Dependence of hippocampal function on ERRγ-regulated mitochondrial metabolism
Open accessAbstract
Neurons utilize mitochondrial oxidative phosphorylation (OxPhos) to generate energy essential for survival, function, and behavioral output. Unlike most cells that burn both fat and sugar, neurons only burn sugar. Despite its importance, how neurons meet the increased energy demands of complex behaviors such as learning and memory is poorly understood. Here we show that the estrogen-related receptor gamma (ERRγ) orchestrates the expression of a distinct neural gene network promoting mitochondrial oxidative metabolism that reflects the extraordinary neuronal dependence on glucose. ERRγ(-/-) neurons exhibit decreased metabolic capacity. Impairment of long-term potentiation (LTP) in ERRγ(-/-) hippocampal slices can be fully rescued by the mitochondrial OxPhos substrate pyruvate, functionally linking the ERRγ knockout metabolic phenotype and memory formation. Consistent with this notion, mice lacking neuronal ERRγ in cerebral cortex and hippocampus exhibit defects in spatial learning and memory. These findings implicate neuronal ERRγ in the metabolic adaptations required for memory formation.
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In neurons, genomic binding sites for ERRγ have extensive overlap with NRFs.
“in neurons the genomic binding sites for ERRγ have extensive overlap with NRFs (Pei et al., 2015).”
From Metabolic reprogramming during neuronal differentiation from aerobic glycolysis to neuronal oxidative phosphorylation (2016) · cites this paper as Pei et al., 2015
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“…to the broad effect of PGC-1a, ERRg was mainly required for maintaining expression of NRF1 and mitochondrial respiratory complexes (Figure 5F), which is consistent with a recent finding that in neurons the geno- mic binding sites for ERRg have extensive overlap with NRFs (Pei et al., 2015).”
ResultSelf-citationMartin, S. A., DeMuth, T. M., Miller, K. N., Pugh, T. D., Polewski, M. A., Colman, R. J., Eliceiri, K. W., Beasley, T. M., Johnson, S. C., & Anderson, R. M. (2016) · Aging Cell · doi:10.1111/acel.12418 · Cited by 32 · see citing works
- Authors
- Pei, L., Mu, Y., Leblanc, M., Alaynick, W., Barish, G. D., Pankratz, M., Tseng, T. W., Kaufman, S., Liddle, C., Yu, R. T., Downes, M., Pfaff, S. L., Auwerx, J., Gage, F. H., & Evans, R. M.
- Affiliations
- Children's Hospital of Philadelphia (US)
- Salk Institute for Biological Studies (US)
- Northwestern University (US)
- The University of Sydney (AU)
- École Polytechnique Fédérale de Lausanne (CH)
- Corresponding author
- Pei, Liming
- Evans, Ronald M.
- ORCID
- Venue
- Cell Metabolism
- Publisher
- Elsevier BV
- Published
- 2015-04
- Volume
- 21
- Issue
- 4
- Pages
- 628-636
- ISSN
- 1550-4131 (ISSN-L)
- PMC
- PMC4393848
- OpenAlex
- W2024327968
- Cited by
- 65
- References
- 34
- Citations by year
- 2026: 7 · 2025: 10 · 2024: 4 · 2023: 2 · 2022: 7 · 2021: 5 · 2020: 3 · 2019: 3 · 2018: 7 · 2017: 10 · 2016: 5 · 2015: 2
- FWCI
- 3.71
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell Metabolism (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Infoscience (Ecole Polytechnique Fédérale de Lausanne) (submittedVersion)
- Infoscience (Ecole Polytechnique Fédérale de Lausanne) (submittedVersion, cc-by-nc-nd)
- Funders
- Howard Hughes Medical Institute
- National Heart, Lung, and Blood Institute (HL105278, R01HL105278)
- National Institute of Mental Health (R01MH090258, MH090258)
- National Cancer Institute (CA014195, P30CA014195)
- National Institute of General Medical Sciences (T32GM007507)
- National Institute of Diabetes and Digestive and Kidney Diseases (R37DK057978, DK057978, R01DK057978, R24DK090962, DK090962, P30DK063491)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Life Sciences › Neuroscience › Cognitive Neuroscience › Memory and Neural Mechanisms
- Keywords
- estrogen-related receptor gamma, oxidative phosphorylation, glucose metabolism, hippocampus, long-term potentiation, spatial learning and memory, pyruvate, gene expression networks
- MeSH terms
- Analysis of Variance, Animals, Galactosides, Glycolysis, Hippocampus, Indoles, Memory, Mitochondria, Neurons, Receptors, Estrogen, Long-Term Potentiation, Pyruvic Acid, Microarray Analysis, Chromatin Immunoprecipitation, Mice, Gene Knockout Techniques, Real-Time Polymerase Chain Reaction, Spatial Learning
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