{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,8]],"date-time":"2026-11-08T00:34:02Z","timestamp":1794098042928,"version":"4.8.0"},"reference-count":85,"publisher":"National Academy of Sciences","issue":"28","license":[{"start":{"date-parts":[[2025,7,8]],"date-time":"2025-07-08T00:00:00Z","timestamp":1751932800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000060","name":"HHS | NIH | National Institute of Allergy and Infectious Diseases","doi-asserted-by":"publisher","award":["U19-AI057229"],"award-info":[{"award-number":["U19-AI057229"]}],"id":[{"id":"10.13039\/100000060","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"HHS | NIH","doi-asserted-by":"publisher","award":["5R01AI139550"],"award-info":[{"award-number":["5R01AI139550"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Khosla family gift fund","award":["NA"],"award-info":[{"award-number":["NA"]}]},{"DOI":"10.13039\/100000011","name":"HHMI","doi-asserted-by":"publisher","award":["NA"],"award-info":[{"award-number":["NA"]}],"id":[{"id":"10.13039\/100000011","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2025,7,15]]},"abstract":"<jats:p>Over 65 million individuals worldwide are estimated to have Long COVID (LC), a complex multisystemic condition marked by fatigue, post-exertional malaise, and other symptoms resembling myalgic encephalomyelitis\/chronic fatigue syndrome (ME\/CFS). With no clinically approved treatments or reliable diagnostic markers, there is an urgent need to define the molecular underpinnings of these conditions. By studying bioenergetic characteristics of peripheral blood lymphocytes in 25 healthy controls, 27 ME\/CFS, and 20 LC donors, we find both ME\/CFS and LC donors exhibit signs of elevated oxidative stress, especially in the memory subset. Using a combination of flow cytometry, RNA-seq, mass spectrometry, and systems chemistry analysis, we observed aberrations in reactive oxygen species (ROS) clearance pathways including elevated glutathione levels, decreases in mitochondrial superoxide dismutase protein levels, and glutathione peroxidase 4\u2013mediated lipid oxidative damage. Strikingly, these redox pathways changes show sex-specific trends. While ME\/CFS females exhibit higher total ROS and mitochondrial calcium levels, males have normal ROS levels, with pronounced mitochondrial lipid oxidative damage. In females, these higher ROS levels correlate with T cell hyperproliferation, consistent with the known role of elevated ROS in initiating proliferation. This hyperproliferation can be attenuated by metformin, suggesting this Food and Drug Administration (FDA)-approved drug as a possible treatment, as also suggested by a recent clinical study of LC patients. Moreover, these results suggest a shared mechanistic basis for the systemic phenotypes of ME\/CFS and LC, which can be detected by quantitative blood cell measurements, and that effective, patient-tailored drugs might be discovered using standard lymphocyte stimulation assays.<\/jats:p>","DOI":"10.1073\/pnas.2426564122","type":"journal-article","created":{"date-parts":[[2025,7,8]],"date-time":"2025-07-08T11:39:52Z","timestamp":1751974792000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":40,"title":["Oxidative stress is a shared characteristic of ME\/CFS and Long COVID"],"prefix":"10.1073","volume":"122","author":[{"given":"Vishnu","family":"Shankar","sequence":"first","affiliation":[{"name":"Program in Immunology, Stanford University School of Medicine","place":["Stanford"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julie","family":"Wilhelmy","sequence":"additional","affiliation":[{"name":"Myalgic Encephalomyelitis\/Chronic Fatigue Syndrome Collaborative Research Center at Stanford, Stanford Genome Technology Center, Stanford University School of Medicine","place":["Palo Alto"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ellis J.","family":"Curtis","sequence":"additional","affiliation":[{"name":"Department of Pathology, Stanford University School of Medicine, Stanford University","place":["Stanford"]},{"name":"Medical Scientist Training Program, University of California San Diego","place":["La Jolla"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Basil","family":"Michael","sequence":"additional","affiliation":[{"name":"Department of Genetics, Stanford University School of Medicine","place":["Stanford"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Layla","family":"Cervantes","sequence":"additional","affiliation":[{"name":"Myalgic Encephalomyelitis\/Chronic Fatigue Syndrome Collaborative Research Center at Stanford, Stanford Genome Technology Center, Stanford University School of Medicine","place":["Palo Alto"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vamsee","family":"Mallajosyula","sequence":"additional","affiliation":[{"name":"Institute of Immunity, Transplantation and Infection, Stanford University","place":["Stanford"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3123-2333","authenticated-orcid":false,"given":"Ronald W.","family":"Davis","sequence":"additional","affiliation":[{"name":"Myalgic Encephalomyelitis\/Chronic Fatigue Syndrome Collaborative Research Center at Stanford, Stanford Genome Technology Center, Stanford University School of Medicine","place":["Palo Alto"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Snyder","sequence":"additional","affiliation":[{"name":"Department of Genetics, Stanford University School of Medicine","place":["Stanford"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4319-1738","authenticated-orcid":false,"given":"Shady","family":"Younis","sequence":"additional","affiliation":[{"name":"Division of Immunology and Rheumatology, Department of Medicine, Stanford University School of Medicine","place":["Stanford"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4385-704X","authenticated-orcid":false,"given":"William H.","family":"Robinson","sequence":"additional","affiliation":[{"name":"Division of Immunology and Rheumatology, Department of Medicine, Stanford University School of Medicine","place":["Stanford"]},{"name":"The Geriatric Research, Education, and Clinical Center, Veterans Affairs Palo Alto Health Care System","place":["Palo Alto"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sadasivan","family":"Shankar","sequence":"additional","affiliation":[{"name":"SLAC National Accelerator Laboratory","place":["Menlo Park"]},{"name":"Materials Science and Engineering, Stanford University","place":["Stanford"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4560-2211","authenticated-orcid":false,"given":"Paul S.","family":"Mischel","sequence":"additional","affiliation":[{"name":"Department of Pathology, Stanford University School of Medicine, Stanford University","place":["Stanford"]},{"name":"Sarafan Chemistry, Engineering and Medicine for Human Health","place":["Stanford"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0513-8733","authenticated-orcid":false,"given":"Hector","family":"Bonilla","sequence":"additional","affiliation":[{"name":"Division of Infectious Diseases and Geographic Medicine, Department of Medicine, Stanford University School of Medicine","place":["Stanford"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark M.","family":"Davis","sequence":"additional","affiliation":[{"name":"Institute of Immunity, Transplantation and Infection, Stanford University","place":["Stanford"]},{"name":"Department of Microbiology and Immunology, Stanford University","place":["Stanford"]},{"name":"HHMI, Stanford University","place":["Stanford"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2025,7,8]]},"reference":[{"key":"e_1_3_4_1_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41579-022-00846-2"},{"key":"e_1_3_4_2_2","doi-asserted-by":"publisher","DOI":"10.1001\/jamanetworkopen.2021.11417"},{"key":"e_1_3_4_3_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pmed.1003773"},{"key":"e_1_3_4_4_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41591-022-01689-3"},{"key":"e_1_3_4_5_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2022.06.008"},{"key":"e_1_3_4_6_2","doi-asserted-by":"publisher","DOI":"10.1177\/01410768211032850"},{"key":"e_1_3_4_7_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.eclinm.2021.101019"},{"key":"e_1_3_4_8_2","author":"Institute of Medicine","year":"2015","unstructured":"Institute of Medicine, Beyond Myalgic Encephalomyelitis\/Chronic Fatigue Syndrome: Redefining an Illness (The National Academies Press, Washington, DC, 2015).","journal-title":"Beyond Myalgic Encephalomyelitis\/Chronic Fatigue Syndrome: Redefining an Illness"},{"key":"e_1_3_4_9_2","doi-asserted-by":"publisher","DOI":"10.1186\/s12967-020-02269-0"},{"key":"e_1_3_4_10_2","first-page":"1","article-title":"Myalgic encephalomyelitis\/chronic fatigue syndrome in adults: United States, 2021\u20132022","volume":"488","author":"Vahratian A.","year":"2023","unstructured":"A. Vahratian, J.-M. S. Lin, J. Bertolli, E. R. Unger, Myalgic encephalomyelitis\/chronic fatigue syndrome in adults: United States, 2021\u20132022. NCHS Data Brief 488, 1\u20136 (2023).","journal-title":"NCHS Data Brief"},{"key":"e_1_3_4_11_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41591-022-01810-6"},{"key":"e_1_3_4_12_2","doi-asserted-by":"publisher","DOI":"10.3390\/healthcare9101290"},{"key":"e_1_3_4_13_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-022-32507-6"},{"key":"e_1_3_4_14_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1607571113"},{"key":"e_1_3_4_15_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1710519114"},{"key":"e_1_3_4_16_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-023-38682-4"},{"key":"e_1_3_4_17_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-023-06651-y"},{"key":"e_1_3_4_18_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41577-023-00904-7"},{"key":"e_1_3_4_19_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2023.09.013"},{"key":"e_1_3_4_20_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ebiom.2023.104851"},{"key":"e_1_3_4_21_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.chom.2023.01.001"},{"key":"e_1_3_4_22_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.chom.2023.01.004"},{"key":"e_1_3_4_23_2","doi-asserted-by":"publisher","DOI":"10.1186\/s12933-022-01579-5"},{"key":"e_1_3_4_24_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-018-28477-9"},{"key":"e_1_3_4_25_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrrheum.2017.172"},{"key":"e_1_3_4_26_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2796.2010.02218.x"},{"key":"e_1_3_4_27_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2016.05.035"},{"key":"e_1_3_4_28_2","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20110367"},{"key":"e_1_3_4_29_2","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.abq1533"},{"key":"e_1_3_4_30_2","doi-asserted-by":"crossref","unstructured":"F. Jahanbani Phenotypic characteristics of peripheral immune cells of Myalgic encephalomyelitis\/chronic fatigue syndrome via transmission electron microscopy: A pilot study. PLoS One 17 e0272703 (2022) 10.1371\/journal.pone.0272703.","DOI":"10.1371\/journal.pone.0272703"},{"key":"e_1_3_4_31_2","doi-asserted-by":"publisher","DOI":"10.1002\/JLB.3MA0322-279RRR"},{"key":"e_1_3_4_32_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0186802"},{"key":"e_1_3_4_33_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2024358118"},{"key":"e_1_3_4_34_2","doi-asserted-by":"publisher","DOI":"10.1089\/ars.2012.5149"},{"key":"e_1_3_4_35_2","unstructured":"Stanford Blood Center Medical History Questionnaire \u2014 Stanford Blood Center. https:\/\/stanfordbloodcenter.org\/medical-history-questionnaire\/. Accessed 15 August 2024."},{"key":"e_1_3_4_36_2","doi-asserted-by":"publisher","DOI":"10.7326\/0003-4819-121-12-199412150-00009"},{"key":"e_1_3_4_37_2","author":"David S.","unstructured":"S. David, M. Bell, The Doctor\u2019s Guide to Chronic Fatigue Syndrome (Balance, 1995).","journal-title":"The Doctor\u2019s Guide to Chronic Fatigue Syndrome"},{"key":"e_1_3_4_38_2","unstructured":"Long COVID Basics. https:\/\/www.cdc.gov\/covid\/long-term-effects\/?CDC_AAref_Val=https:\/\/www.cdc.gov\/coronavirus\/2019-ncov\/long-term-effects\/index.html. Accessed 1 September 2022"},{"key":"e_1_3_4_39_2","doi-asserted-by":"publisher","DOI":"10.1183\/13993003.01494-2020"},{"key":"e_1_3_4_40_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmi.2021.11.002"},{"key":"e_1_3_4_41_2","doi-asserted-by":"crossref","unstructured":"S. V. Sylvester Sex differences in sequelae from COVID-19 infection and in long COVID syndrome: A review. Curr. Med. Res. Opin. 38 1391\u20131399 (2022) 10.1080\/03007995.2022.2081454.","DOI":"10.1080\/03007995.2022.2081454"},{"key":"e_1_3_4_42_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pgph.0001188"},{"key":"e_1_3_4_43_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.redox.2015.08.010"},{"key":"e_1_3_4_44_2","doi-asserted-by":"publisher","DOI":"10.1089\/ars.2011.3999"},{"key":"e_1_3_4_45_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0212193"},{"key":"e_1_3_4_46_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-024-47720-8"},{"key":"e_1_3_4_47_2","doi-asserted-by":"publisher","DOI":"10.1021\/acsinfecdis.0c00288"},{"key":"e_1_3_4_48_2","doi-asserted-by":"publisher","DOI":"10.1016\/0891-5849(94)90129-5"},{"key":"e_1_3_4_49_2","doi-asserted-by":"publisher","DOI":"10.3389\/fphys.2020.00694"},{"key":"e_1_3_4_50_2","doi-asserted-by":"publisher","DOI":"10.1074\/mcp.M114.046508"},{"key":"e_1_3_4_51_2","unstructured":"V. Shankar S. Shankar \u201cA novel computational artificial intelligence framework for complex physical chemical and biological networks\u201d in APS March Meeting Abstracts (Bulletin of the American Physical Society 2021) pp. H71.176."},{"key":"e_1_3_4_52_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.chemphyslip.2008.09.004"},{"key":"e_1_3_4_53_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.freeradbiomed.2017.04.363"},{"key":"e_1_3_4_54_2","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awv132"},{"key":"e_1_3_4_55_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41590-023-01724-6"},{"key":"e_1_3_4_56_2","first-page":"435","article-title":"Lipid droplets and the management of cellular stress","volume":"92","author":"Jarc E.","year":"2019","unstructured":"E. Jarc, T. Petan, Lipid droplets and the management of cellular stress. Yale J. Biol. Med. 92, 435\u2013452 (2019).","journal-title":"Yale J. Biol. Med."},{"key":"e_1_3_4_57_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.it.2018.01.005"},{"key":"e_1_3_4_58_2","doi-asserted-by":"publisher","DOI":"10.4110\/in.2018.18.e14"},{"key":"e_1_3_4_59_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.freeradbiomed.2019.06.004"},{"key":"e_1_3_4_60_2","doi-asserted-by":"publisher","DOI":"10.1002\/eji.201040589"},{"key":"e_1_3_4_61_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2012.10.020"},{"key":"e_1_3_4_62_2","doi-asserted-by":"publisher","DOI":"10.3389\/fphy.2020.604053"},{"key":"e_1_3_4_63_2","doi-asserted-by":"publisher","DOI":"10.1186\/1471-2172-13-71"},{"key":"e_1_3_4_64_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41423-021-00792-8"},{"key":"e_1_3_4_65_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41590-020-0714-5"},{"key":"e_1_3_4_66_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2012.02.009"},{"key":"e_1_3_4_67_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbadis.2019.165621"},{"key":"e_1_3_4_68_2","doi-asserted-by":"publisher","DOI":"10.1016\/S1473-3099(23)00299-2"},{"key":"e_1_3_4_69_2","doi-asserted-by":"publisher","DOI":"10.2337\/dca24-0032"},{"key":"e_1_3_4_70_2","doi-asserted-by":"publisher","DOI":"10.1038\/ncb3064"},{"key":"e_1_3_4_71_2","doi-asserted-by":"publisher","DOI":"10.1021\/acscentsci.7b00028"},{"key":"e_1_3_4_72_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41380-022-01836-9"},{"key":"e_1_3_4_73_2","doi-asserted-by":"publisher","DOI":"10.3233\/CH-180469"},{"key":"e_1_3_4_74_2","doi-asserted-by":"publisher","DOI":"10.3389\/fmed.2023.1187163"},{"key":"e_1_3_4_75_2","doi-asserted-by":"publisher","DOI":"10.1089\/jwh.2021.0411"},{"key":"e_1_3_4_76_2","doi-asserted-by":"publisher","DOI":"10.1038\/nri.2016.90"},{"key":"e_1_3_4_77_2","doi-asserted-by":"publisher","DOI":"10.1038\/gene.2009.12"},{"key":"e_1_3_4_78_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.redox.2013.05.003"},{"key":"e_1_3_4_79_2","doi-asserted-by":"crossref","unstructured":"J. Silva Sex differences in symptomatology and immune profiles of Long COVID. medRxiv [Preprint] (2024). https:\/\/doi.org\/10.1101\/2024.02.29.24303568 (Accessed 1 October 2024).","DOI":"10.1101\/2024.02.29.24303568"},{"key":"e_1_3_4_80_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-024-45107-3"},{"key":"e_1_3_4_81_2","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20061839"},{"key":"e_1_3_4_82_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1118458109"},{"key":"e_1_3_4_83_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.1214935"},{"key":"e_1_3_4_84_2","doi-asserted-by":"crossref","unstructured":"M. P. Murphy L. A. J. O\u2019Neill A break in mitochondrial endosymbiosis as a basis for inflammatory diseases. Nature 626 271\u2013279 (2024) 10.1038\/s41586-023-06866-z.","DOI":"10.1038\/s41586-023-06866-z"},{"key":"e_1_3_4_85_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMc2031364"}],"container-title":["Proceedings of the National Academy of Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pnas.org\/doi\/pdf\/10.1073\/pnas.2426564122","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,7,8]],"date-time":"2025-07-08T11:41:00Z","timestamp":1751974860000},"score":1,"resource":{"primary":{"URL":"https:\/\/pnas.org\/doi\/10.1073\/pnas.2426564122"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,7,8]]},"references-count":85,"journal-issue":{"issue":"28","published-print":{"date-parts":[[2025,7,15]]}},"alternative-id":["10.1073\/pnas.2426564122"],"URL":"https:\/\/doi.org\/10.1073\/pnas.2426564122","relation":{},"ISSN":["0027-8424","1091-6490"],"issn-type":[{"value":"0027-8424","type":"print"},{"value":"1091-6490","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,7,8]]},"assertion":[{"value":"2025-01-02","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-04-13","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-07-08","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e2426564122"}}