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

22 Citations (Scopus)

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

Fingerprint

Electron Transport Complex IV
Cell Differentiation
Mitochondrial Diseases
T-Lymphocytes
T-Lymphocyte Subsets
Energy Metabolism
Oxidoreductases
Gene Targeting
Oxidative Phosphorylation
Apoptosis
Infection

Keywords

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

ASJC Scopus subject areas

  • Physiology
  • Molecular Biology
  • Cell Biology

Cite this

Tarasenko, T. N., Pacheco, S. E., Koenig, M. K., Gomez-Rodriguez, J., Kapnick, S. M., Diaz, F., ... 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

Cytochrome c Oxidase Activity Is a Metabolic Checkpoint that Regulates Cell Fate Decisions During T Cell Activation and Differentiation. / Tarasenko, Tatyana N.; Pacheco, Susan E.; Koenig, Mary Kay; Gomez-Rodriguez, Julio; Kapnick, Senta M.; Diaz, Francisca; Zerfas, Patricia M.; Barca, Emanuele; Sudderth, Jessica; DeBerardinis, Ralph J.; Covian, Raul; Balaban, Robert S.; DiMauro, Salvatore; McGuire, Peter J.

In: Cell Metabolism, Vol. 25, No. 6, 06.06.2017, p. 1254-1268.e7.

Research output: Contribution to journalArticle

Tarasenko, TN, Pacheco, SE, Koenig, MK, Gomez-Rodriguez, J, Kapnick, SM, Diaz, F, Zerfas, PM, Barca, E, Sudderth, J, DeBerardinis, RJ, Covian, R, Balaban, RS, DiMauro, S & McGuire, PJ 2017, 'Cytochrome c Oxidase Activity Is a Metabolic Checkpoint that Regulates Cell Fate Decisions During T Cell Activation and Differentiation', Cell Metabolism, vol. 25, no. 6, pp. 1254-1268.e7. https://doi.org/10.1016/j.cmet.2017.05.007
Tarasenko, Tatyana N. ; Pacheco, Susan E. ; Koenig, Mary Kay ; Gomez-Rodriguez, Julio ; Kapnick, Senta M. ; Diaz, Francisca ; Zerfas, Patricia M. ; Barca, Emanuele ; Sudderth, Jessica ; DeBerardinis, Ralph J. ; Covian, Raul ; Balaban, Robert S. ; DiMauro, Salvatore ; McGuire, Peter J. / Cytochrome c Oxidase Activity Is a Metabolic Checkpoint that Regulates Cell Fate Decisions During T Cell Activation and Differentiation. In: Cell Metabolism. 2017 ; Vol. 25, No. 6. pp. 1254-1268.e7.
@article{16a9ebbf4422488cbf7348c17910e073,
title = "Cytochrome c Oxidase Activity Is a Metabolic Checkpoint that Regulates Cell Fate Decisions During T Cell Activation and Differentiation",
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, cytochrome c oxidase, immunometabolism, mitochondria, mitochondrial disease, oxidative phosphorylation, T-lymphocytes",
author = "Tarasenko, {Tatyana N.} and Pacheco, {Susan E.} and Koenig, {Mary Kay} and Julio Gomez-Rodriguez and Kapnick, {Senta M.} and Francisca Diaz and Zerfas, {Patricia M.} and Emanuele Barca and Jessica Sudderth and DeBerardinis, {Ralph J.} and Raul Covian and Balaban, {Robert S.} and Salvatore DiMauro and McGuire, {Peter J.}",
year = "2017",
month = "6",
day = "6",
doi = "10.1016/j.cmet.2017.05.007",
language = "English (US)",
volume = "25",
pages = "1254--1268.e7",
journal = "Cell Metabolism",
issn = "1550-4131",
publisher = "Cell Press",
number = "6",

}

TY - JOUR

T1 - Cytochrome c Oxidase Activity Is a Metabolic Checkpoint that Regulates Cell Fate Decisions During T Cell Activation and Differentiation

AU - Tarasenko, Tatyana N.

AU - Pacheco, Susan E.

AU - Koenig, Mary Kay

AU - Gomez-Rodriguez, Julio

AU - Kapnick, Senta M.

AU - Diaz, Francisca

AU - Zerfas, Patricia M.

AU - Barca, Emanuele

AU - Sudderth, Jessica

AU - DeBerardinis, Ralph J.

AU - Covian, Raul

AU - Balaban, Robert S.

AU - DiMauro, Salvatore

AU - McGuire, Peter J.

PY - 2017/6/6

Y1 - 2017/6/6

N2 - 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.

AB - 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.

KW - COX10

KW - cytochrome c oxidase

KW - immunometabolism

KW - mitochondria

KW - mitochondrial disease

KW - oxidative phosphorylation

KW - T-lymphocytes

UR - http://www.scopus.com/inward/record.url?scp=85020251212&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85020251212&partnerID=8YFLogxK

U2 - 10.1016/j.cmet.2017.05.007

DO - 10.1016/j.cmet.2017.05.007

M3 - Article

VL - 25

SP - 1254-1268.e7

JO - Cell Metabolism

JF - Cell Metabolism

SN - 1550-4131

IS - 6

ER -