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

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. We analyzed Tregs (CD4+CD25high) isolated from the spleen of old DJ-1 knockout (KO) mice vs. age- and gender-matched WT littermates (3 WT, 3 KO) using the Affymetrix Mouse Gene 2.0 ST Array. RNA samples of Tregs sorted from 45-weeks old DJ-1-/- mice and DJ-1+/+ littermates using BD FACSAria III, were analysed at EMBL Genomics Core Facility (Heidelberg. Germany). Array data was processed by Affymetrix Expression Console v1.4 using Exon-level analysis. No techinical replicates were performed.