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.

丙酮酸脱氢酶 (PDH) 是三羧酸 (TCA) 循环的看门人酶。在这里，我们显示去糖酶 DJ-1（由PARK7编码，一种关键的家族性帕金森病基因）是调节 CD4 ⁺调节性 T 细胞（T _reg细胞）中 PDH 活性的起搏器。DJ-1 与 PDHE1-β (PDHB) 结合，抑制 PDHE1-α (PDHA) 的磷酸化，从而促进 PDH 活性和氧化磷酸化 (OXPHOS)。Park7 ( Dj-1 ) 缺失会损害年轻小鼠的T _{reg存活并降低 T reg}仅在老年小鼠中的稳态增殖和细胞结构。这导致实验性自身免疫性脑脊髓炎 (EAE) 缓解期间老年小鼠的严重程度增加。Dj-1缺失也会损害诱导型 T _reg细胞的分化，尤其是在老年小鼠中，并且通过调节 PDHB 发生损伤。这些发现为 PDH 复合体的复杂监管机制提供了不可预见的洞察力。由于 T _reg稳态在许多复杂疾病中失调，DJ-1-PDHB 轴代表了维持或重建 T _reg稳态的潜在目标。