Brain energy metabolism spurns fatty acids as fuel due to their inherent mitotoxicity and potential capacity to unleash neurodegeneration
Abstract
The brain uses long-chain fatty acids (LCFAs) to a negligible extent as fuel for the mitochondrial energy generation, in contrast to other tissues that also demand high energy. Besides this generally accepted view, some studies using cultured neural cells or whole brain indicate a moderately active mitochondrial β-oxidation. Here, we corroborate the conclusion that brain mitochondria are unable to oxidize fatty acids. In contrast, the combustion of liver-derived ketone bodies by neural cells is long-known. Furthermore, new insights indicate the use of odd-numbered medium-chain fatty acids as valuable source for maintaining the level of intermediates of the citric acid cycle in brain mitochondria. Non-esterified LCFAs or their activated forms exert a large variety of harmful side-effects on mitochondria, such as enhancing the mitochondrial ROS generation in distinct steps of the β-oxidation and therefore potentially increasing oxidative stress. Hence, the question arises: Why do in brain energy metabolism mitochondria selectively spurn LCFAs as energy source? The most likely answer are the relatively higher content of peroxidation-sensitive polyunsaturated fatty acids and the low antioxidative defense in brain tissue. There are two remarkable peroxisomal defects, one relating to α-oxidation of phytanic acid and the other to uptake of very long-chain fatty acids (VLCFAs) which lead to pathologically high tissue levels of such fatty acids. Both, the accumulation of phytanic acid…
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Increased FAs and reduced LDs suggest a lower ability of E4 neurons to store FA in LDs against lipid toxicity.
“Because neurons have limited FA-degrading capacity via β-oxidation (Schönfeld and Reiser, 2017), increased FAs and reduced LDs suggested a lower ability of E4 neurons to store FA in LDs against lipid toxicity.”
From ApoE4 Impairs Neuron-Astrocyte Coupling of Fatty Acid Metabolism (2021) · cites this paper as Schönfeld and Reiser, 2017
Fine control and timely elimination of neuronal free FAs is critical to protect against neurodegeneration.
“Because neurons have minimum capacity to catabolize FAs, and excessive FAs induce mitochondrial uncoupling and dysfunction, fine control and timely elimination of neuronal free FAs is critical to protect against neurodegeneration (Schönfeld and Reiser, 2017).”
From ApoE4 Impairs Neuron-Astrocyte Coupling of Fatty Acid Metabolism (2021) · cites this paper as Schönfeld and Reiser, 2017
High levels of fatty acids or acyl-CoA have a detrimental effect on mitochondrial function.
“This is consistent with the detrimental effect of high levels of FAs or acyl-CoA on mitochondrial function (Li et al., 2010; Schönfeld and Reiser, 2017).”
From ApoE4 Impairs Neuron-Astrocyte Coupling of Fatty Acid Metabolism (2021) · cites this paper as Schönfeld and Reiser, 2017
Neurons have minimum capacity to catabolize FAs.
“Because neurons have minimum capacity to catabolize FAs, and excessive FAs induce mitochondrial uncoupling and dysfunction, fine control and timely elimination of neuronal free FAs is critical to protect against neurodegeneration (Schönfeld and Reiser, 2017).”
From ApoE4 Impairs Neuron-Astrocyte Coupling of Fatty Acid Metabolism (2021) · cites this paper as Schönfeld and Reiser, 2017
Excessive FAs induce mitochondrial uncoupling and dysfunction.
“Because neurons have minimum capacity to catabolize FAs, and excessive FAs induce mitochondrial uncoupling and dysfunction, fine control and timely elimination of neuronal free FAs is critical to protect against neurodegeneration (Schönfeld and Reiser, 2017).”
From ApoE4 Impairs Neuron-Astrocyte Coupling of Fatty Acid Metabolism (2021) · cites this paper as Schönfeld and Reiser, 2017
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Neuron-Astrocyte Metabolic Coupling Protects against Activity-Induced Fatty Acid Toxicity
Ioannou, M. S., Jackson, J., Sheu, S.-H., Chang, C.-L., Weigel, A. V., Liu, H., Pasolli, H. A., Xu, C. S., Pang, S., Matthies, D., et al. (2019) · Cell · doi:10.1016/j.cell.2019.04.001 · Cited by 760 · see citing works
ApoE4 Impairs Neuron-Astrocyte Coupling of Fatty Acid Metabolism
Qi, G., Mi, Y., Shi, X., Gu, H., Brinton, R. D., & Yin, F. (2021) · Cell Reports · doi:10.1016/j.celrep.2020.108572 · Cited by 379 · see citing works
Lipid droplets in the nervous system
Ralhan, I., Chang, C.-L., Lippincott-Schwartz, J., & Ioannou, M. S. (2021) · Journal of Cell Biology · doi:10.1083/jcb.202102136 · Cited by 281 · see citing works
Lipid metabolism and storage in neuroglia: role in brain development and neurodegenerative diseases
Yang, D., Wang, X., Zhang, L., Fang, Y., Zheng, Q., Liu, X., Yu, W., Chen, S., Ying, J., & Hua, F. (2022) · Cell & Bioscience · doi:10.1186/s13578-022-00828-0 · Cited by 179 · see citing works
- Authors
- Schönfeld, P., & Reiser, G.
- Affiliations
- Otto-von-Guericke-Universität Magdeburg (DE)
- Corresponding author
- Reiser, Georg
- Venue
- Neurochemistry International
- Publisher
- Elsevier BV
- Published
- 2017-10
- Volume
- 109
- Pages
- 68-77
- ISSN
- 0197-0186 (ISSN-L)
- OpenAlex
- W2599888581
- Cited by
- 99
- References
- 5
- Citations by year
- 2026: 13 · 2025: 16 · 2024: 15 · 2023: 12 · 2022: 10 · 2021: 11 · 2020: 12 · 2019: 6 · 2018: 3 · 2017: 1
- FWCI
- 0.57
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Neurochemistry International (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Deutsche Forschungsgemeinschaft (Re 563/22-1)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Clinical Biochemistry › Metabolism and Genetic Disorders
- Health Sciences › Medicine › Physiology › Diet and metabolism studies
- Keywords
- brain energy metabolism, long-chain fatty acids, mitochondrial beta-oxidation, fatty acid oxidation, mitochondrial ROS generation, oxidative stress, phytanic acid, very long chain fatty acids, Refsum disease, X-linked adrenoleukodystrophy, medium-chain fatty acids, citric acid cycle intermediates, neurodegeneration, polyunsaturated fatty acids, ketone bodies
- MeSH terms
- Animals, Brain, Energy Metabolism, Fatty Acids, Humans, Mitochondria, Reactive Oxygen Species, Oxidative Stress, Neurodegenerative Diseases
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