (MIT: Massachusetts Institute of Technology)H-Index: 16
#2Margaret E. Torrence (MIT: Massachusetts Institute of Technology)H-Index: 6
Last. Matthew G. Vander HeidenH-Index: 91
view all 17 authors...
Tumor genetics guides patient selection for many new therapies, and cell culture studies have demonstrated that specific mutations can promote metabolic phenotypes. However, whether tissue context defines cancer dependence on specific metabolic pathways is unknown. Kras activation and Trp53 deletion in the pancreas or the lung result in pancreatic ductal adenocarinoma (PDAC) or non–small cell lung carcinoma (NSCLC), respectively, but despite the same initiating events, these tumors use branched-...
286 CitationsSource
#1Shawn M. Davidson (MIT: Massachusetts Institute of Technology)H-Index: 21
#2Thales Papagiannakopoulos (MIT: Massachusetts Institute of Technology)H-Index: 27
Last. Matthew G. Vander HeidenH-Index: 91
view all 20 authors...
Summary Cultured cells convert glucose to lactate, and glutamine is the major source of tricarboxylic acid (TCA)-cycle carbon, but whether the same metabolic phenotype is found in tumors is less studied. We infused mice with lung cancers with isotope-labeled glucose or glutamine and compared the fate of these nutrients in tumor and normal tissue. As expected, lung tumors exhibit increased lactate production from glucose. However, glutamine utilization by both lung tumors and normal lung was mini...
426 CitationsSource
#1Christopher T. Hensley (UTSW: University of Texas Southwestern Medical Center)H-Index: 8
#2Brandon Faubert (UTSW: University of Texas Southwestern Medical Center)H-Index: 24
Last. Ralph J. DeBerardinis (UTSW: University of Texas Southwestern Medical Center)H-Index: 87
view all 21 authors...
Summary Non-small cell lung cancer (NSCLC) is heterogeneous in the genetic and environmental parameters that influence cell metabolism in culture. Here, we assessed the impact of these factors on human NSCLC metabolism in vivo using intraoperative 13 C-glucose infusions in nine NSCLC patients to compare metabolism between tumors and benign lung. While enhanced glycolysis and glucose oxidation were common among these tumors, we observed evidence for oxidation of multiple nutrients in each of them...
534 CitationsSource
#1Joerg Martin Buescher (Katholieke Universiteit Leuven)H-Index: 2
#2Maciek R. Antoniewicz (UD: University of Delaware)H-Index: 47
Last. Sarah-Maria Fendt (Katholieke Universiteit Leuven)H-Index: 37
view all 37 authors...
Measuring intracellular metabolism has increasingly led to important insights in biomedical research. 13C tracer analysis, although less information-rich than quantitative 13C flux analysis that requires computational data integration, has been established as a time-efficient method to unravel relative pathway activities, qualitative changes in pathway contributions, and nutrient contributions. Here, we review selected key issues in interpreting 13C metabolite labeling patterns, with the goal of...
361 CitationsSource
#1Laura Nocito (BU: Boston University)H-Index: 4
#2Amber S. Kleckner (BU: Boston University)H-Index: 7
Last. Barbara E. Corkey (BU: Boston University)H-Index: 84
view all 6 authors...
Circulating redox state changes, determined by the ratio of reduced/oxidized pairs of different metabolites, have been associated with metabolic diseases. However, the pathogenic contribution of these changes and whether they modulate normal tissue function is unclear. As alterations in hepatic gluconeogenesis and glycogen metabolism are hallmarks that characterize insulin resistance and type 2 diabetes, we tested whether imposed changes in the extracellular redox state could modulate these proc...
29 CitationsSource
#1Simon G. Lamarre (MUN: Memorial University of Newfoundland)H-Index: 17
#2Luke MacMillan (MUN: Memorial University of Newfoundland)H-Index: 6
Last. John T. Brosnan (MUN: Memorial University of Newfoundland)H-Index: 56
view all 7 authors...
Formate, a crucial component of one-carbon metabolism, is increasingly recognized as an important intermediate in production and transport of one-carbon units. Unlike tetrahydrofolate-linked intermediates, it is not restricted to the intracellular milieu so that circulating levels of formate can provide insight into cellular events. We report a novel isotope-dilution, GC–MS assay employing derivatization by 2,3,4,5,6-pentafluorobenzyl bromide for the determination of formate in biological sample...
36 CitationsSource
#1Kelly M. Kennedy (Duke University)H-Index: 7
#2Peter M. Scarbrough (Duke University)H-Index: 11
Last. Mark W. Dewhirst (Duke University)H-Index: 132
view all 11 authors...
Lactate accumulation in tumors has been associated with metastases and poor overall survival in cancer patients. Lactate promotes angiogenesis and metastasis, providing rationale for understanding how it is processed by cells. The concentration of lactate in tumors is a balance between the amount produced, amount carried away by vasculature and if/how it is catabolized by aerobic tumor or stromal cells. We examined lactate metabolism in human normal and breast tumor cell lines and rat breast can...
117 CitationsSource
#1Shoba Shetty (UTSW: University of Texas Southwestern Medical Center)H-Index: 8
Last. Elizabeth J. Parks (UTSW: University of Texas Southwestern Medical Center)H-Index: 39
view all 9 authors...
Adiponectin overexpression in mice increases insulin sensitivity independent of adiposity. Here, we combined stable isotope infusion and in vivo measurements of lipid flux with transcriptomic analysis to characterize fatty acid metabolism in transgenic mice that overexpress adiponectin via the aP2-promoter (ADNTg). Compared with controls, fasted ADNTg mice demonstrated a 31% reduction in plasma free fatty acid concentrations (P = 0.008), a doubling of ketones (P = 0.028), and a 68% increase in f...
27 CitationsSource
#1Masahiro Sugimoto (YU: Yamagata University)H-Index: 32
#2Satsuki Ikeda (YU: Yamagata University)H-Index: 12
Last. Tomoyoshi Soga (YU: Yamagata University)H-Index: 78
view all 6 authors...
The Mouse Multiple Tissue Metabolome Database (MMMDB) provides comprehensive and quantitative metabolomic information for multiple tissues from single mice. Manually curated databases that integrate literature-based individual metabolite information have been available so far. However, data sets on the absolute concentration of a single metabolite integrated from multiple resources are often difficult to be used when different metabolomic studies are compared because the relative balance of the ...
34 CitationsSource
#1Nihed Draoui (UCL: Université catholique de Louvain)H-Index: 11
#2Olivier FeronH-Index: 86
Hypoxia and oncogene expression both stimulate glycolytic metabolism in tumors, thereby leading to lactate production. However, lactate is more than merely a by-product of glycolysis: it can be used as a metabolic fuel by oxidative cancer cells. This phenomenon resembles processes that have been described for skeletal muscle and brain that involve what are known as cell-cell and intracellular lactate shuttles. Two control points regulate lactate shuttles: the lactate dehydrogenase (LDH)-dependen...
198 CitationsSource
Cited By552
#1Tianjiao Zhao (CSU: Central South University)
#2Wei Wu (CSU: Central South University)
Last. Kelong Ai (CSU: Central South University)H-Index: 2
view all 7 authors...
Abstract null null Interventional coronary reperfusion strategies are widely adopted to treat acute myocardial infarction, but morbidity and mortality of acute myocardial infarction are still high. Reperfusion injuries are inevitable due to the generation of reactive oxygen species (ROS) and apoptosis of cardiac muscle cells. However, many antioxidant and anti-inflammatory drugs are largely limited by pharmacokinetics and route of administration, such as short half-life, low stability, low bioav...
#1Cilian Ó Maoldomhnaigh (Trinity College, Dublin)H-Index: 2
#2Donal J. Cox (Trinity College, Dublin)H-Index: 6
Last. Kate McQuaid (Trinity College, Dublin)H-Index: 1
view all 14 authors...
In order to mount an appropriate immune response to infection, the macrophage must alter its metabolism by increasing aerobic glycolysis and concomitantly decreasing oxidative phosphorylation; a process known as the Warburg effect. Consequently, lactate, the end-product of glycolysis, accumulates in the extracellular environment. The subsequent effect of lactate on surrounding macrophages is poorly understood. Mycobacterium tuberculosis (Mtb), the causative organism of Tuberculosis (TB), is phag...
Abstract null null Gluconeogenesis and glycolysis are the two major opposing metabolic pathways in central carbon metabolism. In vertebrates, biomass generation has been linked primarily to glycolysis, whereas gluconeogenesis has been classically regarded to be limited to specialized gluconeogenic organs. Studies from the recent years, however, show that gluconeogenesis is used by peripheral tissues, immune cells, and cancer cells of different origins to generate glycolytic/gluconeogenic interme...
#1Caroline Bartman (Ludwig Institute for Cancer Research)H-Index: 11
#2Yihui Shen (Princeton University)H-Index: 18
Last. Taijin Lan (RU: Rutgers University)H-Index: 1
view all 15 authors...
The tricarboxylic acid (TCA) cycle oxidizes carbon substrates to carbon dioxide, with the resulting high energy electrons fed into the electron transport chain to produce ATP by oxidative phosphorylation. Healthy tissues derive most of their ATP from oxidative metabolism, and the remainder from glycolysis. The corresponding balance in tumors remains unclear. Tumors upregulate aerobic glycolysis (the Warburg effect), yet they also typically require an intact TCA cycle and electron transport chain...
#1Kimberly Veliz (UPenn: University of Pennsylvania)H-Index: 2
#2Ulf H. Beier (Children's Hospital of Philadelphia)H-Index: 3
T cells undergo activation, maturation, and differentiation in which they can substantially transform and restructure. This includes metabolic adaptations which have been well recognized to be specific for T cell subsets. T cell subset-specific metabolism is thought to reflect different bioenergetic requirements as well as adaptations to environmental conditions in which the T cells operate. The metabolic changes that occur in T cells are orchestrated by signaling cascades that lead to rapid pos...
#1Danyu Du (CPU: China Pharmaceutical University)H-Index: 4
#2Chan Liu (CPU: China Pharmaceutical University)
Last. Jing Xiong (CPU: China Pharmaceutical University)H-Index: 11
view all 8 authors...
Abstract null null Hepatocellular carcinoma (HCC) is an aggressive human cancer with increasing incidence worldwide. Multiple efforts have been made to explore pharmaceutical therapies to treat HCC, such as targeted tyrosine kinase inhibitors, immune based therapies and combination of chemotherapy. However, limitations exist in current strategies including chemoresistance for instance. Tumor initiation and progression is driven by reprogramming of metabolism, in particular during HCC development...
Immune escape is one of the hallmarks of cancer. While metabolic reprogramming provides survival advantage to tumor cancer cells, accumulating data also suggest such metabolic rewiring directly affects the activation, differentiation and function of immune cells, particularly in the tumor microenvironment. Understanding how metabolic reprogramming affects both tumor and immune cells, as well as their interplay, is therefore critical to better modulate tumor immune microenvironment in the era of ...
#1Jeremy F. Weinberger (Brigham and Women's Hospital)H-Index: 4
#2Michael Klompas (Brigham and Women's Hospital)H-Index: 64
Last. Chanu Rhee (Harvard University)H-Index: 26
view all 3 authors...
Elevations in blood lactate concentrations have been studied in sepsis and other disease states for decades and are well known to be associated with increased mortality. Many studies have also demonstrated the prognostic accuracy of serial lactate levels, and some have suggested that lactate clearance may be a useful therapeutic target for resuscitation. Lactate measurements have therefore gained an increasingly prominent role in sepsis definitions, screening protocols, management guidelines, an...
#1Brandon Faubert (UTSW: University of Texas Southwestern Medical Center)H-Index: 24
#2Alpaslan Tasdogan (UTSW: University of Texas Southwestern Medical Center)H-Index: 14
Last. Ralph J. DeBerardinis (UTSW: University of Texas Southwestern Medical Center)H-Index: 87
view all 5 authors...
Cancer cells undergo diverse metabolic adaptations to meet the energetic demands imposed by dysregulated growth and proliferation. Assessing metabolism in intact tumors allows the investigator to observe the combined metabolic effects of numerous cancer cell-intrinsic and -extrinsic factors that cannot be fully captured in culture models. We have developed methods to use stable isotope-labeled nutrients (e.g., [13C]glucose) to probe metabolic activity within intact tumors in vivo, in mice and hu...