The tortuous path of lactate shuttle discovery: From cinders and boards to the lab and ICU

George A Brooks, George A Brooks

Abstract

Once thought to be a waste product of oxygen limited (anaerobic) metabolism, lactate is now known to form continuously under fully oxygenated (aerobic) conditions. Lactate shuttling between producer (driver) and consumer cells fulfills at least 3 purposes; lactate is: (1) a major energy source, (2) the major gluconeogenic precursor, and (3) a signaling molecule. The Lactate Shuttle theory is applicable to diverse fields such as sports nutrition and hydration, resuscitation from acidosis and Dengue, treatment of traumatic brain injury, maintenance of glycemia, reduction of inflammation, cardiac support in heart failure and following a myocardial infarction, and to improve cognition. Yet, dysregulated lactate shuttling disrupts metabolic flexibility, and worse, supports oncogenesis. Lactate production in cancer (the Warburg effect) is involved in all main sequela for carcinogenesis: angiogenesis, immune escape, cell migration, metastasis, and self-sufficient metabolism. The history of the tortuous path of discovery in lactate metabolism and shuttling was discussed in the 2019 American College of Sports Medicine Joseph B. Wolffe Lecture in Orlando, FL.

Keywords: Anaerobic metabolism; Exercise; Glycolysis; Oxidative metabolism, Warburg Effect.

Copyright © 2020. Production and hosting by Elsevier B.V.

Figures

Graphical abstract
Graphical abstract
Fig. 1
Fig. 1
The lactate shuttle concept, depicting lactate as the vehicle linking glycolytic and oxidative metabolism. Linkages between lactate “producer” and “consumer” exist within and among cells, tissues, and organs. As the product of one metabolic pathway (glycolysis) and the substrate for a downstream pathway of disposal (mitochondrial respiration), lactate is the link between the glycolytic and aerobic pathways. Importantly, according to the lactate shuttle hypothesis, this linkage occurs continuously under fully aerobic conditions, can transcend compartment barriers and occur within and among cells, tissues and organs. Modified from Refs , , with permission.
Fig. 2
Fig. 2
Lactate production occurs continuously under fully aerobic conditions in intact animals, mammalian tissue preparations, intact animals, and humans in vivo. In muscles and arterial blood of resting healthy humans, lactate concentration approximates 1.0 mmol/L, while pyruvate concentration approximates 0.1 mmol/L. The lactate/pyruvate (L/P) approximates 10, with net lactate production and release from resting muscle of healthy individuals occurring when arterial partial pressure of oxygen (PO2) approximates 100 Torr and intramuscular PO2 approximates 40 Torr, well above the critical mitochondrial PO2 for maximal mitochondrial respiration (1–2 Torr)., , During exercise at about 65% of maximal oxygen consumption (VO2max), lactate production and net lactate release from working muscle beds rise and the L/P rises more than an order of magnitude (to approximately 500). However, the intramuscular PO2 remains at 3–4 Torr, well above the critical mitochondrial O2 level. Hence, it is appropriate to conclude that in healthy humans, glycolysis proceeds to lactate under fully aerobic conditions. Importantly, most (75%–80%) lactate is disposed of immediately within the tissue or subsequent to release and reuptake by working muscle, with significant uptake and oxidation by heart or oxidation by liver for gluconeogenesis. From diverse sources,,,,, with permission.
Fig. 3
Fig. 3
The Meyerhof calorimeter. m1 is the device for indirect electrical stimulation of frog hemicorpus thighs; the horizontal line (m2) is Ringers solution level. This device was used to demonstrate quantitative conversion of glycogen to lactate under nonperfused and nonoxygenated conditions. From Ref. 1 with permission.
Fig. 4
Fig. 4
Devices use to support the presence of lactate shuttling in resting and exercising mammals in vivo. These include (A) a motorized treadmill with sensors to determine oxygen consumption (VO2), rate of elimination of carbon dioxide (VCO2), electrocardiogram (ECG), RER (= VCO2/VO2) and (B) blood-specific activities of glucose, lactate glucose (Gluc), fructose di-phosphate (FDP), and other metabolic intermediates using 2-dimensional paper chromatography, autoradiography and enzymatic analyses. See original papers, for details on how lactate flux (production and disposal, oxidation and gluconeogenic) rates were determined in a mammalian model organism during physical exercise. From Ref. 23 with permission.
Fig. 5
Fig. 5
Depiction of the lactate shuttle as it fulfills 3 physiologic functions: (1) lactate as a major energy source, (2) lactate as the major gluconeogenic precursor, and (3) lactate as a signaling molecule with autocrine-, paracrine-, and endocrine-like effects (called a “lactormone”). “Cell–Cell” and “Intracellular Lactate Shuttle” concepts describe the roles of lactate in the delivery of oxidative and gluconeogenic substrates as well as in cell signaling. Examples of the Cell–Cell Lactate Shuttles include lactate exchanges between white glycolytic and red oxidative fibers within a working muscle bed and between working skeletal muscle and heart, brain, liver, and kidneys. Examples of Intracellular Lactate Shuttles include cytosol–mitochondrial and cytosol–peroxisome exchanges. Indeed, most, if not all, lactate shuttles are driven by a concentration or pH gradient or by redox state. FG = fast glycolytic; SO = slow oxidative. The figure is annotated because the original model did not anticipate cerebral lactate oxidation and hepatic and renal gluconeogenesis. Compiled from diverse sources, , and with permission.
Fig. 6
Fig. 6
A schematic showing the putative mitochondrial lactate oxidation complex (mLOC). The lactate-pyruvate transporter (MCT1) is inserted into the mitochondrial inner membrane, strongly interacting with its chaperone protein CD147, and is also associated with cytochrome oxidase (COx) as well as mitochondrial lactate dehydrogenase (mLDH), which could be located at the outer side of the inner membrane. Lactate, which is always produced in the cytosol of muscle and other tissues because of the abundance, activity, and characteristics of cytosolic LDH, is oxidized to pyruvate via the lactate oxidation complex in mitochondria of the same cell. This endergonic lactate oxidation reaction is coupled to the exergonic redox change in COx during mitochondrial electron transport. ETC = electron transport chain; GP = glycerol phosphate; Mal-Asp = malate-aspartate; MCT = monocarboxylate (lactate) transporter; mPC = mitochondrial pyruvate carrier; TCA = tricarboxylic acid. Redrawn from Ref. 75 with permission.
Fig. 7
Fig. 7
Immunohistochemical images demonstrating some components of the mitochondrial lactate oxidation complex (mLOC) in L6 cells. The mLOC contains the inner mitochondrial membrane cytochrome oxidase (COX), the lactate-pyruvate transporter (MCT1), lactate dehydrogenase (LDH) and the MCT anchoring protein, CD147 (Basigin). MCT1 was detected at both sarcolemmal and intracellular domains (A-1). Mitochondrial reticulum (MR), identified by MitoTracker, was extensively elaborated in L6 cells (A-2). The merged images of MCT1 (green, A-1) and MR (red, A-2) showed intense yellow, indicating co-localization of MCT1 and components of the MR, particularly at perinuclear cell domains (A-3). (B) LDH (B-1) and COX (B-2) are imaged. Superposition of signals for LDH (red, B-1) and COX (green, B-2) shows co-localization of LDH in the MR (yellow) of muscle cells (B-3). Depth of field approximately 1 μm, scale bar = 10 μm. Similar data have been obtained on rat plantaris leg muscles in vivo. From Ref. 75 with permission.
Fig. 8
Fig. 8
First images assessing co-localization of the monocarboxylate (lactate, pyruvate, β-hydroxybutyrate) transporter (MCT1) and mitochondrial the pyruvate carrier (mPC) in L6 cells, which shows the localization of DAPI-positive nuclei (A), MCT1 (B), mPC1 (C), and Mito Tracker-positive MR (D) in L6 cells. The merged images are shown in E. Co-localization analysis of mPC1 (C) and mitochondria (D) showed a Pearson correlation coefficient (r2) value of 0.8. Co-localization analysis of MCT1 (B) and mPC1 (C) showed an r2 of 0.3, largely because MCT1 occupies sarcolemmal, mitochondrial, and peroxisomal compartments. A channel to represent the co-localization of MCT1 and mitochondria was created to image mMCT1; subsequent co-localization of mMCT1 with mPC1 resulted in an r2 of 0.8 (F). White dots indicate the co-localization of mMCT1 and mPC1 as observed in Image J software. Whole images were contrast enhanced in A, B, C, D, and E. Similar results were observed for mPC2. Scale bar = 20 μm. It appears that both MCT1 and the putative mPC are co-localized to the mitochondria (r2 = 0.8). However, at the light microscopic level, it is impossible to know if the 2 proteins interact physically and functionally. Also, with benefit of the Orbitrap liquid chromatography/mass spectrometry device, we would be able to determine fractional synthesis rates of mitochondrial lactate oxidation complex and mPC proteins.
Fig. 9
Fig. 9
Illustration of how lactatemia affects blood (glucose) and peripheral glucose uptake as well as the production, uptake and oxidation of FFA, giving rise to metabolic inflexibility in muscle. Lactate is the inevitable consequence of glycolysis, the minimal muscle lactate (L) to pyruvate (P) ratio (L/P) being 10 and rising to an L/P of >100 when glycolytic flux is high. Lactate is the favored oxidizable substrate and provides product inhibition of glucose and FFA oxidation. As the products of glycolysis, lactate and pyruvate provide negative feedback inhibition of glucose disposal (blue dashed lines). Also, as the predominant mitochondrial substrate, lactate gives rise to acetyl-coenzyme A (CoA), and in turn malonyl-CoA. Acetyl-CoA inhibits β-ketothiolase and, hence, β-oxidation, while malonyl-CoA inhibits mitochondrial FFA-derivative uptake via CPT1 (T). Moreover, lactate is the main gluconeogenic precursor raising glucose production and blood (glucose) (red lines). Via GPR81 binding, lactate inhibits lipolysis in WAT (T), depressing circulating FFA., This model explains the paradoxical presence of lactatemia in high-intensity exercise and insulin-resistant states with limited ability to oxidize fat (green lines). Modified from. CPT1 = carnitine palmitoyl transporter-1; FAT = fatty acid translocator comprised of CD36 and FABPc; FFA = free fatty acid; GLUT = glucose transporter; m = mitochondrial; Malonyl = CoA formed from exported TCA citrate controlled by the interactions of malonyl-CoA decarboxylase (MCD) and acetyl-CoA carboxylase (ACC); MCT = monocarboxylate transporter; mPC = mitochondrial pyruvate transporter; PDH = pyruvate dehydrogenase; s = sarcolemmal; T = inhibition; WAT = white adipose tissue. Not shown is fatty acyl-Co (FA-CoA) that will accumulate if FFAs are taken up by myocytes, but blocked from mitochondrial entry by the effect of malonyl-CoA on CPT1. Accumulated intracellular FA-CoA will give rise to intramyocellular triglyceride (IMTG) and the formulation of LC-FA, DAG, and ceramides via inhibition of PI3 Kinase (PI3-K) and reducing GLUT4 translocation; from Ref. with permission.

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