{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,15]],"date-time":"2026-10-15T03:47:09Z","timestamp":1792036029862,"version":"4.4.0"},"reference-count":38,"publisher":"National Academy of Sciences","issue":"7","license":[{"start":{"date-parts":[[2024,2,5]],"date-time":"2024-02-05T00:00:00Z","timestamp":1707091200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004063","name":"Knut och Alice Wallenbergs Stiftelse","doi-asserted-by":"publisher","award":["2015-0279"],"award-info":[{"award-number":["2015-0279"]}],"id":[{"id":"10.13039\/501100004063","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Swedish research council","award":["2018-02532"],"award-info":[{"award-number":["2018-02532"]}]}],"content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2024,2,13]]},"abstract":"<jats:p>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\u2013neuron 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.<\/jats:p>","DOI":"10.1073\/pnas.2305035121","type":"journal-article","created":{"date-parts":[[2024,2,5]],"date-time":"2024-02-05T15:09:16Z","timestamp":1707145756000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":18,"title":["Brain energy metabolism is optimized to minimize the cost of enzyme synthesis and transport"],"prefix":"10.1073","volume":"121","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5072-2659","authenticated-orcid":false,"given":"Johan","family":"Gustafsson","sequence":"first","affiliation":[{"name":"Department of Biology and Biological Engineering, Chalmers University of Technology, Gothenburg, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jonathan L.","family":"Robinson","sequence":"additional","affiliation":[{"name":"Department of Biology and Biological Engineering, Chalmers University of Technology, Gothenburg, Sweden"},{"name":"BioInnovation Institute, Copenhagen DK-2200, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3930-4354","authenticated-orcid":false,"given":"Henrik","family":"Zetterberg","sequence":"additional","affiliation":[{"name":"Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, Sahlgrenska Academy at University of Gothenburg, M\u00f6lndal 431 30, Sweden"},{"name":"Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, M\u00f6lndal 431 30, Sweden"},{"name":"Department of Neurodegenerative Disease, University College London Queen Square Institute of Neurology, London WC1E 6BT, United Kingdom"},{"name":"United Kingdom Dementia Research Institute, University College London, London WC1E 6BT, United Kingdom"},{"name":"Hong Kong Center for Neurodegenerative Diseases, Hong Kong 999077, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9955-6003","authenticated-orcid":false,"given":"Jens","family":"Nielsen","sequence":"additional","affiliation":[{"name":"Department of Biology and Biological Engineering, Chalmers University of Technology, Gothenburg, Sweden"},{"name":"Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, Sahlgrenska Academy at University of Gothenburg, M\u00f6lndal 431 30, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2024,2,5]]},"reference":[{"key":"e_1_3_4_1_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuroimage.2012.02.013"},{"key":"e_1_3_4_2_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.3260686"},{"key":"e_1_3_4_3_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.1096485"},{"key":"e_1_3_4_4_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1010459107"},{"key":"e_1_3_4_5_2","doi-asserted-by":"publisher","DOI":"10.3389\/fnmol.2016.00053"},{"key":"e_1_3_4_6_2","doi-asserted-by":"publisher","DOI":"10.1038\/s42003-019-0495-2"},{"key":"e_1_3_4_7_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.91.22.10625"},{"key":"e_1_3_4_8_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2017.06.021"},{"key":"e_1_3_4_9_2","doi-asserted-by":"publisher","DOI":"10.1038\/nbt.1614"},{"key":"e_1_3_4_10_2","doi-asserted-by":"publisher","DOI":"10.1126\/scisignal.aaz1482"},{"key":"e_1_3_4_11_2","doi-asserted-by":"publisher","DOI":"10.1038\/nbt.4072"},{"key":"e_1_3_4_12_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-022-31421-1"},{"key":"e_1_3_4_13_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pcbi.1002575"},{"key":"e_1_3_4_14_2","doi-asserted-by":"crossref","unstructured":"J. Gustafsson Metabolic collaboration between cells in the tumor microenvironment has a negligible effect on tumor growth. bioRxiv [Preprint] (2022). https:\/\/doi.org\/10.1101\/2022.02.08.479584. Accessed 14 November 2023","DOI":"10.1101\/2022.02.08.479584"},{"key":"e_1_3_4_15_2","doi-asserted-by":"publisher","DOI":"10.1152\/physrev.00048.2009"},{"key":"e_1_3_4_16_2","doi-asserted-by":"publisher","DOI":"10.3389\/fnmol.2020.556175"},{"key":"e_1_3_4_17_2","doi-asserted-by":"publisher","DOI":"10.5483\/BMBRep.2015.48.3.010"},{"key":"e_1_3_4_18_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2012.08.019"},{"key":"e_1_3_4_19_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1471-4159.2009.06003.x"},{"key":"e_1_3_4_20_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-019-12934-8"},{"key":"e_1_3_4_21_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2016.03.011"},{"key":"e_1_3_4_22_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.copbio.2017.02.007"},{"key":"e_1_3_4_23_2","doi-asserted-by":"publisher","DOI":"10.3389\/fnins.2017.00312"},{"key":"e_1_3_4_24_2","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.58362"},{"key":"e_1_3_4_25_2","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.1316-20.2020"},{"key":"e_1_3_4_26_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature24057"},{"key":"e_1_3_4_27_2","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.4707-08.2009"},{"key":"e_1_3_4_28_2","doi-asserted-by":"publisher","DOI":"10.1002\/glia.23252"},{"key":"e_1_3_4_29_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1748-1716.2010.02122.x"},{"key":"e_1_3_4_30_2","doi-asserted-by":"publisher","DOI":"10.3389\/fcell.2018.00122"},{"key":"e_1_3_4_31_2","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-05-1679"},{"key":"e_1_3_4_32_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.tibs.2015.12.001"},{"key":"e_1_3_4_33_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2019.06.002"},{"key":"e_1_3_4_34_2","doi-asserted-by":"publisher","DOI":"10.1002\/jnr.24015"},{"key":"e_1_3_4_35_2","doi-asserted-by":"publisher","DOI":"10.3389\/fphys.2020.00973"},{"key":"e_1_3_4_36_2","doi-asserted-by":"publisher","DOI":"10.1021\/pr101183k"},{"key":"e_1_3_4_37_2","unstructured":"J. Gustafsson Code and data for \u201cBrain energy metabolism is optimized to minimize the cost of enzyme synthesis and transport\u201d (Version 3). Zenodo. https:\/\/zenodo.org\/records\/10206796. Accessed 14 January 2024."},{"key":"e_1_3_4_38_2","doi-asserted-by":"crossref","unstructured":"J. Gustafsson Code and data for \u201cBrain energy metabolism is optimized to minimize the cost of enzyme synthesis and transport\u201d. Github. https:\/\/github.com\/SysBioChalmers\/BrainMetabolismModeling\/. Deposited 14 January 2024.","DOI":"10.1073\/pnas.2305035121"}],"container-title":["Proceedings of the National Academy of Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pnas.org\/doi\/pdf\/10.1073\/pnas.2305035121","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,11,10]],"date-time":"2024-11-10T08:46:27Z","timestamp":1731228387000},"score":1,"resource":{"primary":{"URL":"https:\/\/pnas.org\/doi\/10.1073\/pnas.2305035121"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,2,5]]},"references-count":38,"journal-issue":{"issue":"7","published-print":{"date-parts":[[2024,2,13]]}},"alternative-id":["10.1073\/pnas.2305035121"],"URL":"https:\/\/doi.org\/10.1073\/pnas.2305035121","relation":{"has-preprint":[{"id-type":"doi","id":"10.1101\/2022.11.14.516523","asserted-by":"object"}]},"ISSN":["0027-8424","1091-6490"],"issn-type":[{"value":"0027-8424","type":"print"},{"value":"1091-6490","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,2,5]]},"assertion":[{"value":"2023-04-08","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2023-12-22","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2024-02-05","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e2305035121"}}