Gustafsson, Johan;
Robinson, Jonathan L;
Zetterberg, Henrik;
Nielsen, Jens;
(2024)
Brain energy metabolism is optimized to minimize the cost of enzyme synthesis and transport.
Proceedings of the National Academy of Sciences (PNAS)
, 121
(7)
, Article e2305035121. 10.1073/pnas.2305035121.
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Abstract
The energy metabolism of the brain is poorly understood partly due to the complex morphology of neurons and fluctuations in ATP demand over time. To investigate this, we used metabolic models that estimate enzyme usage per pathway, enzyme utilization over time, and enzyme transportation to evaluate how these parameters and processes affect ATP costs for enzyme synthesis and transportation. Our models show that the total enzyme maintenance energy expenditure of the human body depends on how glycolysis and mitochondrial respiration are distributed both across and within cell types in the brain. We suggest that brain metabolism is optimized to minimize the ATP maintenance cost by distributing the different ATP generation pathways in an advantageous way across cell types and potentially also across synapses within the same cell. Our models support this hypothesis by predicting export of lactate from both neurons and astrocytes during peak ATP demand, reproducing results from experimental measurements reported in the literature. Furthermore, our models provide potential explanation for parts of the astrocyte-neuron lactate shuttle theory, which is recapitulated under some conditions in the brain, while contradicting other aspects of the theory. We conclude that enzyme usage per pathway, enzyme utilization over time, and enzyme transportation are important factors for defining the optimal distribution of ATP production pathways, opening a broad avenue to explore in brain metabolism.
| Type: | Article |
|---|---|
| Title: | Brain energy metabolism is optimized to minimize the cost of enzyme synthesis and transport |
| Location: | United States |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1073/pnas.2305035121 |
| Publisher version: | http://dx.doi.org/10.1073/pnas.2305035121 |
| Language: | English |
| Additional information: | Copyright © 2024 the Author(s). Published by PNAS. This open access article is distributed under Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND). |
| Keywords: | ANLS, brain metabolism, genome-scale models, mathematical modeling, metabolism, Humans, Glucose, Energy Metabolism, Lactic Acid, Brain, Astrocytes, Adenosine Triphosphate |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology > Neurodegenerative Diseases |
| URI: | https://discovery-pp.ucl.ac.uk/id/eprint/10186896 |
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