The Astrocyte: Powerhouse and Recycling Center

Abstract

Brain metabolism is characterized by fuel monodependence, high-energy expenditure, autonomy from the rest of body, local recycling, and marked division of labor between cell types. Although neurons spend most of the brain's energy on signaling, astrocytes bear the brunt of the metabolic load, controlling the composition of the interstitial fluid, supplying neurons with energy substrates and precursors for biosynthesis, and recycling neurotransmitters, oxidized scavengers, and other waste products. Outstanding questions in this field are the role of oligodendrocytes, the metabolic behavior of the different subtypes of astrocytes during development and disease, and the emerging notion that metabolism may participate directly in information processing.

Figure 1.

Overview of astrocytic metabolism. (Inset) Astrocytes (green) reside between blood vessels (red) and neurons (yellow). Neurons and oligodendrocytes (blue) are not in direct contact with vessels. Astrocytes form metabolic domains and are coupled by gap junctions, through which they exchange metabolites and ions. Energy: The main energy substrate of the brain is glucose (glc), which crosses the endothelium and enters astrocytes via the glucose transporter GLUT1. Glucose is converted by glycolysis into pyruvate (pyr), which is oxidized to CO₂ by the mitochondrial Krebs cycle, producing NADH and then ATP. Pyruvate also generates lactate (lac), which is shuttled via monocarboxylate transporters MCT4 and MCT2 to be used as an energy substrate by neurons. Astrocytes store energy in the form of glycogen. A fast mechanism of neuronal energization is redox cycling, whereby astrocytic lactate is exchanged for neuronal pyruvate, with the net transfer of one energy-rich NADH per cycle. Neurons capture glucose via the glucose transporter GLUT3 to be metabolized via glycolysis and the pentose phosphate pathway (PPP) to promote antioxidation. Neurotransmission: Glutamate and γ-aminobutyric acid (GABA) are captured by astrocytic excitatory amino acid transporters (EAAT) and GAT, respectively, converted into glutamine and shuttled back to neurons for recycling via multiple astrocytic and neuronal transporters (SN1, SAT/ATA, and others). Biosynthesis: Glucose diverted through the astrocytic PPP generates NADPH and precursors for the synthesis of nucleotides and amino acids. Pyruvate is carboxylated into the Krebs cycle intermediate oxaloacetate (OAA), which is a precursor of multiple biosynthetic pathways in astrocytes and, through shuttling of glutamine, is also the main precursor for neuronal biosynthesis. Waste recycling: Reactive oxygen species (ROS) in neurons are scavenged by ascorbate (AA) with the production of dehydroascorbic acid (DHA), which diffuses through the glucose transporters toward astrocytes to be recycled into AA, and is returned to neurons via anion channels and the SVCT2. Glutathione (GSH) reacts with ROS to generate glutathione disulfide (GSSG), or with xenobiotics to generate conjugated glutathione (GS-X), both of which are discarded via multidrug resistance proteins (MDR). GSH synthesized and released by astrocytes is cleaved in the interstice to cysteine, which controls the neuronal synthesis of GSH. Ammonia (NH₃) released by the deamidation of glutamine into glutamate leaves neurons by an unknown pathway and is captured as ammonium (NH₄⁺) by K⁺ channels in astrocytes, where it is recycled by glutamine synthase. Some nitrogen is returned to astrocytes in the form of alanine and other amino acids (not shown). K⁺ released by neurons during synaptic activity enters astrocytes via K⁺ channels and the Na⁺/K⁺ ATPase. Methylglyoxal is a side product of glycolysis, which is detoxified mostly in astrocytes by the glyoxalase system.