Oxidative stress is a shared characteristic of ME/CFS and Long COVID

• 成果类型: Article
• 署名作者: Shankar, Vishnu; Wilhelmy, Julie; Curtis, Ellis J.; Michael, Basil; Cervantes, Layla; Mallajosyula, Vamsee; Davis, Ronald W.; Snyder, Michael; Younis, Shady; Robinson, William H.; Shankar, Sadasivan; Mischel, Paul S.; Bonilla, Hector; Davis, Mark M.
• 署名单位: Stanford University; Stanford University; Stanford University; University of California System; University of California San Diego; Stanford University; Stanford University; Stanford University; Geriatric Research Education & Clinical Center; Stanford University; United States Department of Energy (DOE); SLAC National Accelerator Laboratory; Stanford University; Stanford University; Stanford University; Howard Hughes Medical Institute; Stanford University
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-8715
• DOI: 10.1073/pnas.2426564122
• 发表日期: 2025-07-15
• 关键词: chronic-fatigue-syndrome; lipid-peroxidation; gut microbiome; inflammation; omics

摘要

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-mediated 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.