Cited by 262Neuroscience and Neuropharmacology ResearchCancer, Hypoxia, and MetabolismRedox biology and oxidative stress

Bioenergetics and redox adaptations of astrocytes to neuronal activity

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Bolaños, Juan P.·2016·Journal of Neurochemistry

Abstract

Neuronal activity is a high-energy demanding process recruiting all neural cells that adapt their metabolism to sustain the energy and redox balance of neurons. During neurotransmission, synaptic cleft glutamate activates its receptors in neurons and in astrocytes, before being taken up by astrocytes through energy costly transporters. In astrocytes, the energy requirement for glutamate influx is likely to be met by glycolysis. To enable this, astrocytes are constitutively glycolytic, robustly expressing 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase-3 (PFKFB3), an enzyme that is negligibly present in neurons by continuous degradation because of the ubiquitin-proteasome pathway via anaphase-promoting complex/cyclosome (APC)-Cdh1. Additional factors contributing to the glycolytic frame of astrocytes may include 5'-AMP-activated protein kinase (AMPK), hypoxia-inducible factor-1 (HIF-1), pyruvate kinase muscle isoform-2 (PKM2), pyruvate dehydrogenase kinase-4 (PDK4), lactate dehydrogenase-B, or monocarboxylate transporter-4 (MCT4). Neurotransmission-associated messengers, such as nitric oxide or ammonium, stimulate lactate release from astrocytes. Astrocyte-derived glycolytic lactate thus sustains the energy needs of neurons, which in contrast to astrocytes mainly rely on oxidative phosphorylation. Neuronal activity unavoidably triggers reactive oxygen species, but the antioxidant defense of neurons is weak; hence, they use glucose for oxidation through the pentose-phosphate pathway to preserve the redox status. Furthermore, neural activity is coupled with erythroid-derived erythroid-derived 2-like 2 (Nrf2) mediated transcriptional activation of antioxidant genes in astrocytes, which boost the de novo glutathione biosynthesis in neighbor neurons. Thus, the bioenergetics and redox programs of astrocytes are adapted to sustain neuronal activity and survival. Developing therapeutic strategies to interfere with these pathways may be useful to combat neurological diseases. Our current knowledge on brain's management of bioenergetics and redox requirements associated with neural activity is herein revisited. The astrocyte-neuronal lactate shuttle (ANLS) explains the energy needs of neurotransmission. Furthermore, neurotransmission unavoidably triggers increased mitochondrial reactive oxygen species in neurons. By coupling glutamatergic activity with transcriptional activation of antioxidant genes, astrocytes provide neurons with neuroprotective glutathione through an astrocyte-neuronal glutathione shuttle (ANGS). This article is part of the 60th Anniversary special issue.

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  • PFKFB3 is posttranslationally down-regulated in neurons and thus cannot participate in glycolytic stimulation.

    “Although one specific enzyme for up-regulation of glycolysis, the bifunctional 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase (isoform PFKFB3), is posttranslationally down-regulated in neurons and thus cannot participate in glycolytic stimulation (Herrero-Mendez et al., 2009; Bolaños, 2016), this rules out only one of many mechanisms that neurons can use to stimulate glycolysis.”

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Authors
Bolaños, J. P.
Affiliations
Universidad de Salamanca (ES)
Corresponding author
Bolaños, Juan P.
Venue
Journal of Neurochemistry
Publisher
Wiley
Published
2016-03-10
Volume
139
Issue
S2
Pages
115-125
ISSN
  • 0022-3042 (ISSN-L)
  • 1471-4159
OpenAlex
W2293679413
Cited by
262
References
123
Citations by year
2026: 18 · 2025: 21 · 2024: 24 · 2023: 20 · 2022: 34 · 2021: 38 · 2020: 38 · 2019: 23 · 2018: 21 · 2017: 19 · 2016: 5 · 2015: 1
FWCI
2.48
Type
journal article
Language
en
Open access
Locations
  • Journal of Neurochemistry (publishedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • DIGITAL.CSIC (Spanish National Research Council (CSIC)) (submittedVersion, cc-by-nc-nd)
Funders
  • Ministerio de Economía y Competitividad (SAF2013‐41177‐R, RTC‐2015‐3237‐1)
  • Instituto de Salud Carlos III (RD12/0043/0021)
Topics
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Redox biology and oxidative stress
Keywords
astrocyte-neuron lactate shuttle, glycolysis, glutamate uptake, PFKFB3, AMPK, HIF-1, PKM2, PDK4, LDHB, MCT4, lactate release, oxidative phosphorylation, pentose phosphate pathway, reactive oxygen species, Nrf2, glutathione synthesis, antioxidant defense
MeSH terms
Animals, Astrocytes, Brain, Energy Metabolism, Humans, Neurons, Oxidation-Reduction, Synapses, Reactive Oxygen Species

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