Language
English
Publication Date
12-15-2025
Journal
Journal of Clinical Investigation
DOI
10.1172/JCI194134
PMID
41392980
PMCID
PMC12700539
PubMedCentral® Posted Date
12-15-2025
PubMedCentral® Full Text Version
Post-print
Abstract
Mitochondrial metabolism orchestrates T cell functions, yet the role of specific mitochondrial components in distinct T cell subsets remains poorly understood. Here, we explored the role of mitochondrial complex II (MC II), the only complex from the electron transport chain (ETC) that plays a role in both ETC and metabolism, in regulating T cell functions. Surprisingly, MC II exerts divergent effects on CD4+ and CD8+ T cell activation and function. Using T cell-specific MC II subunit, succinate dehydrogenase A-deficient (SDHA-deficient) mice, we integrated single-cell RNA-seq and metabolic profiling, with in vitro and in vivo T cell functional assays to illuminate these differences. SDHA deficiency induced metabolic changes and remodeled gene expression exclusively in activated T cells. In CD4+ T cells, SDHA loss dampened both oxidative phosphorylation (OXPHOS) and glycolysis, impaired cytokine production, proliferation, and reduced CD4+ T cell-mediated graft-versus-host disease after allogeneic stem cell transplantation (SCT). In contrast, SDHA deficiency in CD8+ T cells reduced OXPHOS but paradoxically upregulated glycolysis and demonstrated enhanced cytotoxic functions in vitro and in vivo. This metabolic reprogramming endowed SDHA-KO CD8+ T cells with superior in vivo antitumor efficacy after immune checkpoint inhibitor therapy and allogeneic SCT. These findings reveal MC II as a bifurcation point for metabolic and functional specialization in CD4+ and CD8+ T cells.
Keywords
Animals, CD8-Positive T-Lymphocytes, Mice, CD4-Positive T-Lymphocytes, Electron Transport Complex II, Mice, Knockout, Oxidative Phosphorylation, Mitochondria, Succinate Dehydrogenase, Graft vs Host Disease, Glycolysis, Lymphocyte Activation, Hematology, Immunology, Metabolism, Bone marrow transplantation, Mitochondria, T cells
Published Open-Access
yes
Recommended Citation
Seike, Keisuke; Chu, Shih-Chun A; Sumii, Yuichi; et al., "Mitochondrial Complex II Orchestrates Divergent Effects in CD4+ and CD8+ T Cells" (2025). Faculty, Staff and Students Publications. 6364.
https://digitalcommons.library.tmc.edu/baylor_docs/6364