Cytochrome c oxidase dependent respiration is essential for T cell activation, proliferation and memory formation

Tatiana N. Tarasenko, Emily Warren, Bharati Singh, Amanda Fuchs, Jose Marin, Marten Szibor, Christopher King and Peter J. McGuire ()
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Tatiana N. Tarasenko: National Institutes of Health, Metabolism, Infection, and Immunity Section, National Human Genome Research Institute
Emily Warren: National Institutes of Health, Metabolism, Infection, and Immunity Section, National Human Genome Research Institute
Bharati Singh: National Institutes of Health, Metabolism, Infection, and Immunity Section, National Human Genome Research Institute
Amanda Fuchs: National Institutes of Health, Metabolism, Infection, and Immunity Section, National Human Genome Research Institute
Jose Marin: National Institutes of Health, Metabolism, Infection, and Immunity Section, National Human Genome Research Institute
Marten Szibor: Faculty of Medicine and Health Technology
Christopher King: National Institutes of Health, Division of Veterinary Recourses
Peter J. McGuire: National Institutes of Health, Metabolism, Infection, and Immunity Section, National Human Genome Research Institute

Nature Communications, 2025, vol. 16, issue 1, 1-16

Abstract: Abstract T cell activation requires extensive metabolic reprogramming, but the specific requirement for mitochondrial respiration (MR) remains unresolved. While most studies have focused on aerobic glycolysis as the primary driver of proliferation and effector function, the role of MR has not been completely defined. To isolate MR from proton pumping by cytochrome c oxidase (COX), we expressed the non-proton-pumping alternative oxidase (AOX) in activated COX-deficient T cells. AOX restored electron flow, membrane potential, and mitochondrial ATP production, ultimately rescuing proliferation, effector and memory differentiation, and antiviral immunity. These improvements required upstream electron input, particularly from Complex I, with Complex II and DHODH contributing more modestly. Despite restored MR, glycolysis remained elevated, likely due to altered redox signaling. These findings demonstrate that MR, normally mediated by COX, is necessary and can be sufficient to support T cell activation and function, independent of proton translocation, provided upstream electron input is maintained.

Date: 2025
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DOI: 10.1038/s41467-025-65910-w

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