XB-ART-56589
Front Neurosci
2019 Mar 15;13:1301. doi: 10.3389/fnins.2019.01301.
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Energy Dynamics in the Brain: Contributions of Astrocytes to Metabolism and pH Homeostasis.
Deitmer JW
,
Theparambil SM
,
Ruminot I
,
Noor SI
,
Becker HM
.
Abstract
Regulation of metabolism is complex and involves enzymes and membrane transporters, which form networks to support energy dynamics. Lactate, as a metabolic intermediate from glucose or glycogen breakdown, appears to play a major role as additional energetic substrate, which is shuttled between glycolytic and oxidative cells, both under hypoxic and normoxic conditions. Transport of lactate across the cell membrane is mediated by monocarboxylate transporters (MCTs) in cotransport with H+, which is a substrate, a signal and a modulator of metabolic processes. MCTs form a "transport metabolon" with carbonic anhydrases (CAs), which not only provide a rapid equilibrium between CO2, HCO3- and H+, but, in addition, enhances lactate transport, as found in Xenopus oocytes, employed as heterologous expression system, as well as in astrocytes and cancer cells. Functional interactions between different CA isoforms and MCTs have been found to be isoform-specific, independent of the enzyme's catalytic activity, and they require physical interaction between the proteins. CAs mediate between different states of metabolic acidosis, induced by glycolysis and oxidative phosphorylation, and play a relay function in coupling pH regulation and metabolism. In the brain, metabolic processes in astrocytes appear to be linked to bicarbonate transport and to neuronal activity. Here, we focus on physiological processes of energy dynamics in astrocytes as well as on the transfer of energetic substrates to neurons.
PubMed ID: 31866811
PMC ID: PMC6909239
Article link: Front Neurosci
Genes referenced: ca2 ca4.1 ldha mcts1 slc16a3 slc16a7 slc4a4
Article Images: [+] show captions
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FIGURE 1. The Astrocyte to Neuron Lactate Shuttle. Astrocytes take up glucose from the blood capillaries via glucose transporters (GLUTs). In astrocytes, glucose is either stored as glycogen or metabolized to pyruvate in the glycolysis. Pyruvate is then converted to lactate by the oxidoreductase lactate dehydrogenase (LDH) isoform 5 (LDH5). The lactate is transferred from astrocytes to neurons by the monocarboxylate transporters (MCTs) MCT1, MCT2, and MCT4 in cotransport with a proton. MCT transport activity was found to be facilitated by interaction with the carbonic anhydrases (CAs) CAII and CAIV, which catalyze the equilibrium of H+, HCO3– and CO2 both intra- and extracellularly, and by the activity of the electrogenic sodium-bicarbonate cotransporter NBCe1. In neurons, lactate is converted back to pyruvate by LDH1 and transferred into mitochondria for aerobic energy production in the tricarboxylic acid cycle (TCA). In addition, glucose is directly taken up into neurons where it can either serve as energy source in the glycolysis or is shuttled into the pentose phosphate pathway (PPP) for production of NADPH and cellular building blocks like ribose-6-phosphate. |
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