{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,4]],"date-time":"2026-03-04T08:01:57Z","timestamp":1772611317950,"version":"3.50.1"},"reference-count":92,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2026,2,25]],"date-time":"2026-02-25T00:00:00Z","timestamp":1771977600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100015082","name":"Catholic University of Valencia San Vicente M\u00e1rtir","doi-asserted-by":"crossref","award":["2018-203-001"],"award-info":[{"award-number":["2018-203-001"]}],"id":[{"id":"10.13039\/501100015082","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Multiple sclerosis (MS) is characterized by progressive mitochondrial dysfunction affecting complexes I, III, and IV of the electron transport chain, contributing to axonal energy failure and neurodegeneration. This review examines the potential of combining \u03b2-hydroxybutyrate (\u03b2HB), epigallocatechin-3-gallate (EGCG), and ellagic acid (EA) as a multi-target therapeutic strategy to restore mitochondrial function in patients with MS. Experimental and clinical studies demonstrate that each compound exerts complementary mechanisms. Ketone bodies provide an alternative energy substrate and restore complex I activity via sirtuin-dependent pathways. EGCG acts predominantly at the peripheral level by reducing systemic inflammation and oxidative stress. EA-derived urolithins effectively cross the blood\u2013brain barrier to directly enhance mitochondrial biogenesis and respiratory chain function in the central nervous system. Clinical trials have reported improvements in fatigue, cognition, mood, and muscle function following supplementation with these compounds. The convergence of their actions on energy restoration, reactive oxygen species reduction, and epigenetic modulation of protective pathways suggests their synergistic potential. Optimized delivery strategies, including exogenous ketone salts, liposomal EGCG, and microencapsulated EA, may overcome bioavailability limitations and interindividual variability in the gut microbiota metabolism.<\/jats:p>","DOI":"10.3390\/ijms27052168","type":"journal-article","created":{"date-parts":[[2026,2,26]],"date-time":"2026-02-26T09:31:32Z","timestamp":1772098292000},"page":"2168","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Impact of the Combination of Epigallocatechin Gallate and Ellagic Acid Supplemented with Ketone Bodies on Energetic Restoration of Mitochondrial Dysfunction and Metabolic Inefficiencies in Patients with Multiple Sclerosis: A Review"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6808-9505","authenticated-orcid":false,"given":"Jose Enrique","family":"de la Rubia Ort\u00ed","sequence":"first","affiliation":[{"name":"Department of Nutrition and Dietetics, Catholic University of Valencia San Vicente M\u00e1rtir, 46001 Valencia, Spain"}]},{"given":"Alba","family":"Roig-Soriano","sequence":"additional","affiliation":[{"name":"Department of Nutrition and Dietetics, Catholic University of Valencia San Vicente M\u00e1rtir, 46001 Valencia, Spain"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2497-7337","authenticated-orcid":false,"given":"Sandra","family":"Carrera-Juli\u00e1","sequence":"additional","affiliation":[{"name":"Department of Nutrition and Dietetics, Catholic University of Valencia San Vicente M\u00e1rtir, 46001 Valencia, Spain"}]},{"given":"Alejandra","family":"Castell\u00f3-Guillen","sequence":"additional","affiliation":[{"name":"Department of Nutrition and Dietetics, Catholic University of Valencia San Vicente M\u00e1rtir, 46001 Valencia, Spain"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2900-6097","authenticated-orcid":false,"given":"Marisa","family":"Machado","sequence":"additional","affiliation":[{"name":"UCIBIO\u2014Applied Molecular Biosciences Unit, Translational Toxicology Research Laboratory, University Institute of Health Sciences (1H-TOXRUN, IUCS-CESPU), 4585-116 Gandra, Portugal"},{"name":"Associate Laboratory i4HB\u2014Institute for Health and Bioeconomy, University Institute of Health Sciences\u2014CESPU, 4585-116 Gandra, Portugal"},{"name":"H<sup>2<\/sup>M\u2014Health and Human Movement Unit, Instituto Polit\u00e9cnico de Sa\u00fade do Norte, Cooperativa de Ensino Superior Polit\u00e9cnico e Universit\u00e1rio (CESPU), CRL, 4760-409 Vila Nova de Famalic\u00e3o, Portugal"}]},{"given":"Roc\u00edo","family":"Garc\u00eda-Villalba","sequence":"additional","affiliation":[{"name":"Quality, Safety and Bioactivity of Plant-Derived Foods, Centro de Edafolog\u00eda y Biolog\u00eda Aplicada del Segura-Consejo Superior de Investigaciones Cient\u00edficas (CEBAS-CSIC), 30100 Murcia, Spain"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8904-3749","authenticated-orcid":false,"given":"Jorge","family":"Alarc\u00f3n-Jim\u00e9nez","sequence":"additional","affiliation":[{"name":"Department of Physiotherapy, Catholic University San Vicente M\u00e1rtir, 46001 Valencia, Spain"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8125-8972","authenticated-orcid":false,"given":"Nieves","family":"de Bernardo","sequence":"additional","affiliation":[{"name":"Department of Physiotherapy, Catholic University San Vicente M\u00e1rtir, 46001 Valencia, Spain"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3342-6732","authenticated-orcid":false,"given":"Mar\u00eda","family":"Benlloch","sequence":"additional","affiliation":[{"name":"Department of Basic Biomedical Sciences, Catholic University of Valencia San Vicente M\u00e1rtir, 46001 Valencia, Spain"}]}],"member":"1968","published-online":{"date-parts":[[2026,2,25]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"169","DOI":"10.1056\/NEJMra1401483","article-title":"Multiple Sclerosis","volume":"378","author":"Reich","year":"2018","journal-title":"N. 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