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

Tatyana N. Tarasenko, Susan E. Pacheco, Mary Kay Koenig, Julio Gomez-Rodriguez, Senta M. Kapnick, Francisca Diaz, Patricia M. Zerfas, Emanuele Barca, Jessica Sudderth, Ralph J. DeBerardinis, Raul Covian, Robert S. Balaban, Salvatore DiMauro, Peter J. McGuire

Research output: Contribution to journalArticle

34 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1254-1268.e7
JournalCell Metabolism
Volume25
Issue number6
DOIs
StatePublished - Jun 6 2017

Keywords

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

ASJC Scopus subject areas

  • Physiology
  • Molecular Biology
  • Cell Biology

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    Tarasenko, T. N., Pacheco, S. E., Koenig, M. K., Gomez-Rodriguez, J., Kapnick, S. M., Diaz, F., Zerfas, P. M., Barca, E., Sudderth, J., DeBerardinis, R. J., Covian, R., Balaban, R. S., DiMauro, S., & McGuire, P. J. (2017). Cytochrome c Oxidase Activity Is a Metabolic Checkpoint that Regulates Cell Fate Decisions During T Cell Activation and Differentiation. Cell Metabolism, 25(6), 1254-1268.e7. https://doi.org/10.1016/j.cmet.2017.05.007