title: Fine-Tuning of CD8(+) T Cell Mitochondrial Metabolism by the Respiratory Chain Repressor MCJ Dictates Protection to Influenza Virus.
abstract: Mitochondrial respiration is regulated in CD8(+) T cells during the transition from naive to effector and memory cells, but mechanisms controlling this process have not been defined. Here we show that MCJ (methylation-controlled J protein) acted as an endogenous break for mitochondrial respiration in CD8(+) T cells by interfering with the formation of electron transport chain respiratory supercomplexes. Metabolic profiling revealed enhanced mitochondrial metabolism in MCJ-deficient CD8(+) T cells. Increased oxidative phosphorylation and subcellular ATP accumulation caused by MCJ deficiency selectively increased the secretion, but not expression, of interferon-γ. MCJ also adapted effector CD8(+) T cell metabolism during the contraction phase. Consequently, memory CD8(+) T cells lacking MCJ provided superior protection against influenza virus infection. Thus, MCJ offers a mechanism for fine-tuning CD8(+) T cell mitochondrial metabolism as an alternative to modulating mitochondrial mass, an energetically expensive process. MCJ could be a therapeutic target to enhance CD8(+) T cell responses.
authors.affiliation: Program in Immunobiology, Department of Medicine, University of Vermont, Burlington, Vermont, 05405 USA.
authors.forename: Devin P
authors.initials: DP
authors.lastname: Champagne
authors.affiliation: Program in Immunobiology, Department of Medicine, University of Vermont, Burlington, Vermont, 05405 USA.
authors.forename: Ketki M
authors.initials: KM
authors.lastname: Hatle
authors.affiliation: Program in Immunobiology, Department of Medicine, University of Vermont, Burlington, Vermont, 05405 USA.
authors.forename: Karen A
authors.initials: KA
authors.lastname: Fortner
authors.affiliation: Department of Biochemistry and Molecular Genetics, University of Colorado Denver, Aurora, CO 80045, USA.
authors.forename: Angelo
authors.initials: A
authors.lastname: D'Alessandro
authors.affiliation: Program in Immunobiology, Department of Medicine, University of Vermont, Burlington, Vermont, 05405 USA.
authors.forename: Tina M
authors.initials: TM
authors.lastname: Thornton
authors.affiliation: Program in Immunobiology, Department of Medicine, University of Vermont, Burlington, Vermont, 05405 USA.
authors.forename: Rui
authors.initials: R
authors.lastname: Yang
authors.affiliation: Program in Immunobiology, Department of Medicine, University of Vermont, Burlington, Vermont, 05405 USA.
authors.forename: Daniel
authors.initials: D
authors.lastname: Torralba
authors.affiliation: Center for Cooperative Research in Biosciences (CIC bioGUNE), Derio 48160 Bizkaia, Spain.
authors.forename: Julen
authors.initials: J
authors.lastname: Tomás-Cortázar
authors.affiliation: Department of Chemistry, Center for Electro-Photo Behaviors in Advanced Molecular Systems, Pohang University of Science and Technology (POSTECH), Nam-Gu, Pohang, 790-784 Gyeongbuk, Republic of Korea.
authors.forename: Yong Woong
authors.initials: YW
authors.lastname: Jun
authors.affiliation: Department of Chemistry, Center for Electro-Photo Behaviors in Advanced Molecular Systems, Pohang University of Science and Technology (POSTECH), Nam-Gu, Pohang, 790-784 Gyeongbuk, Republic of Korea.
authors.forename: Kyo Han
authors.initials: KH
authors.lastname: Ahn
authors.affiliation: Department of Biochemistry and Molecular Genetics, University of Colorado Denver, Aurora, CO 80045, USA.
authors.forename: Kirk C
authors.initials: KC
authors.lastname: Hansen
authors.affiliation: Center on Aging and Department of Immunology, University of Connecticut Health Center, Farmington, CT 06030 USA.
authors.forename: Laura
authors.initials: L
authors.lastname: Haynes
authors.affiliation: Center for Cooperative Research in Biosciences (CIC bioGUNE), Derio 48160 Bizkaia, Spain; Ikerbasque, Basque Foundation for Science, Bilbao, Bizkaia, Spain.
authors.forename: Juan
authors.initials: J
authors.lastname: Anguita
authors.affiliation: Program in Immunobiology, Department of Medicine, University of Vermont, Burlington, Vermont, 05405 USA. Electronic address: mrincon@uvm.edu.
authors.forename: Mercedes
authors.initials: M
authors.lastname: Rincon
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000502:physiology*; D019069:Cell Respiration; D002478:Cells, Cultured; D045222:Electron Transport Chain Complex Proteins / Q000378:metabolism*; D007156:Immunologic Memory; D007371:Interferon-gamma / Q000378:metabolism; D008213:Lymphocyte Activation; D055442:Metabolome; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008928:Mitochondria / Q000378:metabolism*; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism*; D018832:Molecular Chaperones / Q000235:genetics / Q000378:metabolism*; D009975:Orthomyxoviridae / Q000276:immunology*; D009976:Orthomyxoviridae Infections / Q000276:immunology*; D010085:Oxidative Phosphorylation
chemical_list: D045222:Electron Transport Chain Complex Proteins; C582292:Mcj protein, mouse; D024101:Mitochondrial Proteins; D018832:Molecular Chaperones; D007371:Interferon-gamma; D000255:Adenosine Triphosphate