Mitochondrial Biogenesis and Proteome Remodeling Promote One-Carbon Metabolism for T Cell Activation

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Naive Tcell stimulation activates anabolic metabolism to fuel the transition from quiescence to growth and proliferation. Here we show that naive CD4(+) Tcell activation induces a unique program of mitochondrial biogenesis and remodeling. Using mass spectrometry, we quantified protein dynamics during Tcell activation. We identified substantial remodeling of the mitochondrial proteome over the first 24hr of Tcell activation to generate mitochondria with a distinct metabolic signature, with one-carbon metabolism as the most induced pathway. Salvage pathways and mitochondrial one-carbon metabolism, fed by serine, contribute to purine and thymidine synthesis to enable Tcell proliferation and survival. Genetic inhibition of the mitochondrial serine catabolic enzyme SHMT2 impaired Tcell survival in culture and antigen-specific Tcell abundance invivo. Thus, during Tcell activation, mitochondrial proteome remodeling generates specialized mitochondria with enhanced one-carbon metabolism that is critical for Tcell activation and survival.