Sodium perturbs mitochondrial respiration and induces dysfunctional Tregs

Beatriz F. Côrte-Real, Ibrahim Hamad, Rebeca Arroyo Hornero, Sabrina Geisberger, Joris Roels, Lauren Van Zeebroeck, Aleksandra Dyczko, Marike W. van Gisbergen, Henry Kurniawan, Allon Wagner, Nir Yosef, Susanne N.Y. Weiss, Klaus G. Schmetterer, Agnes Schröder, Luka Krampert, Stefanie Haase, Hendrik Bartolomaeus, Niels Hellings, Yvan Saeys, Ludwig J. DuboisDirk Brenner, Stefan Kempa, David A. Hafler, Johannes Stegbauer, Ralf A. Linker, Jonathan Jantsch, Dominik N. Müller, Markus Kleinewietfeld*

*Corresponding author for this work

Research output: Contribution to journalArticleResearchpeer-review

12 Citations (Scopus)

Abstract

FOXP3+ regulatory T cells (Tregs) are central for peripheral tolerance, and their deregulation is associated with autoimmunity. Dysfunctional autoimmune Tregs display pro-inflammatory features and altered mitochondrial metabolism, but contributing factors remain elusive. High salt (HS) has been identified to alter immune function and to promote autoimmunity. By investigating longitudinal transcriptional changes of human Tregs, we identified that HS induces metabolic reprogramming, recapitulating features of autoimmune Tregs. Mechanistically, extracellular HS raises intracellular Na+, perturbing mitochondrial respiration by interfering with the electron transport chain (ETC). Metabolic disturbance by a temporary HS encounter or complex III blockade rapidly induces a pro-inflammatory signature and FOXP3 downregulation, leading to long-term dysfunction in vitro and in vivo. The HS-induced effect could be reversed by inhibition of mitochondrial Na+/Ca2+ exchanger (NCLX). Our results indicate that salt could contribute to metabolic reprogramming and that short-term HS encounter perturb metabolic fitness and long-term function of human Tregs with important implications for autoimmunity.

Original languageEnglish
Pages (from-to)299-315.e8
JournalCell Metabolism
Volume35
Issue number2
DOIs
Publication statusPublished - 7 Feb 2023

Keywords

  • autoimmunity
  • FOXP3
  • high salt
  • mitochondrial respiration
  • regulatory T cells

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