{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,15]],"date-time":"2026-09-15T01:48:41Z","timestamp":1789436921674,"version":"build-2803163510"},"reference-count":71,"publisher":"American Society for Clinical Investigation","issue":"17","license":[{"start":{"date-parts":[[2023,9,8]],"date-time":"2023-09-08T00:00:00Z","timestamp":1694131200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Max Planck Institute, Karolinska Institutet","award":["WAF2017"],"award-info":[{"award-number":["WAF2017"]}]},{"name":"the Knut & Alice Wallenberg Foundation","award":["KAW 2018.0080,KAW 2015.0063"],"award-info":[{"award-number":["KAW 2018.0080,KAW 2015.0063"]}]},{"DOI":"10.13039\/501100001862","name":"the Swedish Research Council","doi-asserted-by":"crossref","award":["VR2016-02179,VR2015-02662"],"award-info":[{"award-number":["VR2016-02179,VR2015-02662"]}],"id":[{"id":"10.13039\/501100001862","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2023,9,8]]},"abstract":"<jats:p>\n                    Pathogenic mutations in mitochondrial (mt) tRNA genes that compromise oxidative phosphorylation (OXPHOS) exhibit heteroplasmy and cause a range of multisyndromic conditions. Although mitochondrial disease patients are known to suffer from abnormal immune responses, how heteroplasmic mtDNA mutations affect the immune system at the molecular level is largely unknown. Here, in mice carrying pathogenic C5024T in mt-tRNA\n                    <jats:sup>Ala<\/jats:sup>\n                    and in patients with mitochondrial encephalomyopathy, lactic acidosis, stroke-like episodes (MELAS) syndrome carrying A3243G in mt-tRNA\n                    <jats:sup>Leu<\/jats:sup>\n                    , we found memory T and B cells to have lower pathogenic mtDNA mutation burdens than their antigen-inexperienced naive counterparts, including after vaccination. Pathogenic burden reduction was less pronounced in myeloid compared with lymphoid lineages, despite C5024T compromising macrophage OXPHOS capacity. Rapid dilution of the C5024T mutation in T and B cell cultures could be induced by antigen receptor\u2013triggered proliferation and was accelerated by metabolic stress conditions. Furthermore, we found C5024T to dysregulate CD8\n                    <jats:sup>+<\/jats:sup>\n                    T cell metabolic remodeling and IFN-\u03b3 production after activation. Together, our data illustrate that the generation of memory lymphocytes shapes the mtDNA landscape, wherein pathogenic variants dysregulate the immune response.\n                  <\/jats:p>","DOI":"10.1172\/jci.insight.167656","type":"journal-article","created":{"date-parts":[[2023,9,7]],"date-time":"2023-09-07T14:00:46Z","timestamp":1694095246000},"source":"Crossref","is-referenced-by-count":20,"title":["Antigen receptor stimulation induces purifying selection against pathogenic mitochondrial tRNA mutations"],"prefix":"10.1172","volume":"8","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5685-8386","authenticated-orcid":true,"given":"Jingdian","family":"Zhang","sequence":"first","affiliation":[{"name":"Department of Medical Biochemistry and Biophysics, and"},{"name":"Max Planck Institute Biology of Ageing-Karolinska Institutet Laboratory, Karolinska Institutet, Stockholm, Sweden."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Camilla","family":"Koolmeister","sequence":"additional","affiliation":[{"name":"Department of Medical Biochemistry and Biophysics, and"},{"name":"Max Planck Institute Biology of Ageing-Karolinska Institutet Laboratory, Karolinska Institutet, Stockholm, Sweden."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6084-3275","authenticated-orcid":true,"given":"Jinming","family":"Han","sequence":"additional","affiliation":[{"name":"Applied Immunology and Immunotherapy, Department of Clinical Neuroscience, Center for Molecular Medicine, Karolinska University Hospital, Stockholm, Sweden."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roberta","family":"Filograna","sequence":"additional","affiliation":[{"name":"Department of Medical Biochemistry and Biophysics, and"},{"name":"Max Planck Institute Biology of Ageing-Karolinska Institutet Laboratory, Karolinska Institutet, Stockholm, Sweden."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leo","family":"Hanke","sequence":"additional","affiliation":[{"name":"Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Monika","family":"\u00c0dori","sequence":"additional","affiliation":[{"name":"Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0227-5636","authenticated-orcid":true,"given":"Daniel J.","family":"Sheward","sequence":"additional","affiliation":[{"name":"Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden."},{"name":"Institute of Infectious Diseases and Molecular Medicine, University of Cape Town, Cape Town, South Africa."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9100-9542","authenticated-orcid":true,"given":"Sina","family":"Teifel","sequence":"additional","affiliation":[{"name":"Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8555-0292","authenticated-orcid":true,"given":"Shreekara","family":"Gopalakrishna","sequence":"additional","affiliation":[{"name":"Department of Medical Biochemistry and Biophysics, and"},{"name":"Max Planck Institute Biology of Ageing-Karolinska Institutet Laboratory, Karolinska Institutet, Stockholm, Sweden."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0628-2032","authenticated-orcid":true,"given":"Qiuya","family":"Shao","sequence":"additional","affiliation":[{"name":"Department of Medical Biochemistry and Biophysics, and"},{"name":"Max Planck Institute Biology of Ageing-Karolinska Institutet Laboratory, Karolinska Institutet, Stockholm, Sweden."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0574-2877","authenticated-orcid":true,"given":"Yong","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Medical Biochemistry and Biophysics, and"},{"name":"Max Planck Institute Biology of Ageing-Karolinska Institutet Laboratory, Karolinska Institutet, Stockholm, Sweden."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7500-1532","authenticated-orcid":true,"given":"Keying","family":"Zhu","sequence":"additional","affiliation":[{"name":"Applied Immunology and Immunotherapy, Department of Clinical Neuroscience, Center for Molecular Medicine, Karolinska University Hospital, Stockholm, Sweden."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4990-509X","authenticated-orcid":true,"given":"Robert A.","family":"Harris","sequence":"additional","affiliation":[{"name":"Applied Immunology and Immunotherapy, Department of Clinical Neuroscience, Center for Molecular Medicine, Karolinska University Hospital, Stockholm, Sweden."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gerald","family":"McInerney","sequence":"additional","affiliation":[{"name":"Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ben","family":"Murrell","sequence":"additional","affiliation":[{"name":"Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mike","family":"Aoun","sequence":"additional","affiliation":[{"name":"Division of Medical Inflammation Research, Department of Medical Biochemistry and Biophysics, Karolinska Institute, Stockholm, Sweden."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liselotte","family":"B\u00e4ckdahl","sequence":"additional","affiliation":[{"name":"Division of Medical Inflammation Research, Department of Medical Biochemistry and Biophysics, Karolinska Institute, Stockholm, Sweden."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4969-2576","authenticated-orcid":true,"given":"Rikard","family":"Holmdahl","sequence":"additional","affiliation":[{"name":"Division of Medical Inflammation Research, Department of Medical Biochemistry and Biophysics, Karolinska Institute, Stockholm, Sweden."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7623-4370","authenticated-orcid":true,"given":"Marcin","family":"Pekalski","sequence":"additional","affiliation":[{"name":"Wellcome Centre for Human Genetics, University of Oxford, Oxford, United Kingdom."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2612-6301","authenticated-orcid":true,"given":"Anna","family":"Wedell","sequence":"additional","affiliation":[{"name":"Max Planck Institute Biology of Ageing-Karolinska Institutet Laboratory, Karolinska Institutet, Stockholm, Sweden."},{"name":"Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden."},{"name":"Center for Inherited Metabolic Diseases, Karolinska University Hospital, Stockholm, Sweden."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8339-3545","authenticated-orcid":true,"given":"Martin","family":"Engvall","sequence":"additional","affiliation":[{"name":"Center for Inherited Metabolic Diseases, Karolinska University Hospital, Stockholm, Sweden."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna","family":"Wredenberg","sequence":"additional","affiliation":[{"name":"Department of Medical Biochemistry and Biophysics, and"},{"name":"Max Planck Institute Biology of Ageing-Karolinska Institutet Laboratory, Karolinska Institutet, Stockholm, Sweden."},{"name":"Center for Inherited Metabolic Diseases, Karolinska University Hospital, Stockholm, Sweden."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gunilla B.","family":"Karlsson Hedestam","sequence":"additional","affiliation":[{"name":"Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xaquin","family":"Castro Dopico","sequence":"additional","affiliation":[{"name":"Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joanna","family":"Rorbach","sequence":"additional","affiliation":[{"name":"Department of Medical Biochemistry and Biophysics, and"},{"name":"Max Planck Institute Biology of Ageing-Karolinska Institutet Laboratory, Karolinska Institutet, Stockholm, Sweden."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"232","published-online":{"date-parts":[[2023,9,8]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awh259"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1038\/nrg3966"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1016\/j.metabol.2017.11.010"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1001\/archotol.128.4.355"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1007\/s00109-022-02206-2"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1186\/s13023-022-02495-3"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1038\/nri.2017.66"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2013.04.005"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2017.05.007"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2012.10.020"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-019-1311-3"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.0901662"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2013.05.016"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2011.12.007"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1038\/s41590-021-00936-y"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1038\/s41590-020-0598-4"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1016\/j.it.2017.03.001"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1002\/ana.410350407"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1002\/(SICI)1096-8628(19990827)85:5<498::AID-AJMG13>3.0.CO;2-8"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1086\/318190"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1007\/s00125-002-1018-z"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1038\/nrdp.2016.80"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1016\/B978-0-12-821751-1.00011-7"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1002\/ana.24362"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1038\/s41591-018-0165-9"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1007\/s13238-017-0499-y"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2016.08.037"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1038\/s41591-018-0166-8"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1126\/sciadv.aav9824"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1038\/nature17989"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2021.109203"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1136\/bjo.68.11.811"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1016\/j.survophthal.2018.03.002"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1002\/ejhf.1138"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1126\/sciadv.abi5657"},{"issue":"6","key":"B36","first-page":"1201","article-title":"Segregation and manifestations of the mtDNA tRNA(Lys) A\u2192G(8344) mutation of myoclonus epilepsy and ragged-red fibers (MERRF) syndrome","volume":"51","author":"Larsson","year":"1992","journal-title":"Am J Hum Genet"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1002\/(SICI)1098-1004(1996)7:3<193::AID-HUMU2>3.0.CO;2-C"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.1086\/316930"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.a.30220"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.1136\/jmg.2005.039339"},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2001265"},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2007.10.007"},{"key":"B43","doi-asserted-by":"publisher","DOI":"10.1038\/ncb3385"},{"key":"B44","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2021.07.016"},{"key":"B45","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2021.109989"},{"key":"B46","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2021.110171"},{"key":"B47","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-018-04392-5"},{"key":"B48","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2021.109911"},{"key":"B49","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20170771"},{"key":"B50","doi-asserted-by":"publisher","DOI":"10.1016\/j.xcrm.2021.100450"},{"key":"B51","doi-asserted-by":"publisher","DOI":"10.1038\/s42003-021-02069-2"},{"key":"B52","doi-asserted-by":"publisher","DOI":"10.1023\/A:1005569711521"},{"key":"B53","doi-asserted-by":"publisher","DOI":"10.1016\/j.ymgme.2004.10.008"},{"key":"B54","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.aau1167"},{"key":"B55","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2021.06.007"},{"key":"B56","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-019-42262-2"},{"key":"B57","doi-asserted-by":"publisher","DOI":"10.1038\/s42003-022-04303-x"},{"key":"B58","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkr984"},{"key":"B59","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-018-0846-z"},{"key":"B60","doi-asserted-by":"publisher","DOI":"10.1093\/molbev\/msac090"},{"key":"B61","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0511137103"},{"key":"B62","doi-asserted-by":"publisher","DOI":"10.1016\/j.it.2009.04.003"},{"key":"B63","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-021-26829-0"},{"key":"B64","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-020-18174-5"},{"key":"B65","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1300424"},{"key":"B66","doi-asserted-by":"publisher","DOI":"10.1016\/j.cellimm.2022.104516"},{"key":"B67","doi-asserted-by":"publisher","DOI":"10.3791\/51301"},{"key":"B68","doi-asserted-by":"publisher","DOI":"10.1016\/j.xcrm.2021.100252"},{"key":"B69","doi-asserted-by":"publisher","DOI":"10.1111\/joim.13304"},{"key":"B70","doi-asserted-by":"publisher","DOI":"10.1111\/imcb.12228"},{"key":"B71","doi-asserted-by":"publisher","DOI":"10.1186\/1471-2105-6-225"}],"container-title":["JCI Insight"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/insight.jci.org\/articles\/view\/167656\/files\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,5,18]],"date-time":"2026-05-18T21:49:05Z","timestamp":1779140945000},"score":1,"resource":{"primary":{"URL":"https:\/\/insight.jci.org\/articles\/view\/167656"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,9,8]]},"references-count":71,"journal-issue":{"issue":"17","published-online":{"date-parts":[[2023,9,8]]},"published-print":{"date-parts":[[2023,9,8]]}},"alternative-id":["10.1172\/jci.insight.167656"],"URL":"https:\/\/doi.org\/10.1172\/jci.insight.167656","relation":{},"ISSN":["2379-3708"],"issn-type":[{"value":"2379-3708","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,9,8]]},"article-number":"e167656"}}