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Astrocyte metabolism and signaling pathways in the CNS - PubMed

  • ️Sun Jan 01 2023

Review

Astrocyte metabolism and signaling pathways in the CNS

Yong-Mei Zhang et al. Front Neurosci. 2023.

Abstract

Astrocytes comprise half of the cells in the central nervous system and play a critical role in maintaining metabolic homeostasis. Metabolic dysfunction in astrocytes has been indicated as the primary cause of neurological diseases, such as depression, Alzheimer's disease, and epilepsy. Although the metabolic functionalities of astrocytes are well known, their relationship to neurological disorders is poorly understood. The ways in which astrocytes regulate the metabolism of glucose, amino acids, and lipids have all been implicated in neurological diseases. Metabolism in astrocytes has also exhibited a significant influence on neuron functionality and the brain's neuro-network. In this review, we focused on metabolic processes present in astrocytes, most notably the glucose metabolic pathway, the fatty acid metabolic pathway, and the amino-acid metabolic pathway. For glucose metabolism, we focused on the glycolysis pathway, pentose-phosphate pathway, and oxidative phosphorylation pathway. In fatty acid metabolism, we followed fatty acid oxidation, ketone body metabolism, and sphingolipid metabolism. For amino acid metabolism, we summarized neurotransmitter metabolism and the serine and kynurenine metabolic pathways. This review will provide an overview of functional changes in astrocyte metabolism and provide an overall perspective of current treatment and therapy for neurological disorders.

Keywords: astrocyte; energy imbalance; metabolism; neural circuit; neurological disorders.

Copyright © 2023 Zhang, Qi, Gao, Chen, Zhou, Zang and Li.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1

Glucose metabolism in astrocytes. (A) Glucose is transported from the blood brain barrier (BBB) to astrocytes and neurons through glucose transporters (GLUTs) and phosphorylated to glucose-6-phosphate (G6P). G6P enters different pathways, such as glycolysis, the astrocyte-neuron lactate shuttle, the pentose-phosphate pathway (PPP), and the oxidative phosphorylation pathway. (B) In the PPP, G6P catalyzes ribulose-5-phosphate (R5P), converting nicotinamide adenine dinucleotide phosphate (NADP) + to NADPH at the same time. Concurrently, R5P can also be converted to glyceraldehyde-3-phosphate and fructose-6-phosphate (F6P), the latter of which can isomerize back to G6P. (C) The astrocyte-neuron lactate shuttles provide energy for neuron activity. Lactate is transferred from astrocytes into neurons through monocarboxylic acid transporters (MCTs) and is converted to pyruvate to generate ATP in mitochondria. (D) The oxidative phosphorylation pathway in astrocytes converts G6P to pyruvate, which undergoes oxidative decarboxylation to form acetyl-CoA and then enters the tricarboxylic acid (TCA) cycle to generate ATP in mitochondria. MPC1, mitochondrial pyruvate carrier 1; HK, hexokinase; GP, glycogen phosphorylase; LDH1, lactate dehydrogenase 1.

Figure 2
Figure 2

Fatty acid metabolism in astrocytes. When energy is scarce, fatty acids are converted to fatty acyl-CoA and undergo β-oxidation (β-oxid) to produce β-hydroxybutyrate (BHB). BHB converts back to acetyl-CoA via β-ketoacyl-CoA transferase or enters the TCA cycle to generate ATP. It then enters the TCA cycle to generate ATP. FACS, fatty acyl-CoA synthetase; HMG-CoA, 3-hydroxy-3-methylglutaryl coenzyme A; ACAC, acetoacetate.

Figure 3
Figure 3

Glutamate and GABA metabolism. (A) Astrocytes regulate glutamate in the brain through glutamate transporters (GLTs). After being transported in astrocytes, glutamate undergoes the glutamine synthase pathway to produce glutamine or the TCA cycle to generate ATP. (B) The glutamate synthesis pathway in neurons. Glutamine in neurons is transported from astrocytes and is deaminized to generate glutamate by glutaminase. (C) GABA synthesis in neurons. Glutamine in neurons for GABA synthesis is transported from astrocytes or synthesized from glutamate, which is released from the excitatory synapse. Glutamine is then converted to GABA through phosphate-activated glutaminase (PAG). GS, glutamine synthetase; GDH, glutamate dehydrogenase; GABAT, GABA transaminase; GAT1, GABA transporter 1; SSA, succinyl semialdehyde; SSADH, semialdehyde dehydrogenase.

Figure 4
Figure 4

The impacts of astrocyte metabolic pathways on neurological disorders. (A) Targeting astrocyte metabolic pathways in depression. In depression, metabolic pathways are impaired in astrocytes, such as epoxyeicosatrienoic acid (EET) signaling, the PPP, the TCA cycle, and an increase in ROS. These changes in astrocytes lead to a decrease in dopamine, ATP, glutamate, astrocytes and 5-HT, while reactive oxygen species (ROS) are increased. (B) Targeting astrocyte metabolic pathways in Alzheimer’s disease (AD). Some metabolic signaling is impaired in astrocytes, such as the glutamate uptake pathway, glycolysis pathway, and TCA cycle, while ROS are increased, leading to high inflammation levels. (C) Targeting astrocyte metabolic pathways in epilepsy. The pathways involved in epilepsy in astrocytes, such as the metabolism of glutamate, the synthesis of GABA, glycolysis, lactate and glycogen metabolism, were impaired, leading to the accumulation of glutamate, lactate and glycogen and the loss of GABA and glucose.

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