title: Mitochondrial Biogenesis and Proteome Remodeling Promote One-Carbon Metabolism for T Cell Activation.
abstract: Naive T cell stimulation activates anabolic metabolism to fuel the transition from quiescence to growth and proliferation. Here we show that naive CD4(+) T cell activation induces a unique program of mitochondrial biogenesis and remodeling. Using mass spectrometry, we quantified protein dynamics during T cell activation. We identified substantial remodeling of the mitochondrial proteome over the first 24 hr of T cell 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 T cell proliferation and survival. Genetic inhibition of the mitochondrial serine catabolic enzyme SHMT2 impaired T cell survival in culture and antigen-specific T cell abundance in vivo. Thus, during T cell activation, mitochondrial proteome remodeling generates specialized mitochondria with enhanced one-carbon metabolism that is critical for T cell activation and survival.
authors.affiliation: Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Noga
authors.initials: N
authors.lastname: Ron-Harel
authors.affiliation: Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA; CNC-Center for Neuroscience and Cell Biology, University of Coimbra, 3004-504 Coimbra, Portugal.
authors.forename: Daniel
authors.initials: D
authors.lastname: Santos
authors.affiliation: The Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, NJ 08544, USA; Department of Molecular Biology, Princeton University, Princeton, NJ 08544, USA.
authors.forename: Jonathan M
authors.initials: JM
authors.lastname: Ghergurovich
authors.affiliation: Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA 02115, USA; Department of Pathology, Brigham and Women's Hospital, Boston, MA 02115, USA.
authors.forename: Peter T
authors.initials: PT
authors.lastname: Sage
authors.affiliation: Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Anita
authors.initials: A
authors.lastname: Reddy
authors.affiliation: Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA 02115, USA; Department of Pathology, Brigham and Women's Hospital, Boston, MA 02115, USA.
authors.forename: Scott B
authors.initials: SB
authors.lastname: Lovitch
authors.affiliation: Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Noah
authors.initials: N
authors.lastname: Dephoure
authors.affiliation: Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: F Kyle
authors.initials: FK
authors.lastname: Satterstrom
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Michal
authors.initials: M
authors.lastname: Sheffer
authors.affiliation: Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Jessica B
authors.initials: JB
authors.lastname: Spinelli
authors.affiliation: Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Steven
authors.initials: S
authors.lastname: Gygi
authors.affiliation: The Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, NJ 08544, USA; Department of Chemistry, Princeton University, Princeton, NJ 08544, USA.
authors.forename: Joshua D
authors.initials: JD
authors.lastname: Rabinowitz
authors.affiliation: Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA 02115, USA; Department of Pathology, Brigham and Women's Hospital, Boston, MA 02115, USA.
authors.forename: Arlene H
authors.initials: AH
authors.lastname: Sharpe
authors.affiliation: Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA. Electronic address: marcia_haigis@hms.harvard.edu.
authors.forename: Marcia C
authors.initials: MC
authors.lastname: Haigis
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism; D002244:Carbon / Q000378:metabolism*; D002470:Cell Survival; D004734:Energy Metabolism; D000939:Epitopes; D008213:Lymphocyte Activation / Q000276:immunology*; D053858:Metabolic Networks and Pathways; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000378:metabolism; D001678:Organelle Biogenesis; D020543:Proteome / Q000378:metabolism*; D040901:Proteomics; D011743:Pyrimidines / Q000096:biosynthesis; D013601:T-Lymphocytes / Q000378:metabolism*
chemical_list: D000939:Epitopes; D020543:Proteome; D011743:Pyrimidines; D002244:Carbon; C030986:pyrimidine