{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,19]],"date-time":"2026-08-19T08:27:23Z","timestamp":1787128043766,"version":"build-2736575974"},"reference-count":57,"publisher":"MDPI AG","issue":"16","license":[{"start":{"date-parts":[[2026,8,19]],"date-time":"2026-08-19T00:00:00Z","timestamp":1787097600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Nutrients"],"abstract":"<jats:p>Fibromyalgia and myalgic encephalomyelitis\/chronic fatigue syndrome (ME\/CFS) are chronic multisystem disorders characterized by persistent fatigue, pain, cognitive dysfunction, sleep disturbances, and reduced quality of life. Increasing evidence implicates mitochondrial dysfunction, oxidative and nitrosative stress, immune dysregulation, and altered redox and nicotinamide adenine dinucleotide (NAD+) metabolism as interconnected mechanisms contributing to fatigue, although the strength of evidence varies across these pathways. Micronutrients are essential components of mitochondrial bioenergetics, antioxidant defense, and immune\u2013metabolic regulation. This narrative review critically examines the mechanistic and clinical evidence supporting mitochondrial-oriented micronutritional interventions in fibromyalgia and ME\/CFS, including NAD+ precursors, B-complex vitamins, magnesium, coenzyme Q10, alpha-lipoic acid, GlyNAC, L-carnitine, pyrroloquinoline quinone, taurine, and creatine. Mechanistic plausibility is distinguished from clinical efficacy, as disease-specific randomized controlled evidence remains limited for several interventions. We further discuss biomarkers, metabolic phenotyping, and precision nutrition within a systems-based micronutrition framework. Finally, we present the rationale for a future randomized, double-blind, placebo-controlled trial in fibromyalgia patients with clinically significant fatigue, which is planned for 2027, subject to ethics approval and prospective registration, as a strategy for future clinical validation.<\/jats:p>","DOI":"10.3390\/nu18162702","type":"journal-article","created":{"date-parts":[[2026,8,19]],"date-time":"2026-08-19T07:58:23Z","timestamp":1787126303000},"page":"2702","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Micronutrition as a Therapeutic Strategy for Mitochondrial Dysfunction in Myalgic Encephalomyelitis\/Chronic Fatigue Syndrome and Fibromyalgia: A Narrative Review"],"prefix":"10.3390","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0009-0001-2493-740X","authenticated-orcid":false,"given":"Sergio","family":"Abanades","sequence":"first","affiliation":[{"name":"Centre M\u00e8dic ISIC, 08008 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Irene","family":"Fern\u00e1ndez","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Hospital Sant Pau, 08025 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nuria","family":"Capdevila","sequence":"additional","affiliation":[{"name":"Laboratorio LCN, Menac Medical Department, 08036 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francisco","family":"Cardona","sequence":"additional","affiliation":[{"name":"Burrull Centro M\u00e9dico Cardona, Spanish Society of Pulmonology and Thoracic Surgery (SEPAR), 08261 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,8,19]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1144","DOI":"10.1093\/pm\/pnab308","article-title":"Pain-related post-exertional malaise in myalgic encephalomyelitis\/chronic fatigue syndrome (ME\/CFS) and fibromyalgia: A systematic review and three-level meta-analysis","volume":"23","author":"Barhorst","year":"2022","journal-title":"Pain Med."},{"key":"ref_2","first-page":"1","article-title":"Chronic fatigue syndrome and mitochondrial dysfunction","volume":"2","author":"Myhill","year":"2009","journal-title":"Int. J. Clin. Exp. Med."},{"key":"ref_3","first-page":"E5472","article-title":"Metabolic features of chronic fatigue syndrome","volume":"113","author":"Naviaux","year":"2016","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Maes, M., and Twisk, F.N.M. (2010). Chronic fatigue syndrome: Harvey and Wessely\u2019s (bio)psychosocial model versus a bio(psychosocial) model based on inflammatory and oxidative and nitrosative stress pathways. BMC Med., 8.","DOI":"10.1186\/1741-7015-8-35"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"168","DOI":"10.2174\/1570159X11666131120224653","article-title":"Oxidative and nitrosative stress and immune-inflammatory pathways in patients with myalgic encephalomyelitis (ME)\/chronic fatigue syndrome (CFS)","volume":"12","author":"Morris","year":"2014","journal-title":"Curr. Neuropharmacol."},{"key":"ref_6","first-page":"208","article-title":"Mitochondrial dysfunction and the pathophysiology of chronic fatigue syndrome","volume":"5","author":"Booth","year":"2012","journal-title":"Int. J. Clin. Exp. Med."},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Tomas, C., Brown, A., Strassheim, V., Elson, J.L., Newton, J.L., and Manning, P. (2017). Cellular bioenergetics is impaired in patients with chronic fatigue syndrome. PLoS ONE, 12.","DOI":"10.1371\/journal.pone.0186802"},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Missailidis, D., Annesley, S.J., Allan, C.Y., Sanislav, O., Lidbury, B.A., Lewis, D.P., and Fisher, P.R. (2020). An isolated complex V inefficiency and dysregulated mitochondrial function in immortalized lymphocytes from ME\/CFS patients. Int. J. Mol. Sci., 21.","DOI":"10.20944\/preprints201909.0043.v3"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"30247","DOI":"10.1038\/s41598-024-81298-x","article-title":"Mitochondrial function in patients affected with fibromyalgia syndrome is impaired and correlates with disease severity","volume":"14","author":"Macchi","year":"2024","journal-title":"Sci. Rep."},{"key":"ref_10","first-page":"1215","article-title":"Mitochondrial structural alterations in fibromyalgia: A pilot electron microscopy study","volume":"42","author":"Israel","year":"2024","journal-title":"Clin. Exp. Rheumatol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"110083","DOI":"10.1016\/j.abb.2024.110083","article-title":"Impaired mitochondrial quality control in fibromyalgia: Mechanisms involved in skeletal muscle alteration","volume":"758","author":"Inferrera","year":"2024","journal-title":"Arch. Biochem. Biophys."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"17589","DOI":"10.1073\/pnas.0608757103","article-title":"Low micronutrient intake may accelerate the degenerative diseases of aging through allocation of scarce micronutrients by triage","volume":"103","author":"Ames","year":"2006","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"299","DOI":"10.1017\/S0029665113001286","article-title":"Feeding the immune system","volume":"72","author":"Calder","year":"2013","journal-title":"Proc. Nutr. Soc."},{"key":"ref_14","first-page":"291","article-title":"Micronutrition: A new frontier","volume":"14","author":"Cornelli","year":"2010","journal-title":"J. Nutr. Health Aging"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"559","DOI":"10.1136\/pgmj.2006.047670","article-title":"Micronutrients in health and disease","volume":"82","author":"Shenkin","year":"2006","journal-title":"Postgrad. Med. J."},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Davis, A., Higgs, S., Snaith, O., Lodge, T., Strong, M., Espejo-Oltra, A., Kujawski, S., Zalewski, P., Pretorius, E., and Hoerger, M. (2025). Dysregulation of lipid metabolism, energy production, and oxidative stress in myalgic encephalomyelitis\/chronic fatigue syndrome, Gulf War Syndrome and fibromyalgia. Front. Neurosci., 19.","DOI":"10.3389\/fnins.2025.1498981"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"96","DOI":"10.1186\/1479-5876-7-96","article-title":"Plasma cytokines in women with chronic fatigue syndrome","volume":"7","author":"Fletcher","year":"2009","journal-title":"J. Transl. Med."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1202","DOI":"10.1016\/j.bbi.2012.06.006","article-title":"Biomarkers for chronic fatigue","volume":"26","author":"Klimas","year":"2012","journal-title":"Brain Behav. Immun."},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Sep\u00falveda, N., Carneiro, J., Lacerda, E., and Nacul, L. (2019). Myalgic encephalomyelitis\/chronic fatigue syndrome as a hyper-regulated immune system driven by an interplay between regulatory T cells and chronic human herpesvirus infections. Front. Immunol., 10.","DOI":"10.3389\/fimmu.2019.02684"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1186\/1479-5876-9-81","article-title":"Immunological abnormalities as potential biomarkers in chronic fatigue syndrome\/myalgic encephalomyelitis","volume":"9","author":"Brenu","year":"2011","journal-title":"J. Transl. Med."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"2602","DOI":"10.1093\/rheumatology\/keab146","article-title":"Is fibromyalgia associated with a unique cytokine profile? A systematic review and meta-analysis","volume":"60","author":"Srivastava","year":"2021","journal-title":"Rheumatology"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1179\/rer.2000.5.1.35","article-title":"Blood parameters indicative of oxidative stress are associated with symptom expression in chronic fatigue syndrome","volume":"5","author":"Richards","year":"2000","journal-title":"Redox Rep."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"44","DOI":"10.1016\/j.biocel.2006.07.001","article-title":"Free radicals and antioxidants in normal physiological functions and human disease","volume":"39","author":"Valko","year":"2007","journal-title":"Int. J. Biochem. Cell Biol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1582432","DOI":"10.1155\/2022\/1582432","article-title":"Oxidative stress in fibromyalgia: From pathology to treatment","volume":"2022","author":"Assavarittirong","year":"2022","journal-title":"Oxid. Med. Cell. Longev."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"389","DOI":"10.1038\/nri2975","article-title":"Mitochondria in innate immune responses","volume":"11","author":"West","year":"2011","journal-title":"Nat. Rev. Immunol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"42","DOI":"10.1016\/j.mam.2008.05.005","article-title":"Regulation of glutathione synthesis","volume":"30","author":"Lu","year":"2009","journal-title":"Mol. Asp. Med."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1016\/j.cmet.2015.05.023","article-title":"NAD(+) metabolism and the control of energy homeostasis: A balancing act between mitochondria and the nucleus","volume":"22","author":"Menzies","year":"2015","journal-title":"Cell Metab."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"947","DOI":"10.1016\/j.molcel.2015.01.034","article-title":"Biology of poly(ADP-ribose) polymerases: The factotums of cell maintenance","volume":"58","author":"Bai","year":"2015","journal-title":"Mol. Cell"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"4","DOI":"10.2307\/3576299","article-title":"Poly(ADP-ribose) in the cellular response to DNA damage","volume":"101","author":"Berger","year":"1985","journal-title":"Radiat. Res."},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Gureev, A.P., Shaforostova, E.A., and Popov, V.N. (2019). Regulation of mitochondrial biogenesis as a way for active longevity: Interaction between the Nrf2 and PGC-1\u03b1 signaling pathways. Front. Genet., 10.","DOI":"10.3389\/fgene.2019.00435"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"319","DOI":"10.1152\/physiol.00056.2024","article-title":"Mitochondrial dysfunction in myalgic encephalomyelitis\/chronic fatigue syndrome","volume":"40","author":"Syed","year":"2025","journal-title":"Physiology"},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Dorczok, M.C., Mittmann, G., Mossaheb, N., Schrank, B., Bartova, L., Neumann, M., and Steiner-Hofbauer, V. (2025). Dietary supplementation for fatigue symptoms in myalgic encephalomyelitis\/chronic fatigue syndrome (ME\/CFS)\u2014A systematic review. Nutrients, 17.","DOI":"10.3390\/nu17030475"},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Antonelli, A., Bianchi, M., Fear, E.J., Giorgi, L., and Rossi, L. (2025). Management of fibromyalgia: Novel nutraceutical therapies beyond traditional pharmaceuticals. Nutrients, 17.","DOI":"10.3390\/nu17030530"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"12948","DOI":"10.1038\/ncomms12948","article-title":"Nicotinamide riboside is uniquely and orally bioavailable in mice and humans","volume":"7","author":"Trammell","year":"2016","journal-title":"Nat. Commun."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"185","DOI":"10.1016\/S1081-1206(10)62595-1","article-title":"Therapeutic effects of oral NADH on the symptoms of patients with chronic fatigue syndrome","volume":"82","author":"Forsyth","year":"1999","journal-title":"Ann. Allergy Asthma Immunol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"284","DOI":"10.1016\/j.rce.2009.09.015","article-title":"Nicotinamide adenine dinucleotide (NADH) in patients with chronic fatigue syndrome","volume":"210","author":"Alegre","year":"2010","journal-title":"Rev. Clin. Esp."},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Castro-Marrero, J., Segundo, M.J., Lacasa, M., Martinez-Martinez, A., Senta\u00f1es, R.S., and Alegre-Martin, J. (2021). Effect of dietary coenzyme Q10 plus NADH supplementation on fatigue perception and health-related quality of life in individuals with myalgic encephalomyelitis\/chronic fatigue syndrome: A prospective, randomized, double-blind, placebo-controlled trial. Nutrients, 13.","DOI":"10.3390\/nu13082658"},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"Kennedy, D.O. (2016). B vitamins and the brain: Mechanisms, dose and efficacy\u2014A review. Nutrients, 8.","DOI":"10.3390\/nu8020068"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"501","DOI":"10.70749\/ijbr.v3i8.2230","article-title":"Effectiveness of B-complex vitamins in reducing symptoms of chronic fatigue syndrome: A systematic review and meta-analysis","volume":"3","author":"Idris","year":"2025","journal-title":"Indus J. Biosci. Res."},{"key":"ref_40","first-page":"1","article-title":"Magnesium in man: Implications for health and disease","volume":"95","author":"Hoenderop","year":"2015","journal-title":"Physiol. Rev."},{"key":"ref_41","doi-asserted-by":"crossref","unstructured":"Macian, N., Dual\u00e9, C., Voute, M., Leray, V., Courrent, M., Bod\u00e9, P., Giron, F., Sonneville, S., Bernard, L., and Joanny, F. (2022). Short-term magnesium therapy alleviates moderate stress in patients with fibromyalgia: A randomized double-blind clinical trial. Nutrients, 14.","DOI":"10.3390\/nu14102088"},{"key":"ref_42","first-page":"470","article-title":"Coenzyme Q10 deficiency in myalgic encephalomyelitis\/chronic fatigue syndrome is related to fatigue, autonomic and neurocognitive symptoms","volume":"30","author":"Maes","year":"2009","journal-title":"Neuro Endocrinol. Lett."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"227","DOI":"10.1016\/0891-5849(95)00017-R","article-title":"Alpha-lipoic acid as a biological antioxidant","volume":"19","author":"Packer","year":"1995","journal-title":"Free Radic. Biol. Med."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"1149","DOI":"10.1016\/j.bbagen.2009.07.026","article-title":"Alpha-lipoic acid as a dietary supplement: Molecular mechanisms and therapeutic potential","volume":"1790","author":"Shay","year":"2009","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"2365","DOI":"10.2337\/dc06-1216","article-title":"Oral treatment with alpha-lipoic acid improves symptomatic diabetic polyneuropathy: The SYDNEY 2 trial","volume":"29","author":"Ziegler","year":"2006","journal-title":"Diabetes Care"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"561","DOI":"10.1097\/j.pain.0000000000002028","article-title":"Double-blind, randomized, placebo-controlled crossover trial of alpha-lipoic acid for the treatment of fibromyalgia pain: The IMPALA trial","volume":"162","author":"Gilron","year":"2021","journal-title":"Pain"},{"key":"ref_47","doi-asserted-by":"crossref","unstructured":"Schweiger, V., Secchettin, E., Castellani, C., Martini, A., Mazzocchi, E., Picelli, A., Polati, E., Donadello, K., Valenti, M.T., and Dalle Carbonare, L. (2020). Comparison between acupuncture and nutraceutical treatment with Migratens\u00ae in patients with fibromyalgia syndrome: A prospective randomized clinical trial. Nutrients, 12.","DOI":"10.3390\/nu12030821"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"e372","DOI":"10.1002\/ctm2.372","article-title":"Glycine and N-acetylcysteine (GlyNAC) supplementation in older adults improves glutathione deficiency, oxidative stress, mitochondrial dysfunction, inflammation, insulin resistance, endothelial dysfunction, genotoxicity, muscle strength, and cognition: Results of a pilot clinical trial","volume":"11","author":"Kumar","year":"2021","journal-title":"Clin. Transl. Med."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"75","DOI":"10.1093\/gerona\/glac135","article-title":"Supplementing glycine and N-acetylcysteine (GlyNAC) in older adults improves glutathione deficiency, oxidative stress, mitochondrial dysfunction, inflammation, physical function, and aging hallmarks: A randomized clinical trial","volume":"78","author":"Kumar","year":"2023","journal-title":"J. Gerontol. A Biol. Sci. Med. Sci."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"618S","DOI":"10.1093\/ajcn\/72.2.618S","article-title":"Supplemental carnitine and exercise","volume":"72","author":"Brass","year":"2000","journal-title":"Am. J. Clin. Nutr."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"276","DOI":"10.1097\/01.psy.0000116249.60477.e9","article-title":"Exploratory open-label, randomized study of acetyl- and propionylcarnitine in chronic fatigue syndrome","volume":"66","author":"Vermeulen","year":"2004","journal-title":"Psychosom. Med."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"142","DOI":"10.1074\/jbc.M109.030130","article-title":"Pyrroloquinoline quinone stimulates mitochondrial biogenesis through cAMP response element-binding protein phosphorylation and increased PGC-1\u03b1 expression","volume":"285","author":"Chowanadisai","year":"2010","journal-title":"J. Biol. Chem."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"2076","DOI":"10.1016\/j.jnutbio.2013.07.008","article-title":"Dietary pyrroloquinoline quinone (PQQ) alters indicators of inflammation and mitochondrial-related metabolism in human subjects","volume":"24","author":"Harris","year":"2013","journal-title":"J. Nutr. Biochem."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"100889","DOI":"10.1016\/j.crfs.2024.100889","article-title":"Pyrroloquinoline quinone (PQQ): Its impact on human health and potential benefits","volume":"9","author":"Yan","year":"2024","journal-title":"Curr. Res. Food Sci."},{"key":"ref_55","first-page":"1115","article-title":"Physiological roles of taurine in mitochondria","volume":"38","author":"Schaffer","year":"2010","journal-title":"Amino Acids"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"2147","DOI":"10.1098\/rspb.2003.2492","article-title":"Oral creatine monohydrate supplementation improves brain performance: A double-blind, placebo-controlled, cross-over trial","volume":"270","author":"Rae","year":"2003","journal-title":"Proc. R. Soc. Lond. B Biol. Sci."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"1449","DOI":"10.1002\/acr.22020","article-title":"Creatine supplementation in fibromyalgia: A randomized, double-blind, placebo-controlled trial","volume":"65","author":"Alves","year":"2013","journal-title":"Arthritis Care Res."}],"container-title":["Nutrients"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6643\/18\/16\/2702\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,19]],"date-time":"2026-08-19T08:07:26Z","timestamp":1787126846000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6643\/18\/16\/2702"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,8,19]]},"references-count":57,"journal-issue":{"issue":"16","published-online":{"date-parts":[[2026,8]]}},"alternative-id":["nu18162702"],"URL":"https:\/\/doi.org\/10.3390\/nu18162702","relation":{},"ISSN":["2072-6643"],"issn-type":[{"value":"2072-6643","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,8,19]]}}}