{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,4]],"date-time":"2026-02-04T18:23:37Z","timestamp":1770229417604,"version":"3.49.0"},"reference-count":117,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,6,5]],"date-time":"2025-06-05T00:00:00Z","timestamp":1749081600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Comput. Neurosci."],"abstract":"<jats:sec><jats:title>Introduction<\/jats:title><jats:p>Emerging evidence suggests that different metabolic characteristics, particularly bioenergetic differences, between the synaptic terminal and soma may contribute to the selective vulnerability of dopaminergic neurons in patients with Parkinson\u2019s disease (PD).<\/jats:p><\/jats:sec><jats:sec><jats:title>Method<\/jats:title><jats:p>To investigate the metabolic differences, we generated four thermodynamically flux-consistent metabolic models representing the synaptic and non-synaptic (somatic) components under both control and PD conditions. Differences in bioenergetic features and metabolite exchanges were analyzed between these models to explore potential mechanisms underlying the selective vulnerability of dopaminergic neurons. Bioenergetic rescue analyses were performed to identify potential therapeutic targets for mitigating observed energy failure and metabolic dysfunction in PD models.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>All models predicted that oxidative phosphorylation plays a significant role under lower energy demand, while glycolysis predominates when energy demand exceeds mitochondrial constraints. The synaptic PD model predicted a lower mitochondrial energy contribution and higher sensitivity to Complex I inhibition compared to the non-synaptic PD model. Both PD models predicted reduced uptake of lysine and lactate, indicating coordinated metabolic processes between these components. In contrast, decreased methionine and urea uptake was exclusively predicted in the synaptic PD model, while decreased histidine and glyceric acid uptake was exclusive to the non-synaptic PD model. Furthermore, increased flux of the mitochondrial ornithine transaminase reaction (ORNTArm), which converts oxoglutaric acid and ornithine into glutamate-5-semialdehyde and glutamate, was predicted to rescue bioenergetic failure and improve metabolite exchanges for both the synaptic and non-synaptic PD models.<\/jats:p><\/jats:sec><jats:sec><jats:title>Discussion<\/jats:title><jats:p>The predicted differences in ATP contribution between models highlight the bioenergetic differences between these neuronal components, thereby contributing to the selective vulnerability observed in PD. The observed differences in metabolite exchanges reflect distinct metabolic patterns between these neuronal components. Additionally, mitochondrial ornithine transaminase was predicted to be the potential bioenergetic rescue target for both the synaptic and non-synaptic PD models. Further research is needed to validate these dysfunction mechanisms across different components of dopaminergic neurons and to explore targeted therapeutic strategies for PD patients.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fncom.2025.1594330","type":"journal-article","created":{"date-parts":[[2025,6,5]],"date-time":"2025-06-05T05:28:32Z","timestamp":1749101312000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":3,"title":["Constraint-based modeling of bioenergetic differences between synaptic and non-synaptic components of dopaminergic neurons in Parkinson\u2019s disease"],"prefix":"10.3389","volume":"19","author":[{"given":"Xi","family":"Luo","sequence":"first","affiliation":[]},{"given":"Diana C.","family":"El Assal","sequence":"additional","affiliation":[]},{"given":"Yanjun","family":"Liu","sequence":"additional","affiliation":[]},{"given":"Samira","family":"Ranjbar","sequence":"additional","affiliation":[]},{"given":"Ronan M.T.","family":"Fleming","sequence":"additional","affiliation":[]}],"member":"1965","published-online":{"date-parts":[[2025,6,5]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"212","DOI":"10.1159\/000111289","article-title":"Postnatal development of the complexes of the electron transport chain in synaptic mitochondria from rat brain.","volume":"17","author":"Almeida","year":"1995","journal-title":"Dev. Neurosci."},{"key":"B2","doi-asserted-by":"publisher","first-page":"R106","DOI":"10.1186\/gb-2010-11-10-r106","article-title":"Differential expression analysis for sequence count data.","volume":"11","author":"Anders","year":"2010","journal-title":"Genome Biol."},{"key":"B3","doi-asserted-by":"publisher","first-page":"1133","DOI":"10.1097\/00004647-200110000-00001","article-title":"An energy budget for signaling in the grey matter of the brain.","volume":"21","author":"Attwell","year":"2001","journal-title":"J. Cereb. Blood Flow Metab."},{"key":"B4","doi-asserted-by":"publisher","first-page":"391","DOI":"10.1002\/dneu.22579","article-title":"Folate action in nervous system development and disease.","volume":"78","author":"Balashova","year":"2018","journal-title":"Dev. Neurobiol."},{"key":"B5","doi-asserted-by":"publisher","first-page":"51","DOI":"10.1007\/BF02435024","article-title":"Protein content of various regions of rat brain and adult and aging human brain.","volume":"15","author":"Banay-Schwartz","year":"1992","journal-title":"Age"},{"key":"B6","doi-asserted-by":"publisher","first-page":"1326","DOI":"10.4065\/80.10.1326","article-title":"Neuron-astrocyte interactions: Partnership for normal function and disease in the central nervous system.","volume":"80","author":"Benarroch","year":"2005","journal-title":"Mayo Clin. Proc."},{"key":"B7","doi-asserted-by":"publisher","first-page":"469","DOI":"10.1016\/B978-0-08-021345-3.50021-6","article-title":"Aminotransferases and the developing brain","author":"Benuck","year":"1980","journal-title":"Biochemistry of brain"},{"key":"B8","doi-asserted-by":"publisher","first-page":"14304","DOI":"10.1523\/JNEUROSCI.0930-14.2014","article-title":"Loss of mitochondrial fission depletes axonal mitochondria in midbrain dopamine neurons.","volume":"34","author":"Berthet","year":"2014","journal-title":"J. Neurosci."},{"key":"B9","doi-asserted-by":"publisher","first-page":"2284","DOI":"10.1016\/S0140-6736(21)00218-X","article-title":"Parkinson\u2019s disease.","volume":"397","author":"Bloem","year":"2021","journal-title":"Lancet"},{"key":"B10","doi-asserted-by":"publisher","first-page":"1478","DOI":"10.1002\/mds.25135","article-title":"Living on the edge with too many mouths to feed: Why dopamine neurons die.","volume":"27","author":"Bolam","year":"2012","journal-title":"Mov. Disord."},{"key":"B11","doi-asserted-by":"publisher","first-page":"123","DOI":"10.1016\/j.jns.2011.09.010","article-title":"Cerebral oxygen metabolism in patients with early Parkinson\u2019s disease.","volume":"313","author":"Borghammer","year":"2012","journal-title":"J. Neurol. Sci."},{"key":"B12","doi-asserted-by":"publisher","first-page":"45","DOI":"10.3233\/JPD-201981","article-title":"Mitochondria and Parkinson\u2019s disease: Clinical, molecular, and translational aspects.","volume":"11","author":"Borsche","year":"2021","journal-title":"J. Parkinson\u2019s Dis."},{"key":"B13","author":"Bourne","year":"1968","journal-title":"The structure and function of nervous tissue."},{"key":"B14","author":"Boyd","year":"2023","journal-title":"Convex optimization, Version 29."},{"key":"B15","doi-asserted-by":"publisher","first-page":"93","DOI":"10.1085\/jgp.201110659","article-title":"Co-transmission of dopamine and glutamate.","volume":"139","author":"Broussard","year":"2012","journal-title":"J. Gen. Physiol."},{"key":"B16","doi-asserted-by":"publisher","first-page":"11658","DOI":"10.1074\/jbc.M510303200","article-title":"Synaptic mitochondria are more susceptible to Ca2+overload than nonsynaptic mitochondria.","volume":"281","author":"Brown","year":"2006","journal-title":"J. Biol. Chem."},{"key":"B17","doi-asserted-by":"publisher","first-page":"272","DOI":"10.1038\/nbt.4072","article-title":"Recon3D: A resource enabling a three-dimensional view of gene variation in human metabolism.","volume":"36","author":"Brunk","year":"2018","journal-title":"Nat. Biotechnol."},{"key":"B18","doi-asserted-by":"publisher","first-page":"136","DOI":"10.1186\/1471-2202-14-136","article-title":"Parkinson\u2019s disease: Dopaminergic nerve cell model is consistent with experimental finding of increased extracellular transport of \u03b1-synuclein.","volume":"14","author":"B\u00fcchel","year":"2013","journal-title":"BMC Neurosci."},{"key":"B19","doi-asserted-by":"publisher","first-page":"72","DOI":"10.1016\/j.expneurol.2012.01.011","article-title":"Axon degeneration in Parkinson\u2019s disease.","volume":"246","author":"Burke","year":"2013","journal-title":"Exp. Neurol."},{"key":"B20","doi-asserted-by":"publisher","first-page":"48","DOI":"10.1186\/1742-4682-4-48","article-title":"Reconstruction and flux analysis of coupling between metabolic pathways of astrocytes and neurons: Application to cerebral hypoxia.","volume":"4","author":"Cakir","year":"2007","journal-title":"Theor. Biol. Med. Model"},{"key":"B21","doi-asserted-by":"publisher","first-page":"176","DOI":"10.1038\/s41419-023-05672-9","article-title":"Alpha-synuclein in Parkinson\u2019s disease and other synucleinopathies: From overt neurodegeneration back to early synaptic dysfunction.","volume":"14","author":"Calabresi","year":"2023","journal-title":"Cell Death Dis."},{"key":"B22","doi-asserted-by":"publisher","first-page":"1474","DOI":"10.15252\/embj.201695810","article-title":"Brain metabolism in health, aging, and neurodegeneration.","volume":"36","author":"Camandola","year":"2017","journal-title":"EMBO J."},{"key":"B23","doi-asserted-by":"publisher","first-page":"70","DOI":"10.1186\/s13059-018-1438-9","article-title":"UMI-count modeling and differential expression analysis for single-cell RNA sequencing.","volume":"19","author":"Chen","year":"2018","journal-title":"Genome Biol."},{"key":"B24","doi-asserted-by":"publisher","first-page":"1899","DOI":"10.1016\/j.neuron.2022.03.015","article-title":"Programming axonal mitochondrial maintenance and bioenergetics in neurodegeneration and regeneration.","volume":"110","author":"Cheng","year":"2022","journal-title":"Neuron"},{"key":"B25","doi-asserted-by":"publisher","first-page":"609","DOI":"10.1038\/s41573-020-0072-x","article-title":"Brain energy rescue: An emerging therapeutic concept for neurodegenerative disorders of ageing.","volume":"19","author":"Cunnane","year":"2020","journal-title":"Nat. Rev. Drug Discov."},{"key":"B26","doi-asserted-by":"publisher","first-page":"1398","DOI":"10.1046\/j.1471-4159.2003.02277.x","article-title":"Dopamine neurons in culture express VGLUT2 explaining their capacity to release glutamate at synapses in addition to dopamine.","volume":"88","author":"Dal Bo","year":"2004","journal-title":"J. Neurochem."},{"key":"B27","doi-asserted-by":"publisher","first-page":"1617","DOI":"10.1046\/j.1471-4159.1996.66041617.x","article-title":"Threshold effects and control of oxidative phosphorylation in nonsynaptic rat brain mitochondria.","volume":"66","author":"Davey","year":"1996","journal-title":"J. Neurochem."},{"key":"B28","doi-asserted-by":"publisher","first-page":"12753","DOI":"10.1074\/jbc.273.21.12753","article-title":"Energy thresholds in brain mitochondria: Potential involvement in neurodegeneration.","volume":"273","author":"Davey","year":"1998","journal-title":"J. Biol. Chem."},{"key":"B29","doi-asserted-by":"publisher","first-page":"461","DOI":"10.3233\/JPD-130230","article-title":"The role of oxidative stress in Parkinson\u2019s disease.","volume":"3","author":"Dias","year":"2013","journal-title":"J. Parkinsons Dis."},{"key":"B30","doi-asserted-by":"publisher","first-page":"1111","DOI":"10.1016\/j.neurobiolaging.2013.11.001","article-title":"Dysregulation of glucose metabolism is an early event in sporadic Parkinson\u2019s disease.","volume":"35","author":"Dunn","year":"2014","journal-title":"Neurobiol. Aging"},{"key":"B31","doi-asserted-by":"publisher","first-page":"e0116587","DOI":"10.1371\/journal.pone.0116587","article-title":"Metabolic and tissue-specific regulation of acyl-CoA metabolism.","volume":"10","author":"Ellis","year":"2015","journal-title":"PLoS One"},{"key":"B32","doi-asserted-by":"publisher","first-page":"665386","DOI":"10.3389\/fncir.2021.665386","article-title":"Dopamine neurons that cotransmit glutamate, from synapses to circuits to behavior.","volume":"15","author":"Eskenazi","year":"2021","journal-title":"Front. Neural Circuits"},{"key":"B33","doi-asserted-by":"publisher","first-page":"397","DOI":"10.1074\/mcp.M113.035600","article-title":"Analysis of the human tissue-specific expression by genome-wide integration of transcriptomics and antibody-based proteomics.","volume":"13","author":"Fagerberg","year":"2014","journal-title":"Mol. Cell Proteom."},{"key":"B34","doi-asserted-by":"publisher","first-page":"3627","DOI":"10.3390\/ijms23073627","article-title":"Synapses: The brain\u2019s energy-demanding sites.","volume":"23","author":"Faria-Pereira","year":"2022","journal-title":"Int. J. Mol. Sci."},{"key":"B35","doi-asserted-by":"publisher","first-page":"71","DOI":"10.1016\/j.jtbi.2011.09.029","article-title":"A variational principle for computing nonequilibrium fluxes and potentials in genome-scale biochemical networks.","volume":"292","author":"Fleming","year":"2012","journal-title":"J. Theoret. Biol."},{"key":"B36","doi-asserted-by":"publisher","first-page":"18","DOI":"10.3390\/biology6010018","article-title":"Ornithine aminotransferase, an important glutamate-metabolizing enzyme at the crossroads of multiple metabolic pathways.","volume":"6","author":"Ginguay","year":"2017","journal-title":"Biology"},{"key":"B37","doi-asserted-by":"publisher","first-page":"61","DOI":"10.1016\/bs.pbr.2020.02.005","article-title":"Selective neuronal vulnerability in Parkinson\u2019s disease.","volume":"252","author":"Gonzalez-Rodriguez","year":"2020","journal-title":"Prog. Brain Res."},{"key":"B38","doi-asserted-by":"publisher","first-page":"E100","DOI":"10.1152\/ajpendo.2001.281.1.E100","article-title":"A mathematical model of compartmentalized neurotransmitter metabolism in the human brain.","volume":"281","author":"Gruetter","year":"2001","journal-title":"Am. J. Physiol. Endocrinol. Metab."},{"key":"B39","doi-asserted-by":"publisher","first-page":"8940","DOI":"10.1523\/JNEUROSCI.0026-12.2012","article-title":"Oxidative phosphorylation, not glycolysis, powers presynaptic and postsynaptic mechanisms underlying brain information processing.","volume":"32","author":"Hall","year":"2012","journal-title":"J. Neurosci."},{"key":"B40","doi-asserted-by":"publisher","first-page":"639","DOI":"10.1038\/s41596-018-0098-2","article-title":"Creation and analysis of biochemical constraint-based models using the COBRA Toolbox v.3.0.","volume":"14","author":"Heirendt","year":"2019","journal-title":"Nat. Protoc."},{"key":"B41","doi-asserted-by":"publisher","first-page":"107","DOI":"10.1016\/j.steroids.2017.07.001","article-title":"Unconjugated bile acids in rat brain: Analytical method based on LC\/ESI-MS\/MS with chemical derivatization and estimation of their origin by comparison to serum levels.","volume":"125","author":"Higashi","year":"2017","journal-title":"Steroids"},{"key":"B42","doi-asserted-by":"publisher","first-page":"643","DOI":"10.1016\/j.neuron.2010.02.012","article-title":"Vesicular glutamate transport promotes dopamine storage and glutamate corelease in vivo.","volume":"65","author":"Hnasko","year":"2010","journal-title":"Neuron"},{"key":"B43","doi-asserted-by":"publisher","first-page":"D947","DOI":"10.1093\/nar\/gkaa609","article-title":"HRT Atlas v1.0 database: Redefining human and mouse housekeeping genes and candidate reference transcripts by mining massive RNA-seq datasets.","volume":"49","author":"Hounkpe","year":"2021","journal-title":"Nucleic Acids Res."},{"key":"B44","doi-asserted-by":"publisher","first-page":"865","DOI":"10.1038\/sj.jcbfm.9600263","article-title":"Neuronal-glial glucose oxidation and glutamatergic-GABAergic function.","volume":"26","author":"Hyder","year":"2006","journal-title":"J. Cereb. Blood Flow Metab."},{"key":"B45","doi-asserted-by":"publisher","first-page":"8767","DOI":"10.3390\/ijms21228767","article-title":"Effects of ketone bodies on brain metabolism and function in neurodegenerative diseases.","volume":"21","author":"Jensen","year":"2020","journal-title":"Int. J. Mol. Sci."},{"key":"B46","doi-asserted-by":"publisher","first-page":"640","DOI":"10.1097\/NEN.0000000000000091","article-title":"Metabolomics of human brain aging and age-related neurodegenerative diseases.","volume":"73","author":"Jov\u00e9","year":"2014","journal-title":"J. Neuropathol. Exp. Neurol."},{"key":"B47","doi-asserted-by":"publisher","first-page":"588","DOI":"10.1038\/s41593-022-01061-1","article-title":"Single-cell genomic profiling of human dopamine neurons identifies a population that selectively degenerates in Parkinson\u2019s disease.","volume":"25","author":"Kamath","year":"2022","journal-title":"Nat. Neurosci."},{"key":"B48","doi-asserted-by":"publisher","first-page":"e71424","DOI":"10.7554\/eLife.71424","article-title":"Lactate is an energy substrate for rodent cortical neurons and enhances their firing activity.","volume":"10","author":"Karagiannis","year":"2021","journal-title":"Elife"},{"key":"B49","doi-asserted-by":"publisher","first-page":"1385","DOI":"10.1177\/34.11.3534076","article-title":"Immunohistochemical localization of ornithine aminotransferase in normal rat tissues by Fab\u2019-horseradish peroxidase conjugates.","volume":"34","author":"Kasahara","year":"1986","journal-title":"J. Histochem. Cytochem."},{"key":"B50","doi-asserted-by":"publisher","first-page":"e73245","DOI":"10.7554\/eLife.73245","article-title":"Metabolic requirement for GOT2 in pancreatic cancer depends on environmental context.","volume":"11","author":"Kerk","year":"2022","journal-title":"Elife"},{"key":"B51","doi-asserted-by":"publisher","first-page":"423","DOI":"10.1042\/bj1540423","article-title":"Preparation and properties of mitochondria derived from synaptosomes.","volume":"154","author":"Lai","year":"1976","journal-title":"Biochem. J."},{"key":"B52","author":"Lajtha","year":"2008","journal-title":"Handbook of neurochemistry and molecular neurobiology."},{"key":"B53","doi-asserted-by":"publisher","first-page":"1441","DOI":"10.1111\/j.1471-4159.1966.tb04305.x","article-title":"Regional distribution of some chemical structural components of the human nervous system. I. DNA, RNA and ganglioside sialic acid.","volume":"13","author":"Landolt","year":"1966","journal-title":"J. Neurochem."},{"key":"B54","doi-asserted-by":"publisher","first-page":"1306","DOI":"10.1111\/j.1471-4159.1984.tb02788.x","article-title":"The activities of some energy-metabolising enzymes in nonsynaptic (free) and synaptic mitochondria derived from selected brain regions.","volume":"42","author":"Leong","year":"1984","journal-title":"J. Neurochem."},{"key":"B55","doi-asserted-by":"publisher","first-page":"1279","DOI":"10.1038\/nbt.1711","article-title":"Large-scale in silico modeling of metabolic interactions between cell types in the human brain.","volume":"28","author":"Lewis","year":"2010","journal-title":"Nat. Biotechnol."},{"key":"B56","doi-asserted-by":"publisher","first-page":"1653","DOI":"10.1002\/mds.25555","article-title":"3-hydroxykynurenine and other Parkinson\u2019s disease biomarkers discovered by metabolomic analysis.","volume":"28","author":"Lewitt","year":"2013","journal-title":"Mov. Disord."},{"key":"B57","doi-asserted-by":"publisher","first-page":"e14411","DOI":"10.1111\/cns.14411","article-title":"The potential role of glucose metabolism, lipid metabolism, and amino acid metabolism in the treatment of Parkinson\u2019s disease.","volume":"30","author":"Li","year":"2023","journal-title":"CNS Neurosci. Ther."},{"key":"B58","doi-asserted-by":"publisher","first-page":"5715","DOI":"10.1093\/emboj\/20.20.5715","article-title":"Tuning pacemaker frequency of individual dopaminergic neurons by Kv4.3L and KChip3.1 transcription.","volume":"20","author":"Liss","year":"2001","journal-title":"EMBO J."},{"key":"B59","doi-asserted-by":"publisher","first-page":"31","DOI":"10.1016\/S0021-9258(18)51741-5","article-title":"The relationships between substrates and enzymes of glycolysis in brain.","volume":"239","author":"Lowry","year":"1964","journal-title":"J. Biol. Chem."},{"key":"B60","doi-asserted-by":"publisher","first-page":"126","DOI":"10.1038\/s41531-024-00732-z","article-title":"Identification of metabolites reproducibly associated with Parkinson\u2019s Disease via meta-analysis and computational modelling.","volume":"10","author":"Luo","year":"2024","journal-title":"NPJ Parkinsons Dis."},{"key":"B61","doi-asserted-by":"publisher","first-page":"8","DOI":"10.1016\/j.ijcard.2015.08.109","article-title":"Regulation of uric acid metabolism and excretion.","volume":"213","author":"Maiuolo","year":"2016","journal-title":"Int. J. Cardiol."},{"key":"B62","doi-asserted-by":"publisher","first-page":"64","DOI":"10.3389\/fnmol.2017.00064","article-title":"Neuronal mitophagy in neurodegenerative diseases.","volume":"10","author":"Martinez-Vicente","year":"2017","journal-title":"Front. Mol. Neurosci."},{"key":"B63","doi-asserted-by":"publisher","first-page":"1023","DOI":"10.1007\/s13238-010-0128-5","article-title":"Tyrosine aminotransferase: Biochemical and structural properties and molecular dynamics simulations.","volume":"1","author":"Mehere","year":"2010","journal-title":"Protein Cell"},{"key":"B64","doi-asserted-by":"publisher","first-page":"12668","DOI":"10.3390\/ijms222312668","article-title":"Regulation of the fructose transporter gene Slc2a5 expression by glucose in cultured microglial cells.","volume":"22","author":"Mizuno","year":"2021","journal-title":"Int. J. Mol. Sci."},{"key":"B65","doi-asserted-by":"publisher","first-page":"43","DOI":"10.1186\/s40035-021-00262-1","article-title":"Astrocytes and retrograde degeneration of nigrostriatal dopaminergic neurons in Parkinson\u2019s disease: Removing axonal debris.","volume":"10","author":"Morales","year":"2021","journal-title":"Trans. Neurodegenerat."},{"key":"B66","doi-asserted-by":"publisher","first-page":"e55068","DOI":"10.1371\/journal.pone.0055068","article-title":"Dopamine-mediated oxidation of methionine 127 in \u03b1-synuclein causes cytotoxicity and oligomerization of \u03b1-synuclein.","volume":"8","author":"Nakaso","year":"2013","journal-title":"PLoS One"},{"key":"B67","doi-asserted-by":"publisher","first-page":"D614","DOI":"10.1093\/nar\/gky992","article-title":"The Virtual Metabolic Human database: Integrating human and gut microbiome metabolism with nutrition and disease.","volume":"47","author":"Noronha","year":"2019","journal-title":"Nucleic Acids Res."},{"key":"B68","doi-asserted-by":"publisher","first-page":"57","DOI":"10.1002\/jnr.490010106","article-title":"The lipid composition of isolated brain cells and axons.","volume":"1","author":"Norton","year":"1975","journal-title":"J Neurosci. Res."},{"key":"B69","doi-asserted-by":"publisher","first-page":"537","DOI":"10.1016\/S0022-2275(20)39619-X","article-title":"Lipid composition of the normal human brain: Gray matter, white matter, and myelin.","volume":"6","author":"O\u2019Brien","year":"1965","journal-title":"J. Lipid Res."},{"key":"B70","doi-asserted-by":"publisher","first-page":"846183","DOI":"10.3389\/fnhum.2022.846183","article-title":"Exogenous ketones and lactate as a potential therapeutic intervention for brain injury and neurodegenerative conditions.","volume":"16","author":"Omori","year":"2022","journal-title":"Front. Hum. Neurosci."},{"key":"B71","doi-asserted-by":"publisher","first-page":"245","DOI":"10.1038\/nbt.1614","article-title":"What is flux balance analysis?","volume":"28","author":"Orth","year":"2010","journal-title":"Nat. Biotechnol."},{"key":"B72","doi-asserted-by":"publisher","first-page":"195","DOI":"10.1007\/978-3-319-94593-4_7","article-title":"Genome-Scale brain metabolic networks as scaffolds for the systems biology of neurodegenerative diseases: Mapping metabolic alterations.","volume":"21","author":"\u00d6zcan","year":"2018","journal-title":"Adv. Neurobiol."},{"key":"B73","doi-asserted-by":"publisher","first-page":"111216","DOI":"10.1016\/j.mad.2020.111216","article-title":"Regulation and roles of mitophagy at synapses.","volume":"187","author":"Palikaras","year":"2020","journal-title":"Mech. Ageing Dev."},{"key":"B74","doi-asserted-by":"publisher","first-page":"472459","DOI":"10.1155\/2014\/472459","article-title":"Fatty acids in energy metabolism of the central nervous system.","volume":"2014","author":"Panov","year":"2014","journal-title":"Biomed. Res. Int."},{"key":"B75","doi-asserted-by":"publisher","first-page":"34","DOI":"10.1016\/S0014-5793(00)02401-7","article-title":"The essential amino acid lysine acts as precursor of glutamate in the mammalian central nervous system.","volume":"488","author":"Papes","year":"2001","journal-title":"FEBS Lett."},{"key":"B76","doi-asserted-by":"publisher","first-page":"e13034","DOI":"10.1111\/acel.13034","article-title":"Methionine metabolism and methyltransferases in the regulation of aging and lifespan extension across species.","volume":"18","author":"Parkhitko","year":"2019","journal-title":"Aging Cell"},{"key":"B77","doi-asserted-by":"publisher","first-page":"432","DOI":"10.1016\/j.neuroscience.2019.02.033","article-title":"Functional differences between synaptic mitochondria from the striatum and the cerebral cortex.","volume":"406","author":"Petersen","year":"2019","journal-title":"Neuroscience"},{"key":"B78","doi-asserted-by":"publisher","first-page":"13","DOI":"10.3389\/fncom.2013.00013","article-title":"The energy cost of action potential propagation in dopamine neurons: Clues to susceptibility in Parkinson\u2019s disease.","volume":"7","author":"Pissadaki","year":"2013","journal-title":"Front. Comput. Neurosci."},{"key":"B79","doi-asserted-by":"publisher","first-page":"II25","DOI":"10.1007\/pl00007757","article-title":"Glutamate transport and metabolism in dopaminergic neurons of substantia nigra: Implications for the pathogenesis of Parkinson\u2019s disease.","volume":"247","author":"Plaitakis","year":"2000","journal-title":"J. Neurol."},{"key":"B80","doi-asserted-by":"publisher","first-page":"935","DOI":"10.3390\/ph14090935","article-title":"The metabolomic approach reveals the alteration in human serum and cerebrospinal fluid composition in parkinson\u2019s disease patients.","volume":"14","author":"Plewa","year":"2021","journal-title":"Pharmaceuticals"},{"key":"B81","doi-asserted-by":"publisher","first-page":"1754","DOI":"10.1038\/jcbfm.2008.63","article-title":"Cerebral mitochondrial metabolism in early Parkinson\u2019s disease.","volume":"28","author":"Powers","year":"2008","journal-title":"J. Cereb. Blood Flow Metab."},{"key":"B82","doi-asserted-by":"publisher","DOI":"10.1101\/2021.06.30.450562","article-title":"Mechanistic model-driven exometabolomic characterisation of human dopaminergic neuronal metabolism.","author":"Preciat","year":"","journal-title":"bioRxiv [Preprint]"},{"key":"B83","doi-asserted-by":"publisher","DOI":"10.1101\/2021.11.08.467803","article-title":"XomicsToModel: Multiomics data integration and generation of thermodynamically consistent metabolic models.","author":"Preciat","year":"","journal-title":"biorxiv [Preprint]"},{"key":"B84","doi-asserted-by":"publisher","first-page":"81","DOI":"10.1007\/BF00423095","article-title":"Comparison of folylpolyglutamate hydrolases of mouse liver, kidney, muscle and brain.","volume":"43","author":"Priest","year":"1982","journal-title":"Mol. Cell Biochem."},{"key":"B85","doi-asserted-by":"publisher","first-page":"1568","DOI":"10.4161\/auto.7.12.17992","article-title":"Together we are stronger.","volume":"7","author":"Rambold","year":"2011","journal-title":"Autophagy"},{"key":"B86","doi-asserted-by":"publisher","first-page":"200","DOI":"10.3934\/Neuroscience.2023017","article-title":"Depletion of dopamine in Parkinson\u2019s disease and relevant therapeutic options: A review of the literature.","volume":"10","author":"Ramesh","year":"2023","journal-title":"AIMS Neurosci."},{"key":"B87","doi-asserted-by":"publisher","first-page":"449","DOI":"10.1016\/S0022-2275(20)39795-9","article-title":"Synthesis of molecular species of glycerophospholipids from diglyceride-labeled brain microsomes.","volume":"21","author":"Roberti","year":"1980","journal-title":"J. Lipid. Res."},{"key":"B88","doi-asserted-by":"publisher","first-page":"kvad004","DOI":"10.1093\/oons\/kvad004","article-title":"Energy metabolic pathways in neuronal development and function.","volume":"2","author":"Rumpf","year":"2023","journal-title":"Oxf. Open Neurosci."},{"key":"B89","doi-asserted-by":"publisher","first-page":"823","DOI":"10.1111\/j.1471-4159.1990.tb02325.x","article-title":"Mitochondrial complex i deficiency in Parkinson\u2019s disease.","volume":"54","author":"Schapira","year":"1990","journal-title":"J. Neurochem."},{"key":"B90","doi-asserted-by":"publisher","first-page":"544","DOI":"10.1016\/j.bpj.2010.12.3707","article-title":"Elimination of thermodynamically infeasible loops in steady-state metabolic models.","volume":"100","author":"Schellenberger","year":"2011","journal-title":"Biophys. J."},{"key":"B91","doi-asserted-by":"publisher","first-page":"4028","DOI":"10.1038\/ncomms5028","article-title":"iPSC-derived neurons from GBA1-associated Parkinson\u2019s disease patients show autophagic defects and impaired calcium homeostasis.","volume":"5","author":"Sch\u00f6ndorf","year":"2014","journal-title":"Nat. Commun."},{"key":"B92","doi-asserted-by":"publisher","first-page":"1493","DOI":"10.1038\/jcbfm.2013.128","article-title":"Why does brain metabolism not favor burning of fatty acids to provide energy? Reflections on disadvantages of the use of free fatty acids as fuel for brain.","volume":"33","author":"Sch\u00f6nfeld","year":"2013","journal-title":"J. Cereb. Blood Flow Metab."},{"key":"B93","doi-asserted-by":"publisher","first-page":"542","DOI":"10.1016\/j.fob.2014.05.006","article-title":"Systematic analysis of transcription-level effects of neurodegenerative diseases on human brain metabolism by a newly reconstructed brain-specific metabolic network.","volume":"4","author":"Sertba\u015f","year":"2014","journal-title":"FEBS Open Bio"},{"key":"B94","doi-asserted-by":"publisher","first-page":"2620","DOI":"10.1021\/pr500295n","article-title":"Quantitative proteomics of synaptic and nonsynaptic mitochondria: Insights for synaptic mitochondrial vulnerability.","volume":"13","author":"Stauch","year":"2014","journal-title":"J. Proteome Res."},{"key":"B95","doi-asserted-by":"publisher","first-page":"93","DOI":"10.1038\/nprot.2009.203","article-title":"A protocol for generating a high-quality genome-scale metabolic reconstruction.","volume":"5","author":"Thiele","year":"2010","journal-title":"Nat. Protocols"},{"key":"B96","doi-asserted-by":"publisher","first-page":"106","DOI":"10.3389\/fcell.2017.00106","article-title":"Mitochondria and lysosomes: Discovering bonds.","volume":"5","author":"Todkar","year":"2017","journal-title":"Front. Cell Dev. Biol."},{"key":"B97","doi-asserted-by":"publisher","first-page":"13642","DOI":"10.1073\/pnas.1303346110","article-title":"Energetic cost of brain functional connectivity.","volume":"110","author":"Tomasi","year":"2013","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"key":"B98","doi-asserted-by":"publisher","first-page":"dmm049727","DOI":"10.1242\/dmm.049727","article-title":"Increased cysteine metabolism in PINK1 models of Parkinson\u2019s disease.","volume":"16","author":"Travaglio","year":"2023","journal-title":"Dis. Model. Mech."},{"key":"B99","doi-asserted-by":"publisher","first-page":"1401","DOI":"10.1002\/mds.27132","article-title":"Distinct metabolomic signature in cerebrospinal fluid in early parkinson\u2019s disease.","volume":"32","author":"Trezzi","year":"2017","journal-title":"Mov. Disord."},{"key":"B100","doi-asserted-by":"publisher","first-page":"549","DOI":"10.3233\/JPD-140389","article-title":"Metabolite and peptide levels in plasma and CSF differentiating healthy controls from patients with newly diagnosed Parkinson\u2019s disease.","volume":"4","author":"Trupp","year":"2014","journal-title":"J. Parkinsons Dis."},{"key":"B101","doi-asserted-by":"publisher","first-page":"255","DOI":"10.1186\/s12974-019-1659-1","article-title":"The pentose phosphate pathway regulates chronic neuroinflammation and dopaminergic neurodegeneration.","volume":"16","author":"Tu","year":"2019","journal-title":"J. Neuroinflamm."},{"key":"B102","doi-asserted-by":"publisher","first-page":"1260419","DOI":"10.1126\/science.1260419","article-title":"Proteomics. Tissue-based map of the human proteome.","volume":"347","author":"Uhl\u00e9n","year":"2015","journal-title":"Science"},{"key":"B103","doi-asserted-by":"publisher","first-page":"92","DOI":"10.1111\/j.1476-5381.2009.00203.x","article-title":"Effects of L-histidine depletion and L-tyrosine\/L-phenylalanine depletion on sensory and motor processes in healthy volunteers.","volume":"157","author":"van Ruitenbeek","year":"2009","journal-title":"Br. J. Pharmacol."},{"key":"B104","doi-asserted-by":"publisher","first-page":"211","DOI":"10.1016\/0047-6374(89)90072-9","article-title":"Enzyme activities in perikaryal and synaptic mitochondrial fractions from rat hippocampus during development.","volume":"49","author":"Villa","year":"1989","journal-title":"Mech. Ageing Dev."},{"key":"B105","doi-asserted-by":"publisher","first-page":"e1003424","DOI":"10.1371\/journal.pcbi.1003424","article-title":"Fast reconstruction of compact context-specific metabolic network models.","volume":"10","author":"Vlassis","year":"2014","journal-title":"PLoS Comput. Biol."},{"key":"B106","doi-asserted-by":"publisher","first-page":"739","DOI":"10.1038\/npp.2008.132","article-title":"Proline affects brain function in 22q11DS children with the low activity COMT 158 allele.","volume":"34","author":"Vorstman","year":"2009","journal-title":"Neuropsychopharmacology"},{"key":"B107","doi-asserted-by":"publisher","first-page":"1891","DOI":"10.3390\/biom12121891","article-title":"Calcium overload and mitochondrial metabolism.","volume":"12","author":"Walkon","year":"2022","journal-title":"Biomolecules"},{"key":"B108","doi-asserted-by":"publisher","first-page":"1381889","DOI":"10.3389\/fnins.2024.1381889","article-title":"Systems genetics identifies methionine as a high risk factor for Alzheimer\u2019s disease.","volume":"18","author":"Wang","year":"2024","journal-title":"Front. Neurosci."},{"key":"B109","doi-asserted-by":"publisher","first-page":"2009","DOI":"10.3390\/ijms25042009","article-title":"Parkinson\u2019s disease: Cells succumbing to lifelong dopamine-related oxidative stress and other bioenergetic challenges.","volume":"25","author":"Watanabe","year":"2024","journal-title":"Int. J. Mol. Sci."},{"key":"B110","doi-asserted-by":"publisher","first-page":"e0208752","DOI":"10.1371\/journal.pone.0208752","article-title":"Metabolomic investigations in cerebrospinal fluid of Parkinson\u2019s disease.","volume":"13","author":"Willkommen","year":"2018","journal-title":"PLoS One"},{"key":"B111","doi-asserted-by":"publisher","first-page":"466","DOI":"10.1016\/0006-8993(82)90385-7","article-title":"Ornithine aminotransferase in Huntington\u2019s disease.","volume":"231","author":"Wong","year":"1982","journal-title":"Brain Res."},{"key":"B112","doi-asserted-by":"publisher","first-page":"1287","DOI":"10.1039\/c5mb00711a","article-title":"Multi-platform mass spectrometry analysis of the CSF and plasma metabolomes of rigorously matched amyotrophic lateral sclerosis, Parkinson\u2019s disease and control subjects.","volume":"12","author":"Wuolikainen","year":"2016","journal-title":"Mol. Biosyst."},{"key":"B113","doi-asserted-by":"publisher","first-page":"219","DOI":"10.1016\/j.neuroscience.2021.11.035","article-title":"Lactate supply from astrocytes to neurons and its role in ischemic stroke-induced neurodegeneration.","volume":"481","author":"Yamagata","year":"2022","journal-title":"Neuroscience"},{"key":"B114","doi-asserted-by":"publisher","first-page":"E2394","DOI":"10.3390\/cells9112394","article-title":"Metabolic profiling of CSF from people suffering from sporadic and LRRK2 Parkinson\u2019s disease: A pilot study.","volume":"9","author":"Yilmaz","year":"2020","journal-title":"Cells"},{"key":"B115","doi-asserted-by":"publisher","first-page":"8325","DOI":"10.3390\/ijms22158325","article-title":"Tackling dysfunction of mitochondrial bioenergetics in the brain.","volume":"22","author":"Zanfardino","year":"2021","journal-title":"Int. J. Mol. Sci."},{"key":"B116","doi-asserted-by":"publisher","first-page":"e13374","DOI":"10.7554\/eLife.13374","article-title":"Metabolic reprogramming during neuronal differentiation from aerobic glycolysis to neuronal oxidative phosphorylation.","volume":"5","author":"Zheng","year":"2016","journal-title":"Elife"},{"key":"B117","doi-asserted-by":"publisher","first-page":"3843","DOI":"10.1210\/endo.140.8.6907","article-title":"Neurosteroidogenesis in astrocytes, oligodendrocytes, and neurons of cerebral cortex of rat brain.","volume":"140","author":"Zwain","year":"1999","journal-title":"Endocrinology"}],"container-title":["Frontiers in Computational Neuroscience"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fncom.2025.1594330\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,6,5]],"date-time":"2025-06-05T05:28:41Z","timestamp":1749101321000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fncom.2025.1594330\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,6,5]]},"references-count":117,"alternative-id":["10.3389\/fncom.2025.1594330"],"URL":"https:\/\/doi.org\/10.3389\/fncom.2025.1594330","relation":{},"ISSN":["1662-5188"],"issn-type":[{"value":"1662-5188","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,6,5]]},"article-number":"1594330"}}