{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,5]],"date-time":"2026-09-05T19:50:30Z","timestamp":1788637830220,"version":"build-2803163510"},"reference-count":28,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2026,7,20]],"date-time":"2026-07-20T00:00:00Z","timestamp":1784505600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2026,7,20]],"date-time":"2026-07-20T00:00:00Z","timestamp":1784505600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/501100006254","name":"Ruhr-Universit\u00e4t Bochum","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100006254","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Cell Mol Neurobiol"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Fumaric acid esters have proven to be effective medications in relapsing-remitting multiple sclerosis with neuroprotective effects. In this study, we investigated the impact of fumaric acid esters on primary murine microglia in vitro compared to DMSO vehicle control. Monomethyl fumarate (MMF) increased MTT reduction in a dose-dependent manner, whereas dimethyl fumarate (DMF) exhibited a biphasic response with low concentrations enhancing MTT reduction and higher concentrations inducing toxicity. Notably, complementary analyses of cell number and cell death did not reveal differences between MMF-treated and control conditions, indicating that the increased MTT reduction reflects enhanced cellular metabolic activity rather than increased viability. Consistent with this interpretation, MMF-treated cells exhibited higher basal and maximal oxygen consumption, spare respiratory capacity, and ATP production in the Seahorse XF Cell Mito Stress Test. Proteomic analysis did not indicate an upregulation of mitochondrial respiratory chain proteins, but instead suggested a qualitative shift in mitochondrial homeostasis, including increased expression of mitophagy-associated proteins. MMF-treated Nrf2-deficient microglia showed a blunted increase in MTT reduction, suggesting an involvement of Nrf2 in mediating MMF-induced metabolic effects. Additionally, MMF modulated the microglial iron metabolism and reduced the uptake of non-transferrin-bound iron and altered the gene expression of iron transport proteins, promoting a shift toward the uptake of less toxic, transferrin-bound iron. MMF mitigated iron-induced toxicity and was associated with upregulation of the ferroptosis suppressor protein, indicating a protective response to iron overload. Together, these findings suggest that MMF enhances microglial metabolic activity and mitochondrial function while reducing iron-mediated toxicity, thereby contributing to its neuroprotective effects.<\/jats:p>\n                  <jats:p>\n                    <jats:bold>Graphical Abstract<\/jats:bold>\n                  <\/jats:p>\n                  <jats:p>\n                    Summary of the proposed cellular effects of monomethyl fumarate in primary murine microglia. Created in BioRender. Faissner (2026).\n                    <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"https:\/\/help.biorender.com\/hc\/en-gb\/articles\/17605511350685\" ext-link-type=\"uri\">https:\/\/help.biorender.com\/hc\/en-gb\/articles\/17605511350685<\/jats:ext-link>\n                  <\/jats:p>","DOI":"10.1007\/s10571-026-01775-x","type":"journal-article","created":{"date-parts":[[2026,7,20]],"date-time":"2026-07-20T13:28:18Z","timestamp":1784554098000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Monomethyl Fumarate Modulates Iron Metabolism and Mitochondrial Function in Microglia with Implications for Multiple Sclerosis Progression"],"prefix":"10.1007","volume":"46","author":[{"given":"Justus","family":"Dann","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katharina","family":"Kl\u00f6ster","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ulas","family":"Ceylan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-5519-4695","authenticated-orcid":false,"given":"Neele","family":"Heitmann","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6553-4631","authenticated-orcid":false,"given":"Britta","family":"Eggers","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6861-5587","authenticated-orcid":false,"given":"Svitlana","family":"Rozanova","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2687-7444","authenticated-orcid":false,"given":"Martin","family":"Eisenacher","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3313-8845","authenticated-orcid":false,"given":"Katrin","family":"Marcus-Alic","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7256-8231","authenticated-orcid":false,"given":"Konstanze F.","family":"Winklhofer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7223-3052","authenticated-orcid":false,"given":"Ralf","family":"Gold","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3412-762X","authenticated-orcid":false,"given":"Simon","family":"Faissner","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,7,20]]},"reference":[{"key":"1775_CR1","doi-asserted-by":"publisher","first-page":"163","DOI":"10.1186\/1742-2094-9-163","volume":"9","author":"P Albrecht","year":"2012","unstructured":"Albrecht P, Bouchachia I, Goebels N, Henke N, Hofstetter HH, Issberner A, Kovacs Z, Lewerenz J, Lisak D, Maher P, Mausberg A-K, Quasthoff K, Zimmermann C, Hartung H-P, Methner A (2012) Effects of dimethyl fumarate on neuroprotection and immunomodulation. J Neuroinflammation 9:163. https:\/\/doi.org\/10.1186\/1742-2094-9-163","journal-title":"J Neuroinflammation"},{"key":"1775_CR2","doi-asserted-by":"publisher","first-page":"2188","DOI":"10.1172\/JCI72151","volume":"124","author":"H Chen","year":"2014","unstructured":"Chen H, Assmann JC, Krenz A, Rahman M, Grimm M, Karsten CM, K\u00f6hl J, Offermanns S, Wettschureck N, Schwaninger M (2014) Hydroxycarboxylic acid receptor 2 mediates dimethyl fumarate\u2019s protective effect in EAE. J Clin Invest 124:2188\u20132192. https:\/\/doi.org\/10.1172\/JCI72151","journal-title":"J Clin Invest"},{"key":"1775_CR3","doi-asserted-by":"publisher","first-page":"32","DOI":"10.1038\/s41368-025-00360-0","volume":"17","author":"L Chen","year":"2025","unstructured":"Chen L, Hu P, Hong X, Li B, Ping Y, Chen S, Jiang T, Jiang H, Mao Y, Chen Y, Song Z, Ye Z, Sun X, Zhao S, Huang S (2025) Dimethyl fumarate modulates M1\/M2 macrophage polarization to ameliorate periodontal destruction by increasing TUFM-mediated mitophagy. Int J Oral Sci 17:32. https:\/\/doi.org\/10.1038\/s41368-025-00360-0","journal-title":"Int J Oral Sci"},{"key":"1775_CR4","doi-asserted-by":"publisher","first-page":"33","DOI":"10.1016\/0022-510x(95)00206-h","volume":"134","author":"JR Connor","year":"1995","unstructured":"Connor JR, Menzies SL (1995) Cellular management of iron in the brain. J Neurol Sci 134:33\u201344. https:\/\/doi.org\/10.1016\/0022-510x(95)00206-h","journal-title":"J Neurol Sci"},{"key":"1775_CR5","doi-asserted-by":"publisher","DOI":"10.3389\/fneur.2021.632749","volume":"12","author":"A Dal-Bianco","year":"2021","unstructured":"Dal-Bianco A, Schranzer R, Grabner G, Lanzinger M, Kolbrink S, Pusswald G, Altmann P, Ponleitner M, Weber M, Kornek B, Zebenholzer K, Schmied C, Berger T, Lassmann H, Trattnig S, Hametner S, Leutmezer F, Rommer P (2021) Iron rims in patients with multiple sclerosis as neurodegenerative marker? A 7-tesla magnetic resonance study. Front Neurol 12:632749. https:\/\/doi.org\/10.3389\/fneur.2021.632749","journal-title":"Front Neurol"},{"key":"1775_CR6","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-017-02119-6","volume":"8","author":"S Faissner","year":"2017","unstructured":"Faissner S, Mishra M, Kaushik DK, Wang J, Fan Y, Silva C, Rauw G, Metz L, Koch M, Yong VW (2017) Systematic screening of generic drugs for progressive multiple sclerosis identifies clomipramine as a promising therapeutic. Nat Commun 8:1990. https:\/\/doi.org\/10.1038\/s41467-017-02119-6","journal-title":"Nat Commun"},{"key":"1775_CR7","doi-asserted-by":"publisher","first-page":"905","DOI":"10.1038\/s41573-019-0035-2","volume":"18","author":"S Faissner","year":"2019","unstructured":"Faissner S, Plemel JR, Gold R, Yong VW (2019) Progressive multiple sclerosis: from pathophysiology to therapeutic strategies. Nat Rev Drug Discov 18:905\u2013922. https:\/\/doi.org\/10.1038\/s41573-019-0035-2","journal-title":"Nat Rev Drug Discov"},{"key":"1775_CR8","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1114287","author":"R Gold","year":"2012","unstructured":"Gold R, Kappos L, Arnold DL, Bar-Or A, Giovannoni G, Selmaj K, Tornatore C, Sweetser MT, Yang M, Sheikh SI, Dawson KT (2012) Placebo-controlled phase 3 study of oral BG-12 for relapsing multiple sclerosis. N Engl J Med. https:\/\/doi.org\/10.1056\/NEJMoa1114287","journal-title":"N Engl J Med"},{"key":"1775_CR9","doi-asserted-by":"publisher","DOI":"10.1038\/s41419-021-03952-w","author":"S Gumeni","year":"2021","unstructured":"Gumeni S, Papanagnou E-D, Manola MS, Trougakos IP (2021) Nrf2 activation induces mitophagy and reverses Parkin\/Pink1 knock down-mediated neuronal and muscle degeneration phenotypes. Cell Death Dis. https:\/\/doi.org\/10.1038\/s41419-021-03952-w","journal-title":"Cell Death Dis"},{"key":"1775_CR28","doi-asserted-by":"publisher","unstructured":"Hayashi G, Jasoliya M, Sahdeo S, Sacc\u00e0 F, Pane C, Filla A, Marsili A, Puorro G, Lanzillo R, Brescia Morra V, Cortopassi G (2017) Dimethyl fumarate mediates Nrf2-dependent mitochondrial biogenesis in mice and humans. Hum Mol Genet 26:2864\u20132873. https:\/\/doi.org\/10.1093\/hmg\/ddx167","DOI":"10.1093\/hmg\/ddx167"},{"key":"1775_CR10","doi-asserted-by":"publisher","first-page":"1756","DOI":"10.1089\/ars.2017.7176","volume":"29","author":"MJ Kerins","year":"2018","unstructured":"Kerins MJ, Ooi A (2018) The Roles of NRF2 in Modulating Cellular Iron Homeostasis. Antioxid Redox Signal 29:1756\u20131773. https:\/\/doi.org\/10.1089\/ars.2017.7176","journal-title":"Antioxid Redox Signal"},{"key":"1775_CR11","doi-asserted-by":"publisher","first-page":"W207","DOI":"10.1093\/nar\/gkad347","volume":"51","author":"L Kolberg","year":"2023","unstructured":"Kolberg L, Raudvere U, Kuzmin I, Adler P, Vilo J, Peterson H (2023) g:Profiler-interoperable web service for functional enrichment analysis and gene identifier mapping (2023 update). Nucleic Acids Res 51:W207\u2013W212. https:\/\/doi.org\/10.1093\/nar\/gkad347","journal-title":"Nucleic Acids Res"},{"key":"1775_CR12","doi-asserted-by":"publisher","first-page":"210","DOI":"10.1111\/j.1750-3639.2007.00064.x","volume":"17","author":"H Lassmann","year":"2007","unstructured":"Lassmann H, Br\u00fcck W, Lucchinetti CF (2007) The immunopathology of multiple sclerosis: an overview. Brain Pathol 17:210\u2013218. https:\/\/doi.org\/10.1111\/j.1750-3639.2007.00064.x","journal-title":"Brain Pathol"},{"key":"1775_CR13","doi-asserted-by":"publisher","first-page":"678","DOI":"10.1093\/brain\/awq386","volume":"134","author":"RA Linker","year":"2011","unstructured":"Linker RA, Lee D-H, Ryan S, van Dam AM, Conrad R, Bista P, Zeng W, Hronowsky X, Buko A, Chollate S, Ellrichmann G, Br\u00fcck W, Dawson K, Goelz S, Wiese S, Scannevin RH, Lukashev M, Gold R (2011) Fumaric acid esters exert neuroprotective effects in neuroinflammation via activation of the Nrf2 antioxidant pathway. Brain 134:678\u2013692. https:\/\/doi.org\/10.1093\/brain\/awq386","journal-title":"Brain"},{"key":"1775_CR14","doi-asserted-by":"publisher","first-page":"7853","DOI":"10.1074\/jbc.RA118.001949","volume":"293","author":"RC McCarthy","year":"2018","unstructured":"McCarthy RC, Sosa JC, Gardeck AM, Baez AS, Lee C-H, Wessling-Resnick M (2018) Inflammation-induced iron transport and metabolism by brain microglia. J Biol Chem 293:7853\u20137863. https:\/\/doi.org\/10.1074\/jbc.RA118.001949","journal-title":"J Biol Chem"},{"key":"1775_CR15","doi-asserted-by":"publisher","first-page":"5","DOI":"10.3389\/fneur.2018.00005","volume":"9","author":"EA Mills","year":"2018","unstructured":"Mills EA, Ogrodnik MA, Plave A, Mao-Draayer Y (2018) Emerging Understanding of the Mechanism of Action for Dimethyl Fumarate in the Treatment of Multiple Sclerosis. Front Neurol 9:5. https:\/\/doi.org\/10.3389\/fneur.2018.00005","journal-title":"Front Neurol"},{"key":"1775_CR16","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/j.tips.2017.11.002","volume":"39","author":"U Mrowietz","year":"2018","unstructured":"Mrowietz U, Morrison PJ, Suhrkamp I, Kumanova M, Clement B (2018) The pharmacokinetics of fumaric acid esters reveal their in vivo effects. Trends Pharmacol Sci 39:1\u201312. https:\/\/doi.org\/10.1016\/j.tips.2017.11.002","journal-title":"Trends Pharmacol Sci"},{"key":"1775_CR17","doi-asserted-by":"publisher","first-page":"881","DOI":"10.1007\/s00401-021-02293-4","volume":"141","author":"L van Olst","year":"2021","unstructured":"van Olst L, Rodriguez-Mogeda C, Picon C, Kiljan S, James RE, Kamermans A, van der Pol SMA, Knoop L, Michailidou I, Drost E, Franssen M, Schenk GJ, Geurts JJG, Amor S, Mazarakis ND, van Horssen J, de Vries HE, Reynolds R, Witte ME (2021) Meningeal inflammation in multiple sclerosis induces phenotypic changes in cortical microglia that differentially associate with neurodegeneration. Acta Neuropathol 141:881\u2013899. https:\/\/doi.org\/10.1007\/s00401-021-02293-4","journal-title":"Acta Neuropathol"},{"key":"1775_CR18","doi-asserted-by":"publisher","first-page":"241","DOI":"10.1016\/j.neuroscience.2019.10.041","volume":"439","author":"F Pagani","year":"2020","unstructured":"Pagani F, Testi C, Grimaldi A, Corsi G, Cortese B, Basilico B, Baiocco P, Panfilis S, Ragozzino D, Di Angelantonio S (2020) Dimethyl fumarate reduces microglia functional response to tissue damage and favors brain iron homeostasis. Neuroscience 439:241\u2013254. https:\/\/doi.org\/10.1016\/j.neuroscience.2019.10.041","journal-title":"Neuroscience"},{"key":"1775_CR19","doi-asserted-by":"publisher","first-page":"45e","DOI":"10.1093\/nar\/29.9.e45","volume":"29","author":"MW Pfaffl","year":"2001","unstructured":"Pfaffl MW (2001) A new mathematical model for relative quantification in real-time RT-PCR. Nucleic Acids Res 29:45e\u2013445. https:\/\/doi.org\/10.1093\/nar\/29.9.e45","journal-title":"Nucleic Acids Res"},{"key":"1775_CR20","doi-asserted-by":"publisher","first-page":"370","DOI":"10.1016\/j.ab.2004.03.049","volume":"331","author":"J Riemer","year":"2004","unstructured":"Riemer J, Hoepken HH, Czerwinska H, Robinson SR, Dringen R (2004) Colorimetric ferrozine-based assay for the quantitation of iron in cultured cells. Anal Biochem 331:370\u2013375. https:\/\/doi.org\/10.1016\/j.ab.2004.03.049","journal-title":"Anal Biochem"},{"key":"1775_CR21","doi-asserted-by":"publisher","first-page":"104500","DOI":"10.1016\/j.msard.2023.104500","volume":"70","author":"FS Rousseau","year":"2023","unstructured":"Rousseau FS, Wang L, Sprague TN, Lategan TW, Berkovich RR (2023) Comparative pharmacokinetics and bioavailability of monomethyl fumarate following a single oral dose of Bafiertam\u00ae (monomethyl fumarate) versus Vumerity\u00ae (diroximel fumarate). Mult Scler Relat Disord 70:104500. https:\/\/doi.org\/10.1016\/j.msard.2023.104500","journal-title":"Mult Scler Relat Disord"},{"key":"1775_CR22","doi-asserted-by":"publisher","DOI":"10.1016\/j.ecoenv.2023.114646","volume":"252","author":"C Song","year":"2023","unstructured":"Song C, Zhang A, Zhang M, Song Y, Huangfu H, Jin S, Sun Y, Zhang C, Shi D, Wang J, Peng W, Luo Q (2023) Nrf2\/PINK1-mediated mitophagy induction alleviates sodium fluoride-induced hepatic injury by improving mitochondrial function, oxidative stress, and inflammation. Ecotoxicol Environ Saf 252:114646. https:\/\/doi.org\/10.1016\/j.ecoenv.2023.114646","journal-title":"Ecotoxicol Environ Saf"},{"key":"1775_CR23","doi-asserted-by":"publisher","first-page":"731","DOI":"10.1038\/nmeth.3901","volume":"13","author":"S Tyanova","year":"2016","unstructured":"Tyanova S, Temu T, Sinitcyn P, Carlson A, Hein MY, Geiger T, Mann M, Cox J (2016) The Perseus computational platform for comprehensive analysis of (prote)omics data. Nat Methods 13:731\u2013740. https:\/\/doi.org\/10.1038\/nmeth.3901","journal-title":"Nat Methods"},{"key":"1775_CR24","doi-asserted-by":"publisher","first-page":"969","DOI":"10.1016\/0378-4274(95)03532-x","volume":"82\u201383","author":"CC Winterbourn","year":"1995","unstructured":"Winterbourn CC (1995) Toxicity of iron and hydrogen peroxide: the Fenton reaction. Toxicol Lett 82\u201383:969\u2013974. https:\/\/doi.org\/10.1016\/0378-4274(95)03532-x","journal-title":"Toxicol Lett"},{"key":"1775_CR25","doi-asserted-by":"publisher","first-page":"179","DOI":"10.1016\/j.molmed.2013.11.007","volume":"20","author":"ME Witte","year":"2014","unstructured":"Witte ME, Mahad DJ, Lassmann H, van Horssen J (2014) Mitochondrial dysfunction contributes to neurodegeneration in multiple sclerosis. Trends Mol Med 20:179\u2013187. https:\/\/doi.org\/10.1016\/j.molmed.2013.11.007","journal-title":"Trends Mol Med"},{"key":"1775_CR26","doi-asserted-by":"publisher","first-page":"41","DOI":"10.1186\/s12974-019-1430-7","volume":"16","author":"YJ Yauger","year":"2019","unstructured":"Yauger YJ, Bermudez S, Moritz KE, Glaser E, Stoica B, Byrnes KR (2019) Iron accentuated reactive oxygen species release by NADPH oxidase in activated microglia contributes to oxidative stress in vitro. J Neuroinflammation 16:41. https:\/\/doi.org\/10.1186\/s12974-019-1430-7","journal-title":"J Neuroinflammation"},{"key":"1775_CR27","doi-asserted-by":"publisher","first-page":"3534","DOI":"10.1016\/j.neuron.2022.06","volume":"110","author":"VW Yong","year":"2022","unstructured":"Yong VW (2022) Microglia in multiple sclerosis: Protectors turn destroyers. Neuron 110:3534\u20133548. https:\/\/doi.org\/10.1016\/j.neuron.2022.06","journal-title":"Neuron"}],"container-title":["Cellular and Molecular Neurobiology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/article\/10.1007\/s10571-026-01775-x","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s10571-026-01775-x.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s10571-026-01775-x.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,20]],"date-time":"2026-07-20T13:53:20Z","timestamp":1784555600000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1007\/s10571-026-01775-x"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,7,20]]},"references-count":28,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2026,12]]}},"alternative-id":["1775"],"URL":"https:\/\/doi.org\/10.1007\/s10571-026-01775-x","relation":{},"ISSN":["1573-6830"],"issn-type":[{"value":"1573-6830","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,7,20]]},"assertion":[{"value":"12 September 2025","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"30 June 2026","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"20 July 2026","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing interests.","order":1,"name":"Ethics","label":"Competing Interests","group":{"name":"EthicsHeading","label":"Declarations"}}],"article-number":"118"}}