REVIEWS Lactate in the brain: from metabolic end-product to signalling molecule Pierre J. Magistretti1,2,3* and Igor Allaman2 Abstract | Lactate in the brain has long been associated with ischaemia; however, more recent evidence shows that it can be found there under physiological conditions. In the brain, lactate is formed predominantly in astrocytes from glucose or glycogen in response to neuronal activity signals. Thus, neurons and astrocytes show tight metabolic coupling. Lactate is transferred from astrocytes to neurons to match the neuronal energetic needs, and to provide signals that modulate neuronal functions, including excitability, plasticity and memory consolidation. In addition, lactate affects several homeostatic functions. Overall, lactate ensures adequate energy supply, modulates neuronal excitability levels and regulates adaptive functions in order to set the ‘homeostatic tone’ of the nervous system. Pyruvate dehydrogenase When studied at the organ level, brain energy meta­ Notably, under physiological conditions, the (PDH). The first component bolism can be considered as being almost fully oxida­ lactate:pyruvate concentration ratio is at least 10:1 enzyme of the pyruvate tive: elegant studies pioneered in the 1940s and 1950s (REF. 11). Thus, when considering the intercellular trans­ dehydrogenase complex; by Schmitt and Kety1 and later by Sokoloff 2 showed fer of a glycolytic substrate, lactate is the predominant it converts pyruvate into acetyl-CoA, which enters the that glucose is the obligatory physiological energy substrate in the brain. This ratio can also massively tricarboxylic acid (TCA) cycle substrate of the brain and is metabolized to CO2 and increase under hypoxia, as decreases in the partial for cellular respiration. water to yield 32–36 ATP molecules per molecule pressure of oxygen (pO2) impair the oxidative capac­ of oxidized glucose3. Studies over the past 20 years ity of the brain. Indeed, owing to this association with have added a cellular resolution to these organ stud­ hypoxia, lactate has long been considered a metabolic ies, demonstrating a cell­specific metabolism of glu­ end­product, at best a marker of pathology, if not a cose. Given the cellular heterogeneity of the brain, it toxic molecule (BOX 1). However, many recent studies is not surprising that different cell types have distinct in various tissues and cell types under physiological metabolic profiles. In particular, the emerging view is and pathological conditions12–14 now call for lactate to that neurons are mostly oxidative, whereas glial cells also be considered as an important signalling molecule. — notably, astrocytes and oligodendrocytes — pre­ By acting through different molecular effectors, lactate dominantly process glucose glycolytically, meaning contributes to several homeostatic processes (FIG. 2). that they produce lactate and pyruvate from glucose4,5 This Review focuses on the emerging roles of lactate in (FIG. 1). Estimates of glucose uptake from the circulation brain function, with a particular focus on the modu­ indicate that, at the most, neurons take up an amount lation of neuronal excitability, neuronal plasticity and approximately equal to that taken up by astrocytes neuroprotection. 1King Abdullah University of under basal conditions6,7. Science and Technology During functional activation, most of the increase Lactate production and metabolism (KAUST), Thuwal, 7–9 Kingdom of Saudi Arabia. in glucose uptake occurs in astrocytes . As neurons Lactate is formed through glycolysis, one of the var­ 2Brain Mind Institute, use 80–90% of the total energy consumed by the ious metabolic pathways through which glucose can École Polytechnique Fédérale brain10, and as oxidative activity is the most efficient be processed to produce energy (FIG. 1a). With normal de Lausanne (EPFL), ATP­producing pathway (FIG. 1a), energy substrates oxygen tension, ATP is mostly produced through the Lausanne, Switzerland. 3Département de Psychiatrie, such as pyruvate and lactate must be transferred from mitochondrial electron transport chain. Glucose is UNIL-CHUV, Site de Cery, astrocytes to neurons, particularly during functional processed to pyruvate, which under the action of the Prilly Lausanne, Switzerland. activation. This consideration is fully compatible with enzyme pyruvate dehydrogenase (PDH) provides carbon *e-mail: pierre.magistretti@ the original organ­level studies, because the sequential atoms for the tricarboxylic acid (TCA) cycle. TCA­ kaust.edu.sa two­step glucose processing (that is, the transient gly­ cycle products, such as NADH and FADH2, feed the doi:10.1038/nrn.2018.19 colysis in astrocytes followed by oxidation in neurons) electron transport chain, resulting in the production of Published online 8 Mar 2018 results in brain glucose oxidation. 32–36 ATP molecules. By contrast, under hypoxic or NATURE REVIEWS | NEUROSCIENCE VOLUME 19 | APRIL 2018 | 235 ©2018 Mac millan Publishers Li mited, part of Spri nger Nature. All ri ghts reserved. REVIEWS a Glycogen synthesis Lactate production Glycogen LDH Lactate NAD+ GS GP NADH Glycolysis NAD+ NADH Glucose Glucose-6-P Pyruvate HEX PFK PK ADP ATP H+ G6PD Mitochondria CO TCA 2 NADPH cycle Molecules PPP ADP ATP TCA cycle and oxidative phosphorylation b Astrocyte Glycogen Fructose-2,6-BP ATP ADP PFKFB3 PDK4 P PDH Glucose Glucose-6-P Fructose-6-P Phosphoenolpyruvate Pyruvate Acetyl-CoA TCA cycle PKM2 ADP ATP LDH5 LDH1 Lactate Neuron Glycogen PKM1 PDH Glucose Glucose-6-P Fructose-6-P Phosphoenolpyruvate Pyruvate Acetyl-CoA TCA cycle ADP ATP LDH1 Lactate Nature Reviews | Neuroscience Figure 1 | Glucose metabolism in astrocytes and neurons. a | The that are downregulated in these cell types. Glycogen storage and lactate processing of glucose by cells subserves several important functions: the production characterize astrocytes, whereas neurons use glucose storage of energy, the production of energy and the production of reducing predominantly in the PPP and use lactate, after its conversion to pyruvate, as equivalents and substrates for biosynthesis. Glucose is first phosphorylated their preferred mitochondrial energy substrate. Glycogen is almost by hexokinase (HEX) to glucose‑6‑phosphate (glucose‑6‑P), which has three exclusively present in astrocytes, where GS is permanently degraded by a fates that correspond to the three main functions of glucose. First, energy ubiquitin–proteasome process195. In astrocytes, 6‑phosphofructo‑2‑kinase/ can be stored as glycogen through the action of glycogen synthase (GS). fructose‑2,6‑bisphosphatase 3 (PFKFB3) expression is high and produces Glycogen can later be mobilized by glycogen phosphorylase (GP) and fructose‑2,6‑bisphosphate (fructose‑2,6‑BP; a key positive modulator of subsequently metabolized to pyruvate. Second, energy in the form of ATP glycolysis), whereas, in neurons, PFKFB3 is kept low through a can be produced by glucose‑6‑P entering glycolysis, supplying pyruvate for proteasome‑driven process32. PK expression is regulated in a cell‑specific the tricarboxylic acid (TCA) cycle in the mitochondria and the associated manner by differential splicing, resulting in expression of the M1 form oxidative phosphorylation. The main, and irreversible, steps of glycolysis are (PKM1) in neurons and expression of the aerobic glycolysis‑promoting form, catalysed by phosphofructokinase (PFK) and pyruvate kinase (PK). Glycolysis PKM2, in astrocytes34. In astrocytes, pyruvate dehydrogenase kinase produces ATP and NADH. Depending on the cell type, pyruvate can also be isoform 4 (PDK4) is highly expressed and phosphorylates pyruvate converted into lactate through the action of lactate dehydrogenase (LDH); dehydrogenase (PDH), inhibiting its activity in these cells20,34. The opposite in doing so, NAD+ levels (which are necessary to maintain the glycolytic flux) situation exists in neurons, resulting in high PDH activity and favouring are regenerated. Third, reducing equivalents in the form of NADPH are entry of pyruvate into the TCA cycle. LDH5 — the LDH form that drives produced in the pentose phosphate pathway (PPP) through a reaction aerobic glycolysis — is expressed predominantly in astrocytes, whereas catalysed by the enzyme glucose‑6‑P dehydrogenase (G6PD). Pentose neurons express low levels of, if any, LDH5, but rather express LDH1 backbones produced by the PPP are used for various biosynthetic processes, (REFS 25,208). Taken together, these cell‑specific expression and activity profiles including nucleotide and nucleic‑acid synthesis. b | In the brain, the confer to neurons a restricted potential for upregulating glycolysis and an expression of different metabolic pathways for glucose is cell specific. Red active oxidative phosphorylation activity. By contrast, in astrocytes, the arrows depict upregulated pathways; black dashed arrows depict pathways expression profiles favour aerobic glycolysis and limit oxidative activity. 236 | APRIL 2018 | VOLUME 19 www.nature.com/nrn ©2018 Mac millan Publishers Li mited, part of Spri nger Nature. All ri ghts reserved. ©2018 Mac millan Publishers Li mited, part of Spri nger Nature. All ri ghts reserved. REVIEWS anoxic conditions, only 2 ATP molecules are produced isolated neurons and astrocytes revealed that neurons per glucose molecule. Under such conditions, pyruvate produce CO2 at a much higher rate than do astrocytes, is converted to lactate (and NADH to NAD+) by lactate indicating high oxidative activity in neurons, whereas dehydrogenase (LDH) in a process known as anaerobic the enzyme function