{"doi":"10.1172/jci194134","title":"Mitochondrial complex II orchestrates divergent effects in CD4+ and CD8+ T cells","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.","journal":"Journal of Clinical Investigation","year":2025,"id":585366,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9523,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":952380,"name":"Alec Chu","orcid":"0000-0003-3337-7421","position":1,"is_corresponding":false},{"id":1499152,"name":"Y. Sumii","orcid":null,"position":2,"is_corresponding":false},{"id":1498734,"name":"Takashi Ikeda","orcid":"0000-0001-9844-5996","position":3,"is_corresponding":false},{"id":1498735,"name":"Meng-Chih Wu","orcid":"0009-0006-1204-7887","position":4,"is_corresponding":false},{"id":395519,"name":"Laure Maneix","orcid":"0000-0003-0044-5395","position":5,"is_corresponding":false},{"id":708422,"name":"Dongchang Zhao","orcid":null,"position":6,"is_corresponding":false},{"id":1498736,"name":"Yaping Sun","orcid":"0000-0001-9910-443X","position":7,"is_corresponding":false},{"id":108226,"name":"Marcin Cieślik","orcid":"0000-0002-5467-1040","position":8,"is_corresponding":false},{"id":385969,"name":"Pavan Reddy","orcid":"0000-0001-7264-8429","position":9,"is_corresponding":false},{"id":646484,"name":"Keisuke Seike","orcid":"0000-0002-3484-0265","position":0,"is_corresponding":true}],"reference_count":38,"raw_metadata":null,"created_at":"2026-07-19T02:59:20.067334Z","pmid":"41392980","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}