PARK7/DJ-1 promotes pyruvate dehydrogenase activity and maintains T(reg) homeostasis during ageing.

Aging; Animals; Homeostasis; Mice; Oxidoreductases/metabolism; Parkinson Disease/enzymology/genetics/metabolism; Protein Deglycase DJ-1/genetics; Pyruvates/metabolism; T-Lymphocytes, Regulatory/metabolism

Abstract :

[en] 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 (T(reg) 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 T(reg) survival starting in young mice and reduces T(reg) 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 T(reg) 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 T(reg) homeostasis is dysregulated in many complex diseases, the DJ-1-PDHB axis represents a potential target to maintain or re-establish T(reg) homeostasis.

Disciplines :

Neurology

Author, co-author :

Danileviciute, Egle

Zeng, Ni

Capelle, Christophe M.

Paczia, Nicole

Gillespie, Mark A.

Kurniawan, Henry ; University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > Developmental and Cellular Biology

Benzarti, Mohaned

Merz, Myriam P.

Coowar, Djalil ; University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > Scientific Central Services

Fritah, Sabrina

More authors (20 more)

External co-authors :

yes

Language :

English

Title :

PARK7/DJ-1 promotes pyruvate dehydrogenase activity and maintains T(reg) homeostasis during ageing.

Publication date :

26 May 2022

Journal title :

Nature Metabolism

ISSN :

2522-5812

Publisher :

Springer Nature, Berlin, Germany

Volume :

Issue :

Pages :

589-607

Peer reviewed :

Peer Reviewed verified by ORBi

Focus Area :

Systems Biomedicine

Commentary :

Available on ORBilu :

since 20 January 2023

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