{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,2,21]],"date-time":"2025-02-21T08:27:47Z","timestamp":1740126467748,"version":"3.37.3"},"reference-count":37,"publisher":"Oxford University Press (OUP)","issue":"3","license":[{"start":{"date-parts":[[2023,10,20]],"date-time":"2023-10-20T00:00:00Z","timestamp":1697760000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100009945","name":"Merck KGaA","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100009945","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2023,12,13]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Cladribine tablets are a treatment for multiple sclerosis with effects on lymphocytes, yet its mode of action has not been fully established. Here, we analyzed the effects of cladribine on mitochondrial DNA integrity in lymphocytes. We treated cultured human T-cell lines (CCRF-CEM and Jurkat) with varying concentrations of cladribine to mimic the slow cell depletion observed in treated patients. The CCRF-CEM was more susceptible to cladribine than Jurkat cells. In both cells, mitochondrial protein synthesis, mitochondrial DNA copy number, and mitochondrial cytochrome-c oxidase-I mRNA mutagenesis was not affected by cladribine, while caspase-3 cleavage was detected in Jurkat cells at 100 nM concentration. Cladribine treatment at concentrations up to 10 nM in CCRF-CEM and 100 nM in Jurkat cells did not induce significant increase in mitochondrial DNA mutations. Peripheral blood mononuclear cells from eight multiple sclerosis patients and four controls were cultured with or without an effective dose of cladribine (5 nM). However, we did not find any differences in mitochondrial DNA somatic mutations in lymphocyte subpopulations (CD4+, CD8+, and CD19+) between treated versus nontreated cells. The overall mutation rate was similar in patients and controls. When different lymphocyte subpopulations were compared, greater mitochondrial DNA mutation levels were detected in CD8+ (P\u2005=\u20050.014) and CD4+ (P\u2005=\u20050.038) as compared to CD19+ cells, these differences were independent of cladribine treatment. We conclude that T cells have more detectable mitochondrial DNA mutations than B cells, and cladribine has no detectable mutagenic effect on lymphocyte mitochondrial genome nor does it impair mitochondrial function in human T-cell lines.<\/jats:p>","DOI":"10.1093\/cei\/uxad112","type":"journal-article","created":{"date-parts":[[2023,10,20]],"date-time":"2023-10-20T08:25:40Z","timestamp":1697790340000},"page":"304-313","source":"Crossref","is-referenced-by-count":0,"title":["Cultured lymphocytes\u2019 mitochondrial genome integrity is not altered by cladribine"],"prefix":"10.1093","volume":"214","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1499-3608","authenticated-orcid":false,"given":"Elina","family":"J\u00e4rvinen","sequence":"first","affiliation":[{"name":"Merck OY , Espoo , Finland ( an affiliate of Merck KGaA, Darmstadt , Germany )"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8883-3338","authenticated-orcid":false,"given":"Fumi","family":"Suomi","sequence":"additional","affiliation":[{"name":"Translational Stem Cell Biology and Metabolism Program, Research Program Unit, Faculty of Medicine, University of Helsinki , Helsinki , Finland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"James B","family":"Stewart","sequence":"additional","affiliation":[{"name":"Max Planck Institute for Biology of Ageing , Cologne , Germany"},{"name":"Wellcome Centre for Mitochondrial Research, Biosciences Institute, Faculty of Medical Sciences Newcastle University , Newcastle Upon Tyne , UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2245-7557","authenticated-orcid":false,"given":"Dimitri","family":"Guala","sequence":"additional","affiliation":[{"name":"Merck AB , Solna , Sweden ( an affiliate of Merck KGaA, Darmstadt , Germany )"},{"name":"Department of Biochemistry and Biophysics, Stockholm University , Stockholm , Sweden"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9504-3318","authenticated-orcid":false,"given":"Miko","family":"Valori","sequence":"additional","affiliation":[{"name":"Translational Immunology Research Program, University of Helsinki , Helsinki , Finland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lilja","family":"Jansson","sequence":"additional","affiliation":[{"name":"Translational Immunology Research Program, University of Helsinki , Helsinki , Finland"},{"name":"Helsinki University Hospital, Neurocenter , Helsinki , Finland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Janne","family":"Nieminen","sequence":"additional","affiliation":[{"name":"Translational Immunology Research Program, University of Helsinki , Helsinki , Finland"},{"name":"Helsinki University Hospital, Neurocenter , Helsinki , Finland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9570-4152","authenticated-orcid":false,"given":"Thomas G","family":"McWilliams","sequence":"additional","affiliation":[{"name":"Translational Stem Cell Biology and Metabolism Program, Research Program Unit, Faculty of Medicine, University of Helsinki , Helsinki , Finland"},{"name":"Department of Anatomy, Faculty of Medicine, University of Helsinki , Helsinki , Finland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5686-2900","authenticated-orcid":false,"given":"Pentti J","family":"Tienari","sequence":"additional","affiliation":[{"name":"Translational Immunology Research Program, University of Helsinki , Helsinki , Finland"},{"name":"Helsinki University Hospital, Neurocenter , Helsinki , Finland"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2023,10,20]]},"reference":[{"key":"2023121404034487300_CIT0001","doi-asserted-by":"crossref","first-page":"296","DOI":"10.1126\/science.abj8222","article-title":"Longitudinal analysis reveals high prevalence of Epstein-Barr virus associated with multiple sclerosis","volume":"375","author":"Bjornevik","year":"2022","journal-title":"Science"},{"key":"2023121404034487300_CIT0002","doi-asserted-by":"crossref","first-page":"2869","DOI":"10.1111\/ene.15360","article-title":"The contribution of neuropathology to multiple sclerosis research","volume":"29","author":"Lassmann","year":"2022","journal-title":"Eur J Neurol"},{"key":"2023121404034487300_CIT0003","doi-asserted-by":"crossref","first-page":"338","DOI":"10.1016\/S1474-4422(22)00471-9","article-title":"Epstein-Barr virus as a cause of multiple sclerosis: opportunities for prevention and 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