{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,18]],"date-time":"2026-06-18T23:19:38Z","timestamp":1781824778377,"version":"3.54.5"},"reference-count":95,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2024,1,23]],"date-time":"2024-01-23T00:00:00Z","timestamp":1705968000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Israel Science Foundation (ISF)","award":["248\/20 (HK)"],"award-info":[{"award-number":["248\/20 (HK)"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Introduction: Transcranial direct current stimulation (tDCS) is an evolving non-invasive neurostimulation technique. Despite multiple studies, its underlying molecular mechanisms are still unclear. Several previous human studies of the effect of tDCS suggest that it generates metabolic effects. The induction of metabolic effects by tDCS could provide an explanation for how it generates its long-term beneficial clinical outcome. Aim: Given these hints of tDCS metabolic effects, we aimed to delineate the metabolic pathways involved in its mode of action. Methods: To accomplish this, we utilized a broad analytical approach of co-analyzing metabolomics and transcriptomic data generated from anodal tDCS in rat models. Since no metabolomic dataset was available, we performed a tDCS experiment of bilateral anodal stimulation of 200 \u00b5A for 20 min and for 5 consecutive days, followed by harvesting the brain tissue below the stimulating electrode and generating a metabolomics dataset using LC-MS\/MS. The analysis of the transcriptomic dataset was based on a publicly available dataset. Results: Our analyses revealed that tDCS alters the metabolic profile of brain tissue, affecting bioenergetic-related pathways, such as glycolysis and mitochondrial functioning. In addition, we found changes in calcium-related signaling. Conclusions: We conclude that tDCS affects metabolism by modulating energy production-related processes. Given our findings concerning calcium-related signaling, we suggest that the immediate effects of tDCS on calcium dynamics drive modifications in distinct metabolic pathways. A thorough understanding of the underlying molecular mechanisms of tDCS has the potential to revolutionize its applicability, enabling the generation of personalized medicine in the field of neurostimulation and thus contributing to its optimization.<\/jats:p>","DOI":"10.3390\/cells13030205","type":"journal-article","created":{"date-parts":[[2024,1,23]],"date-time":"2024-01-23T04:17:40Z","timestamp":1705983460000},"page":"205","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Molecular Insights into Transcranial Direct Current Stimulation Effects: Metabolomics and Transcriptomics Analyses"],"prefix":"10.3390","volume":"13","author":[{"given":"Bhanumita","family":"Agrawal","sequence":"first","affiliation":[{"name":"Sagol Department of Neurobiology, University of Haifa, Haifa 3103301, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Soad","family":"Boulos","sequence":"additional","affiliation":[{"name":"Sagol Department of Neurobiology, University of Haifa, Haifa 3103301, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6762-2408","authenticated-orcid":false,"given":"Soliman","family":"Khatib","sequence":"additional","affiliation":[{"name":"Department of Biotechnology, Tel-Hai College, Upper Galilee 1220800, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6561-6397","authenticated-orcid":false,"given":"Yonatan","family":"Feuermann","sequence":"additional","affiliation":[{"name":"Sagol Department of Neurobiology, University of Haifa, Haifa 3103301, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2392-4073","authenticated-orcid":false,"given":"Julia","family":"Panov","sequence":"additional","affiliation":[{"name":"Sagol Department of Neurobiology, University of Haifa, Haifa 3103301, Israel"},{"name":"Tauber Bioinformatics Research Center, University of Haifa, Haifa 3103301, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4935-358X","authenticated-orcid":false,"given":"Hanoch","family":"Kaphzan","sequence":"additional","affiliation":[{"name":"Sagol Department of Neurobiology, University of Haifa, Haifa 3103301, Israel"},{"name":"Tauber Bioinformatics Research Center, University of Haifa, Haifa 3103301, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,1,23]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"56","DOI":"10.1016\/j.clinph.2016.10.087","article-title":"Evidence-based guidelines on the therapeutic use of transcranial direct current stimulation (tDCS)","volume":"128","author":"Lefaucheur","year":"2017","journal-title":"Clin. Neurophysiol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"2238","DOI":"10.1093\/brain\/awf238","article-title":"Pharmacological approach to the mechanisms of transcranial DC-stimulation-induced after-effects of human motor cortex excitability","volume":"125","author":"Liebetanz","year":"2002","journal-title":"Brain"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1031","DOI":"10.1016\/j.clinph.2015.11.012","article-title":"A technical guide to tDCS, and related non-invasive brain stimulation tools","volume":"127","author":"Woods","year":"2016","journal-title":"Clin. Neurophysiol."},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Arlotti, M., Rahman, A., Minhas, P., and Bikson, M. (September, January 28). Axon Terminal Polarization Induced by Weak Uniform Dc Electric Fields: A Modeling Study. Proceedings of the 2012 34th Annual International Conference of the IEEE Engineering in Medicine and Biology Society (EMBC), San Diego, CA, USA.","DOI":"10.1109\/EMBC.2012.6346985"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"109832","DOI":"10.1016\/j.celrep.2021.109832","article-title":"The role of sodium channels in direct current stimulation\u2014Axonal perspective","volume":"37","author":"Vasu","year":"2021","journal-title":"Cell Rep."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"293","DOI":"10.1113\/jphysiol.2003.049916","article-title":"Pharmacological Modulation of Cortical Excitability Shifts Induced by Transcranial Direct Current Stimulation in Humans","volume":"553","author":"Nitsche","year":"2003","journal-title":"J. Physiol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"633","DOI":"10.1111\/j.1469-7793.2000.t01-1-00633.x","article-title":"Excitability changes induced in the human motor cortex by weak transcranial direct current stimulation","volume":"527","author":"Nitsche","year":"2000","journal-title":"J. Physiol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"690","DOI":"10.1016\/j.biopsych.2011.05.009","article-title":"Brain Energy Consumption Induced by Electrical Stimulation Promotes Systemic Glucose Uptake","volume":"70","author":"Binkofski","year":"2011","journal-title":"Biol. Psychiatry"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1695","DOI":"10.1017\/S1461145713000084","article-title":"Anodal transcranial direct current stimulation increases brain intracellular pH and modulates bioenergetics","volume":"16","author":"Rae","year":"2013","journal-title":"Int. J. Neuropsychopharmacol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"104491","DOI":"10.1016\/j.neuint.2019.104491","article-title":"Neuroprotective effect of anodal transcranial direct current stimulation on 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced neurotoxicity in mice through modulating mitochondrial dynamics","volume":"129","author":"Lee","year":"2019","journal-title":"Neurochem. Int."},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Magri, C., Vitali, E., Cocco, S., Giacopuzzi, E., Rinaudo, M., Martini, P., Barbon, A., Grassi, C., and Gennarelli, M. (2021). Whole Blood Transcriptome Characterization of 3xTg-AD Mouse and Its Modulation by Transcranial Direct Current Stimulation (tDCS). Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22147629"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1155\/2016\/5942980","article-title":"Transcriptomic Modification in the Cerebral Cortex following Noninvasive Brain Stimulation: RNA-Sequencing Approach","volume":"2016","author":"Holmes","year":"2016","journal-title":"Neural Plast."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"461","DOI":"10.3389\/fncel.2019.00461","article-title":"Transcranial Current Stimulation Alters the Expression of Immune-Mediating Genes","volume":"13","author":"Rabenstein","year":"2019","journal-title":"Front. Cell. Neurosci."},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Lee, J.-W., Jeong, W.-H., Kim, E.-J., Choi, I., and Song, M.-K. (2022). Regulation of Genes Related to Cognition after tDCS in an Intermittent Hypoxic Brain Injury Rat Model. Genes, 13.","DOI":"10.3390\/genes13101824"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"241","DOI":"10.1016\/j.brs.2009.02.004","article-title":"Repetitive transcranial magnetic stimulation or transcranial direct current stimulation?","volume":"2","author":"Priori","year":"2009","journal-title":"Brain Stimul."},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Klimek, A., and Rogalska, J. (2021). Extremely Low-Frequency Magnetic Field as a Stress Factor\u2014Really Detrimental?\u2014Insight into Literature from the Last Decade. Brain Sci., 11.","DOI":"10.3390\/brainsci11020174"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"587771","DOI":"10.3389\/fneur.2021.587771","article-title":"Neurobiological After-Effects of Low Intensity Transcranial Electric Stimulation of the Human Nervous System: From Basic Mechanisms to Metaplasticity","volume":"12","author":"Korai","year":"2021","journal-title":"Front. Neurol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"907","DOI":"10.1038\/s41587-019-0201-4","article-title":"Graph-based genome alignment and genotyping with HISAT2 and HISAT-genotype","volume":"37","author":"Kim","year":"2019","journal-title":"Nat. Biotechnol."},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Li, B., and Dewey, C.N. (2011). RSEM: Accurate transcript quantification from RNA-Seq data with or without a reference genome. BMC Bioinform., 12.","DOI":"10.1186\/1471-2105-12-323"},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Love, M.I., Huber, W., and Anders, S. (2014). Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2. Genome Biol., 15.","DOI":"10.1186\/s13059-014-0550-8"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"W216","DOI":"10.1093\/nar\/gkac194","article-title":"DAVID: A web server for functional enrichment analysis and functional annotation of gene lists (2021 update)","volume":"50","author":"Sherman","year":"2022","journal-title":"Nucleic Acids Res."},{"key":"ref_22","unstructured":"Sergushichev, A.A. (2016). An algorithm for fast preranked gene set enrichment analysis using cumulative statistic calculation. bioRxiv."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"R93","DOI":"10.1186\/gb-2006-7-10-r93","article-title":"Pathway and gene-set activation measurement from mRNA expression data: The tissue distribution of human pathways","volume":"7","author":"Levine","year":"2006","journal-title":"Genome Biol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"W147","DOI":"10.1093\/nar\/gkw419","article-title":"Heatmapper: Web-enabled heat mapping for all","volume":"44","author":"Babicki","year":"2016","journal-title":"Nucleic Acids Res."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"e1900409","DOI":"10.1002\/pmic.201900409","article-title":"PathwayPCA: An R\/Bioconductor Package for Pathway Based Integrative Analysis of Multi-Omics Data","volume":"20","author":"Odom","year":"2020","journal-title":"Proteomics"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"882","DOI":"10.1093\/bioinformatics\/btp085","article-title":"Identification of differential gene pathways with principal component analysis","volume":"25","author":"Ma","year":"2009","journal-title":"Bioinformatics"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"15545","DOI":"10.1073\/pnas.0506580102","article-title":"Gene set enrichment analysis: A knowledge-based approach for interpreting genome-wide expression profiles","volume":"102","author":"Subramanian","year":"2005","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"D638","DOI":"10.1093\/nar\/gkac1000","article-title":"The STRING database in 2023: Protein\u2013protein association networks and functional enrichment analyses for any sequenced genome of interest","volume":"51","author":"Szklarczyk","year":"2023","journal-title":"Nucleic Acids Res."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"766","DOI":"10.1038\/s41598-023-27914-8","article-title":"\u03b2-Aminoisobutyric acid (L-BAIBA) is a novel regulator of mitochondrial biogenesis and respiratory function in human podocytes","volume":"13","author":"Audzeyenka","year":"2023","journal-title":"Sci. Rep."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"e13426","DOI":"10.1111\/obr.13426","article-title":"Sphingosine-1-phosphate in mitochondrial function and metabolic diseases","volume":"23","author":"Duan","year":"2022","journal-title":"Obes. Rev."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"635175","DOI":"10.3389\/fendo.2021.635175","article-title":"Sphingolipids as a Culprit of Mitochondrial Dysfunction in Insulin Resistance and Type 2 Diabetes","volume":"12","author":"Zabielski","year":"2021","journal-title":"Front. Endocrinol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"D1251","DOI":"10.1093\/nar\/gkv1003","article-title":"MitoCarta2.0: An updated inventory of mammalian mitochondrial proteins","volume":"44","author":"Calvo","year":"2016","journal-title":"Nucleic Acids Res."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"112","DOI":"10.1016\/j.cell.2008.06.016","article-title":"A Mitochondrial Protein Compendium Elucidates Complex I Disease Biology","volume":"134","author":"Pagliarini","year":"2008","journal-title":"Cell"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"254","DOI":"10.1016\/j.pbi.2004.03.007","article-title":"Respiratory metabolism: Glycolysis, the TCA cycle and mitochondrial electron transport","volume":"7","author":"Fernie","year":"2004","journal-title":"Curr. Opin. Plant Biol."},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Kang, W., Suzuki, M., Saito, T., and Miyado, K. (2021). Emerging Role of TCA Cycle-Related Enzymes in Human Diseases. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms222313057"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"2787","DOI":"10.1007\/s00018-013-1550-7","article-title":"Neuronal calcium signaling: Function and dysfunction","volume":"71","author":"Brini","year":"2014","journal-title":"Cell. Mol. Life Sci."},{"key":"ref_37","unstructured":"Sterea, A.M., and El Hiani, Y. (2020). Calcium Signaling, Springer."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1111\/j.1469-7793.2000.00057.x","article-title":"Mitochondria and calcium: From cell signalling to cell death","volume":"529","author":"Duchen","year":"2000","journal-title":"J. Physiol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1653","DOI":"10.1126\/science.2163543","article-title":"Intracellular Calcium Release Mediated by Sphingosine Derivatives Generated in Cells","volume":"248","author":"Ghosh","year":"1990","journal-title":"Science"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"e10616","DOI":"10.7554\/eLife.10616","article-title":"Intracellular sphingosine releases calcium from lysosomes","volume":"4","author":"Haberkant","year":"2015","journal-title":"eLife"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"2547","DOI":"10.1093\/bioinformatics\/btx225","article-title":"Mapping genes for calcium signaling and their associated human genetic disorders","volume":"33","author":"Toledo","year":"2017","journal-title":"Bioinformatics"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"883","DOI":"10.1016\/j.neuron.2015.03.035","article-title":"A Cellular Perspective on Brain Energy Metabolism and Functional Imaging","volume":"86","author":"Magistretti","year":"2015","journal-title":"Neuron"},{"key":"ref_43","doi-asserted-by":"crossref","unstructured":"Rajas, F., Gautier-Stein, A., and Mithieux, G. (2019). Glucose-6 Phosphate, a Central Hub for Liver Carbohydrate Metabolism. Metabolites, 9.","DOI":"10.3390\/metabo9120282"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"148097","DOI":"10.1016\/j.brainres.2022.148097","article-title":"Cerebral metabolic rate of oxygen (CMRO2) changes measured with simultaneous tDCS-MRI in healthy adults","volume":"1796","author":"Muccio","year":"2022","journal-title":"Brain Res."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"2","DOI":"10.1016\/j.coph.2007.09.002","article-title":"Adenosine as a neuromodulator in neurological diseases","volume":"8","author":"Boison","year":"2008","journal-title":"Curr. Opin. Pharmacol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"672182","DOI":"10.3389\/fphar.2021.672182","article-title":"Metabolic Aspects of Adenosine Functions in the Brain","volume":"12","author":"Camici","year":"2021","journal-title":"Front. Pharmacol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"347","DOI":"10.1016\/0301-0082(94)00057-O","article-title":"Restoration of brain energy metabolism as the function of sleep","volume":"45","author":"Benington","year":"1995","journal-title":"Prog. Neurobiol."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1146\/annurev.neuro.24.1.31","article-title":"The Role and Regulation of Adenosine in the Central Nervous System","volume":"24","author":"Dunwiddie","year":"2001","journal-title":"Annu. Rev. Neurosci."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"123","DOI":"10.1016\/j.smrv.2010.06.005","article-title":"Adenosine, energy metabolism and sleep homeostasis","volume":"15","author":"Kalinchuk","year":"2011","journal-title":"Sleep Med. Rev."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"135","DOI":"10.3181\/00379727-78-19000","article-title":"Beta-Aminoisobutyric Acid, A Possible Factor in Pyrimidine Metabolism","volume":"78","author":"Fink","year":"1951","journal-title":"Exp. Biol. Med."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"803510","DOI":"10.3389\/fcvm.2022.803510","article-title":"Exercise-Generated \u03b2-Aminoisobutyric Acid (BAIBA) Reduces Cardiomyocyte Metabolic Stress and Apoptosis Caused by Mitochondrial Dysfunction Through the miR-208b\/AMPK Pathway","volume":"9","author":"Yu","year":"2022","journal-title":"Front. Cardiovasc. Med."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"279","DOI":"10.1016\/j.cmet.2013.07.005","article-title":"Loss of Cytochrome c Oxidase Promotes RAS-Dependent ROS Production from the ER Resident NADPH Oxidase, Yno1p, in Yeast","volume":"18","author":"Leadsham","year":"2013","journal-title":"Cell Metab."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"srep05896","DOI":"10.1038\/srep05896","article-title":"Mitochondrial impairment triggers cytosolic oxidative stress and cell death following proteasome inhibition","volume":"4","author":"Maharjan","year":"2014","journal-title":"Sci. Rep."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1016\/j.ibneur.2021.12.001","article-title":"\u03b2-Aminoisobutyric acid, L-BAIBA, protects PC12 cells from hydrogen peroxide-induced oxidative stress and apoptosis via activation of the AMPK and PI3K\/Akt pathway","volume":"12","author":"Minato","year":"2022","journal-title":"IBRO Neurosci. Rep."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"1010","DOI":"10.1016\/j.cellsig.2007.12.006","article-title":"The sphingolipid salvage pathway in ceramide metabolism and signaling","volume":"20","author":"Kitatani","year":"2008","journal-title":"Cell. Signal."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"14134","DOI":"10.1074\/jbc.M109.076810","article-title":"Neurons and Oligodendrocytes Recycle Sphingosine 1-Phosphate to Ceramide","volume":"285","author":"Qin","year":"2010","journal-title":"J. Biol. Chem."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"143","DOI":"10.1007\/s10863-005-6567-7","article-title":"Mitochondrial Ceramide and the Induction of Apoptosis","volume":"37","author":"Siskind","year":"2005","journal-title":"J. Bioenerg. Biomembr."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"600","DOI":"10.1096\/fj.10-167502","article-title":"Sphingosine-1-phosphate produced by sphingosine kinase 2 in mitochondria interacts with prohibitin 2 to regulate complex IV assembly and respiration","volume":"25","author":"Strub","year":"2011","journal-title":"FASEB J."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"831","DOI":"10.1038\/nchembio.1059","article-title":"Ceramide targets autophagosomes to mitochondria and induces lethal mitophagy","volume":"8","author":"Sentelle","year":"2012","journal-title":"Nat. Chem. Biol."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"66","DOI":"10.1016\/j.freeradbiomed.2021.02.016","article-title":"The role of ceramide accumulation in human induced pluripotent stem cell-derived cardiomyocytes on mitochondrial oxidative stress and mitophagy","volume":"167","author":"Bekhite","year":"2021","journal-title":"Free. Radic. Biol. Med."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"116","DOI":"10.1016\/j.freeradbiomed.2019.04.022","article-title":"The S1P mimetic fingolimod phosphate regulates mitochondrial oxidative stress in neuronal cells","volume":"137","author":"Pavia","year":"2019","journal-title":"Free. Radic. Biol. Med."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"541","DOI":"10.1007\/s12192-013-0480-5","article-title":"Sphingosine 1-phosphate (S1P) promotes mitochondrial biogenesis in Hep G2 cells by activating Peroxisome proliferator-activated receptor \u03b3 coactivator 1\u03b1 (PGC-1\u03b1)","volume":"19","author":"Shen","year":"2014","journal-title":"Cell Stress Chaperon."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"399","DOI":"10.1016\/j.bcp.2005.10.011","article-title":"Neuronal and astrocytic shuttle mechanisms for cytosolic-mitochondrial transfer of reducing equivalents: Current evidence and pharmacological tools","volume":"71","author":"McKenna","year":"2006","journal-title":"Biochem. Pharmacol."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"871","DOI":"10.1146\/annurev.bi.48.070179.004255","article-title":"Metabolite Transport in Mitochondria","volume":"48","author":"LaNoue","year":"1979","journal-title":"Annu. Rev. Biochem."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"3879","DOI":"10.1523\/JNEUROSCI.1463-21.2022","article-title":"A Ca2+-Dependent Mechanism Boosting Glycolysis and OXPHOS by Activating Aralar-Malate-Aspartate Shuttle, upon Neuronal Stimulation","volume":"42","author":"Juaristi","year":"2022","journal-title":"J. Neurosci."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/1756-8722-6-19","article-title":"Targeting mitochondrial reactive oxygen species as novel therapy for inflammatory diseases and cancers","volume":"6","author":"Li","year":"2013","journal-title":"J. Hematol. Oncol."},{"key":"ref_67","doi-asserted-by":"crossref","unstructured":"Cardanho-Ramos, C., and Morais, V.A. (2021). Mitochondrial Biogenesis in Neurons: How and Where. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms222313059"},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1111\/bjd.12208","article-title":"The role of mitochondrial function and cellular bioenergetics in ageing and disease","volume":"169","author":"Brand","year":"2013","journal-title":"Br. J. Dermatol."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"397","DOI":"10.3389\/fphys.2021.627837","article-title":"Mitochondrial Reactive Oxygen Species and Their Contribution in Chronic Kidney Disease Progression Through Oxidative Stress","volume":"12","author":"Tirichen","year":"2021","journal-title":"Front. Physiol."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/s40478-022-01424-6","article-title":"Mitochondrial dysfunction is a key pathological driver of early stage Parkinson\u2019s","volume":"10","author":"Toomey","year":"2022","journal-title":"Acta Neuropathol. Commun."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/s13024-020-00376-6","article-title":"Mitochondria dysfunction in the pathogenesis of Alzheimer\u2019s disease: Recent advances","volume":"15","author":"Wang","year":"2020","journal-title":"Mol. Neurodegener."},{"key":"ref_72","doi-asserted-by":"crossref","unstructured":"Zhao, J., Wang, X., Huo, Z., Chen, Y., Liu, J., Zhao, Z., Meng, F., Su, Q., Bao, W., and Zhang, L. (2022). The Impact of Mitochondrial Dysfunction in Amyotrophic Lateral Sclerosis. Cells, 11.","DOI":"10.3390\/cells11132049"},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"2501","DOI":"10.1089\/ars.2011.3940","article-title":"Sphingolipid Metabolism, Oxidant Signaling, and Contractile Function of Skeletal Muscle","volume":"15","author":"Reid","year":"2011","journal-title":"Antioxidants Redox Signal."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"477","DOI":"10.1007\/s11682-019-00195-4","article-title":"Brain glucose uptake during transcranial direct current stimulation measured with functional [18F]FDG-PET","volume":"14","author":"Kraus","year":"2020","journal-title":"Brain Imaging Behav."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"40","DOI":"10.3389\/fpsyt.2020.00040","article-title":"The Onset of Diabetes During Transcranial Direct Current Stimulation Treatment of Anorexia Nervosa\u2014A Case Report","volume":"11","author":"Mares","year":"2020","journal-title":"Front. Psychiatry"},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"780","DOI":"10.1016\/j.brs.2017.03.011","article-title":"Persistent blood glucose reduction upon repeated transcranial electric stimulation in men","volume":"10","author":"Kistenmacher","year":"2017","journal-title":"Brain Stimul."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"148","DOI":"10.4331\/wjbc.v6.i3.148","article-title":"Metabolic interplay between glycolysis and mitochondrial oxidation: The reverse Warburg effect and its therapeutic implication","volume":"6","author":"Lee","year":"2015","journal-title":"World J. Biol. Chem."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"475","DOI":"10.1007\/s12013-013-9750-1","article-title":"Citric Acid Cycle and Role of its Intermediates in Metabolism","volume":"68","author":"Akram","year":"2014","journal-title":"Cell Biochem. Biophys."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"270","DOI":"10.1016\/j.brs.2022.01.005","article-title":"Calcium channels control tDCS-induced spontaneous vesicle release from axon terminals","volume":"15","author":"Vasu","year":"2022","journal-title":"Brain Stimul."},{"key":"ref_80","doi-asserted-by":"crossref","unstructured":"Vasu, S.O., and Kaphzan, H. (2023). Direct Current Stimulation Modulates Synaptic Facilitation via Distinct Presynaptic Calcium Channels. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms242316866"},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"1350","DOI":"10.1016\/j.neuron.2017.08.016","article-title":"Stable Positioning of Unc13 Restricts Synaptic Vesicle Fusion to Defined Release Sites to Promote Synchronous Neurotransmission","volume":"95","author":"Reynolds","year":"2017","journal-title":"Neuron"},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"274","DOI":"10.1016\/j.neuropharm.2015.02.006","article-title":"The human CHRNA7 and CHRFAM7A genes: A review of the genetics, regulation, and function","volume":"96","author":"Sinkus","year":"2015","journal-title":"Neuropharmacology"},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"225","DOI":"10.1086\/316946","article-title":"CHRNB2 Is the Second Acetylcholine Receptor Subunit Associated with Autosomal Dominant Nocturnal Frontal Lobe Epilepsy*","volume":"68","author":"Phillips","year":"2001","journal-title":"Am. J. Hum. Genet."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"5429","DOI":"10.1113\/JP276502","article-title":"Nicotine modulates human brain plasticity via calcium-dependent mechanisms","volume":"596","author":"Grundey","year":"2018","journal-title":"J. Physiol."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"631838","DOI":"10.3389\/fnhum.2021.631838","article-title":"Neurobiological Mechanisms of Transcranial Direct Current Stimulation for Psychiatric Disorders; Neurophysiological, Chemical, and Anatomical Considerations","volume":"15","author":"Yamada","year":"2021","journal-title":"Front. Hum. Neurosci."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"2660","DOI":"10.1002\/jcp.23008","article-title":"Human keratinocytes respond to direct current stimulation by increasing intracellular calcium: Preferential response of poorly differentiated cells","volume":"227","author":"Gauvin","year":"2012","journal-title":"J. Cell. Physiol."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"63","DOI":"10.1016\/j.euroneuro.2020.07.011","article-title":"Ca2+ channel dynamics explain the nonlinear neuroplasticity induction by cathodal transcranial direct current stimulation over the primary motor cortex","volume":"38","author":"Melo","year":"2020","journal-title":"Eur. Neuropsychopharmacol."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"1810","DOI":"10.1161\/CIRCRESAHA.116.305484","article-title":"The Ins and Outs of Mitochondrial Calcium","volume":"116","author":"Finkel","year":"2015","journal-title":"Circ. Res."},{"key":"ref_89","doi-asserted-by":"crossref","unstructured":"Ryan, K.C., Ashkavand, Z., and Norman, K.R. (2020). The Role of Mitochondrial Calcium Homeostasis in Alzheimer\u2019s and Related Diseases. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21239153"},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"C146","DOI":"10.1152\/ajpcell.00086.2017","article-title":"Regulation of ATP production: Dependence on calcium concentration and respiratory state","volume":"313","author":"Fink","year":"2017","journal-title":"Am. J. Physiol. Physiol."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"260","DOI":"10.1016\/j.redox.2015.08.010","article-title":"Calcium and ROS: A mutual interplay","volume":"6","author":"Bertram","year":"2015","journal-title":"Redox Biol."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"2841","DOI":"10.3748\/wjg.v23.i16.2841","article-title":"Oxidative stress, antioxidants and intestinal calcium absorption","volume":"23","author":"Guizzardi","year":"2017","journal-title":"World J. Gastroenterol."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"199","DOI":"10.1016\/S0167-4889(00)00117-8","article-title":"The role of calcium in the activation of glycogen phosphorylase in the fat body of the fruit beetle, Pachnoda sinuata, by hypertrehalosaemic hormone","volume":"1499","author":"Auerswald","year":"2001","journal-title":"Biochim. Biophys. Acta (BBA) Mol. Cell Res."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"584","DOI":"10.1016\/j.sjbs.2015.06.015","article-title":"Systems biology, emergence and antireductionism","volume":"23","year":"2016","journal-title":"Saudi J. Biol. Sci."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"109316","DOI":"10.1016\/j.mehy.2019.109316","article-title":"Rethinking the pragmatic systems biology and systems-theoretical biology divide: Toward a complexity-inspired epistemology of systems biomedicine","volume":"131","year":"2019","journal-title":"Med. Hypotheses"}],"container-title":["Cells"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4409\/13\/3\/205\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T13:47:43Z","timestamp":1760104063000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4409\/13\/3\/205"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,1,23]]},"references-count":95,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2024,2]]}},"alternative-id":["cells13030205"],"URL":"https:\/\/doi.org\/10.3390\/cells13030205","relation":{},"ISSN":["2073-4409"],"issn-type":[{"value":"2073-4409","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,1,23]]}}}