Mitochondrial Dynamics Controls T Cell Fate through Metabolic Programming.
Activated effector T (TE) cells augment anabolic pathways of metabolism, such as aerobic glycolysis, while memory T (TM) cells engage catabolic pathways, like fatty acid oxidation (FAO). However, signals that drive these differences remain unclear. Mitochondria are metabolic organelles that actively transform their ultrastructure. Therefore, we questioned whether mitochondrial dynamics controls T cell metabolism. We show that TE cells have punctate mitochondria, while TM cells maintain fused networks. The fusion protein Opa1 is required for TM, but not TE cells after infection, and enforcing fusion in TE cells imposes TM cell characteristics and enhances antitumor function. Our data suggest that, by altering cristae morphology, fusion in TM cells configures electron transport chain (ETC) complex associations favoring oxidative phosphorylation (OXPHOS) and FAO, while fission in TE cells leads to cristae expansion, reducing ETC efficiency and promoting aerobic glycolysis. Thus, mitochondrial remodeling is a signaling mechanism that instructs T cell metabolic programming.
Department of Immunometabolism, Max Planck Institute of Immunobiology and Epigenetics, 79108 Freiburg, Germany; Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA.
Michael D
MD
Buck
Department of Immunometabolism, Max Planck Institute of Immunobiology and Epigenetics, 79108 Freiburg, Germany.
David
D
O'Sullivan
Department of Immunometabolism, Max Planck Institute of Immunobiology and Epigenetics, 79108 Freiburg, Germany.
Ramon I
RI
Klein Geltink
Department of Immunometabolism, Max Planck Institute of Immunobiology and Epigenetics, 79108 Freiburg, Germany.
Jonathan D
JD
Curtis
Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA.
Chih-Hao
CH
Chang
Department of Immunometabolism, Max Planck Institute of Immunobiology and Epigenetics, 79108 Freiburg, Germany.
David E
DE
Sanin
Department of Immunometabolism, Max Planck Institute of Immunobiology and Epigenetics, 79108 Freiburg, Germany; Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA.
Jing
J
Qiu
Renal Division, University Medical Center Freiburg, 79106 Freiburg, Germany; Department of Neuroanatomy, University of Freiburg, 79104 Freiburg, Germany.
Oliver
O
Kretz
University of California Los Angeles Metabolomics Center, Los Angeles, CA 90095, USA.
Daniel
D
Braas
Academic Medical Center, 1105 AZ Amsterdam, the Netherlands.
Gerritje J W
GJ
van der Windt
Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA.
Qiongyu
Q
Chen
Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA.
Stanley Ching-Cheng
SC
Huang
Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA.
Christina M
CM
O'Neill
Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA.
Brian T
BT
Edelson
Department of Immunometabolism, Max Planck Institute of Immunobiology and Epigenetics, 79108 Freiburg, Germany; Faculty of Biology, University of Freiburg, 79104 Freiburg, Germany.
Edward J
EJ
Pearce
Department of Cell Biology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Hiromi
H
Sesaki
Renal Division, University Medical Center Freiburg, 79106 Freiburg, Germany; BIOSS Centre for Biological Signaling Studies, 79104 Freiburg, Germany.
Tobias B
TB
Huber
Center for Chronic Immunodeficiency, University Medical Center Freiburg and University of Freiburg, 79106 Freiburg, Germany; Department of Developmental Immunology, Max Planck Institute of Immunobiology and Epigenetics, 79108 Freiburg, Germany.
Angelika S
AS
Rambold
Department of Immunometabolism, Max Planck Institute of Immunobiology and Epigenetics, 79108 Freiburg, Germany. Electronic address: pearce@ie-freiburg.mpg.de.
Erika L
EL
Pearce
D000818:Animals; D002454:Cell Differentiation; D004579:Electron Transport; D005227:Fatty Acids / Q000378:metabolism; D020558:GTP Phosphohydrolases / Q000378:metabolism; D006019:Glycolysis; D006801:Humans; D007156:Immunologic Memory; D051379:Mice; D008810:Mice, Inbred C57BL; D063154:Mitochondrial Dynamics; D010084:Oxidation-Reduction; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000166:cytology* / Q000276:immunology / Q000378:metabolism*
D005227:Fatty Acids; D020558:GTP Phosphohydrolases; C498809:Opa1 protein, mouse