PARK7/DJ-1 promotes pyruvate dehydrogenase activity and maintains Treg homeostasis during ageing

Egle Danileviciute, Ni Zeng (Main author), Christophe M. Capelle, Nicole Paczia, Mark A. Gillespie, Henry Kurniawan, Mohaned Benzarti, Myriam P. Merz, Djalil Coowar, Sabrina Fritah, Daniela Maria Vogt Weisenhorn, Gemma Gomez Giro, Melanie Grusdat, Alexandre Baron, Coralie Guerin, Davide G. Franchina, Cathy Léonard, Olivia Domingues, Sylvie Delhalle, Wolfgang WurstJonathan D. Turner, Jens Christian Schwamborn, Johannes Meiser, Rejko Krüger, Jeff Ranish, Dirk Brenner, Carole L. Linster, Rudi Balling, Markus Ollert, Feng Q. Hefeng*

*Corresponding author for this work

Research output: Contribution to journalArticleResearchpeer-review

2 Citations (Scopus)

Abstract

Pyruvate dehydrogenase (PDH) is the gatekeeper enzyme of the tricarboxylic acid (TCA) cycle. Here we show that the deglycase DJ-1 (encoded by PARK7, a key familial Parkinson’s disease gene) is a pacemaker regulating PDH activity in CD4+ regulatory T cells (Treg cells). DJ-1 binds to PDHE1-β (PDHB), inhibiting phosphorylation of PDHE1-α (PDHA), thus promoting PDH activity and oxidative phosphorylation (OXPHOS). Park7 (Dj-1) deletion impairs Treg survival starting in young mice and reduces Treg homeostatic proliferation and cellularity only in aged mice. This leads to increased severity in aged mice during the remission of experimental autoimmune encephalomyelitis (EAE). Dj-1 deletion also compromises differentiation of inducible Treg cells especially in aged mice, and the impairment occurs via regulation of PDHB. These findings provide unforeseen insight into the complicated regulatory machinery of the PDH complex. As Treg homeostasis is dysregulated in many complex diseases, the DJ-1–PDHB axis represents a potential target to maintain or re-establish Treg homeostasis.

Original languageEnglish
Pages (from-to)589-607
Number of pages19
JournalNature Metabolism
Volume4
Issue number5
Early online date26 May 2022
DOIs
Publication statusPublished - May 2022

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