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Cell Metab. 2017 Jun 6;25(6):1254-1268.e7. doi: 10.1016/j.cmet.2017.05.007.

Cytochrome c Oxidase Activity Is a Metabolic Checkpoint that Regulates Cell Fate Decisions During T Cell Activation and Differentiation.

Author information

1
Metabolism, Infection, and Immunity Section, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, USA.
2
Department of Pediatrics, The University of Texas Health Science Center, Houston, TX 77030, USA.
3
Cell Signaling and Immunity Section, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, USA.
4
Department of Neurology, University of Miami Miller School of Medicine, Miami, FL 33136, USA.
5
Office of Research Services, Division of Veterinary Resources, National Institutes of Health, Bethesda, MD 20892, USA.
6
Department of Neurology, Columbia University Medical Center, New York, NY 10032, USA.
7
Children's Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
8
Laboratory of Cardiac Energetics, National Heart Lung and Blood Institute, National Institutes of Health, Bethesda, MD 20892, USA.
9
Metabolism, Infection, and Immunity Section, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, USA. Electronic address: peter.mcguire@nih.gov.

Abstract

T cells undergo metabolic reprogramming with major changes in cellular energy metabolism during activation. In patients with mitochondrial disease, clinical data were marked by frequent infections and immunodeficiency, prompting us to explore the consequences of oxidative phosphorylation dysfunction in T cells. Since cytochrome c oxidase (COX) is a critical regulator of OXPHOS, we created a mouse model with isolated dysfunction in T cells by targeting a gene, COX10, that produces mitochondrial disease in humans. COX dysfunction resulted in increased apoptosis following activation in vitro and immunodeficiency in vivo. Select T cell effector subsets were particularly affected; this could be traced to their bioenergetic requirements. In summary, the findings presented herein emphasize the role of COX particularly in T cells as a metabolic checkpoint for cell fate decisions following T cell activation, with heterogeneous effects in T cell subsets. In addition, our studies highlight the utility of translational models that recapitulate human mitochondrial disease for understanding immunometabolism.

KEYWORDS:

COX10; T-lymphocytes; cytochrome c oxidase; immunometabolism; mitochondria; mitochondrial disease; oxidative phosphorylation

PMID:
28591633
PMCID:
PMC5562283
DOI:
10.1016/j.cmet.2017.05.007
[Indexed for MEDLINE]
Free PMC Article

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