The bioenergetic and antioxidant status of neurons is controlled by continuous degradation of a key glycolytic enzyme by APC/C-Cdh1
Abstract
Neurons are known to have a lower glycolytic rate than astrocytes and when stressed they are unable to upregulate glycolysis because of low Pfkfb3 (6-phosphofructo-2-kinase/fructose-2, 6-bisphosphatase-3) activity. This enzyme generates fructose-2,6-bisphosphate (F2,6P(2)), the most potent activator of 6-phosphofructo-1-kinase (Pfk1; ref. 4), a master regulator of glycolysis. Here, we show that Pfkfb3 is absent from neurons in the brain cortex and that Pfkfb3 in neurons is constantly subject to proteasomal degradation by the action of the E3 ubiquitin ligase, anaphase-promoting complex/cyclosome (APC/C)-Cdh1. By contrast, astrocytes have low APC/C-Cdh1 activity and therefore Pfkfb3 is present in these cells. Upregulation of Pfkfb3 by either inhibition of Cdh1 or overexpression of Pfkfb3 in neurons resulted in the activation of glycolysis. This, however, was accompanied by a marked decrease in the oxidation of glucose through the pentose phosphate pathway (a metabolic route involved in the regeneration of reduced glutathione) resulting in oxidative stress and apoptotic death. Thus, by actively downregulating glycolysis by APC/C-Cdh1, neurons use glucose to maintain their antioxidant status at the expense of its utilization for bioenergetic purposes.
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Protein levels of Pfkfb3 are low in neurons because of its constant proteasomal degradation.
“Protein levels of Pfkfb3 are low in neurons because of its constant proteasomal degradation (Herrero-Mendez et al., 2009;Almeida et al., 2010)”
From An RNA-Sequencing Transcriptome and Splicing Database of Glia, Neurons, and Vascular Cells of the Cerebral Cortex (2014) · cites this paper as Herrero-Mendez et al., 2009
Pfkfb3 is constantly degraded by proteasome through APC/C-Cdh1 to suppress neuronal glycolysis.
“Pfkfb3, the enzyme generating fructose-2,6-bisphosphate, a potent activator of phosphofructokinase, is constantly degraded by proteasome through anaphase-promoting complex/cyclosome (APC/C)-Cdh1 to suppress neuronal glycolysis (Herrero-Mendez, et al., 2009).”
From Metabolic reprogramming during neuronal differentiation from aerobic glycolysis to neuronal oxidative phosphorylation (2016) · cites this paper as Herrero-Mendez, et al., 2009
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 Herrero-Mendez et al., 2009
Neuronal glycolytic regulation probably does not involve the key regulatory enzyme PFKFB3.
“Neuronal glycolytic regulation probably does not involve a key regulatory enzyme, PFKFB3 (Herrero-Mendez et al., 2009),”
From Fueling thought: Management of glycolysis and oxidative phosphorylation in neuronal metabolism (2018) · cites this paper as Herrero-Mendez et al., 2009
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- Authors
- Herrero-Mendez, A., Almeida, A., Fernández, E., Maestre, C., Moncada, S., & Bolaños, J. P.
- Affiliations
- Universidad de Salamanca (ES)
- University College London (GB)
- Corresponding author
- Moncada, Salvador
- Bolaños, Juan P.
- Venue
- Nature Cell Biology
- Published
- 2009-05-17
- Volume
- 11
- Issue
- 6
- Pages
- 747-752
- ISSN
- 1465-7392 (ISSN-L)
- 1476-4679
- OpenAlex
- W2098685543
- Cited by
- 844
- References
- 34
- Citations by year
- 2026: 44 · 2025: 59 · 2024: 62 · 2023: 72 · 2022: 53 · 2021: 58 · 2020: 49 · 2019: 42 · 2018: 49 · 2017: 52 · 2016: 49 · 2015: 43 · 2014: 45 · 2013: 40 · 2012: 38
- FWCI
- 16.91
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Cell Biology (publishedVersion)
- PubMed (publishedVersion)
- UCL Discovery (University College London) (submittedVersion)
- Research Explorer (The University of Manchester) (submittedVersion)
- Funders
- Junta de Castilla y León
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Keywords
- PFKFB3, 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase, APC/C-Cdh1, proteasomal degradation, astrocytes, fructose-2,6-bisphosphate, 6-phosphofructokinase, pentose phosphate pathway, oxidative stress, glutathione regeneration, neuronal apoptosis, brain energy metabolism, E3 ubiquitin ligase
- MeSH terms
- Amino Acid Sequence, Animals, Antioxidants, Cerebral Cortex, Energy Metabolism, Glucose, Glycolysis, Humans, Isoenzymes, Molecular Sequence Data, Neurons, Nitric Oxide, Oxidation-Reduction, Pentose Phosphate Pathway, Mutagenesis, Site-Directed, Sequence Alignment, Rats, Wistar, Reactive Oxygen Species, Phosphofructokinase-2, RNA Interference, RNA, Small Interfering, Ubiquitin-Protein Ligase Complexes, Rats, Anaphase-Promoting Complex-Cyclosome
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