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

摘要

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-beta (PDHB), inhibiting phosphorylation of PDHE1-alpha (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. In this work, Danileviciute, Zeng et al. provide new insights into the regulation of the PDH complex by PARK7/DJ-1 and show its relevance in T-reg homeostasis during ageing.