Bioenergetics and redox adaptations of astrocytes to neuronal activity
Open accessAbstract
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.”
From Fueling thought: Management of glycolysis and oxidative phosphorylation in neuronal metabolism (2018) · cites this paper as Bolaños, 2016
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Cdk5 phosphorylates Cdh1 and modulates cyclin B1 stability in excitotoxicity
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Ionotropic glutamate receptors in astrocytes
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Self-citationNrf2 target genes can be controlled by neuronal activity in the absence of Nrf2 and astrocytes
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Inflammation in Parkinson’s Disease: Mechanisms and Therapeutic Implications
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Fueling thought: Management of glycolysis and oxidative phosphorylation in neuronal metabolism
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“For recent reviews and studies on the regulation of astrocytic metabolism, see Bolaños (2016), Dienel and Cruz (2016), and Nortley and Attwell (2017).”
BackgroundInfluentialBeyond the GFAP-Astrocyte Protein Markers in the Brain
Jurga, A. M., Paleczna, M., Kadluczka, J., & Kuter, K. Z. (2021) · Biomolecules · doi:10.3390/biom11091361 · Cited by 319 · see citing works
Reich, N., & Hölscher, C. (2022) · Frontiers in Neuroscience · doi:10.3389/fnins.2022.970925 · Cited by 248 · see citing works
Diehl, K., Dinges, L.-A., Helm, O., Ammar, N., Plundrich, D., Arlt, A., Röcken, C., Sebens, S., & Schäfer, H. (2018) · Oncogene · doi:10.1038/onc.2017.299 · Cited by 58 · see citing works
Astrocytic transporters in Alzheimer's disease
Ugbode, C., Hu, Y., Whalley, B., Peers, C., Rattray, M., & Dallas, M. L. (2017) · Biochemical Journal · doi:10.1042/bcj20160505 · Cited by 25 · see citing works
- Authors
- Bolaños, J. P.
- Affiliations
- Universidad de Salamanca (ES)
- Corresponding author
- Bolaños, Juan P.
- ORCID
- 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
- PMC
- PMC5018236
- 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
- hybrid
- doi.org
- Licence
- 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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