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

Abstract

Pyruvate dehydrogenase (PDH) is the gatekeeper enzyme into the tricarboxylic acid (TCA) cycle. Here we show that PARK7/DJ-1, a key familial Parkinson's disease (PD) gene, is a pacemaker controlling PDH activity in CD4 regulatory T cells (Tregs). DJ-1 bound to PDH-E1 beta (PDHB), inhibiting the phosphorylation of PDH-E1 alpha (PDHA), thus promoting PDH activity and oxidative phosphorylation (OXPHOS). Dj-1 depletion impaired Treg proliferation and cellularity maintenance in older mice, increasing the severity during the remission phase of experimental autoimmune encephalomyelitis (EAE). The compromised proliferation and differentiation of Tregs in Dj-1 knockout mice were caused via regulating PDH activity. These findings provide novel insight into the already complicated regulatory machinery of the PDH complex and demonstrate that the DJ-1-PDHB axis represents a potent target to maintain Treg homeostasis, which is dysregulated in many complex diseases.

Extracellularly Detectable Electrochemical Signals of Living Cells Originate from Metabolic Reactions

“…We first supplemented the cells with pyruvate (the end product of glycolysis) because it is a key molecule for the synthesis of citrate [ 33 ] (the first metabolite of the TCA cycle) from oxaloacetate and acetyl‐CoA with the help of pyruvate dehydrogenase (PDH). [ 34 ] As shown in Figure 3B, electrochemical signals were enhanced with increasing pyruvate concentrations. Based on this finding, we added other types of metabolic intermediates, including fatty acids as acetyl‐CoA precursors and glutamine to accelerate alpha‐ketoglutarate ( α ‐KG) synthesis.…”

PARK7/DJ-1 in microglia: implications in Parkinson’s disease and relevance as a therapeutic target

“…Interacts with PINK1 and PARKIN SH-SY5Y, HEK293 SH-SY5Y [183,184] Acts as a redox sensitive chaperone SH-SY5Y, HEK293, Undifferentiated murine ES cells, HeLa, CAD (mouse neuroblastoma cell line) [70] Prevents damage to proteins and metabolites caused by 1,3-biphosphoglycerate HCT 116 (human colon cancer cell line), Drosophila melanogaster, Schizosaccharomyces pombe, Escherichia coli [185] Autophagy and phagocytosis of α-syn and mitochondria N9 (mouse microglia cell line), primary mouse microglia [71] DJ-1 KO mouse embryonic fibroblasts, DJ-1 KO mouse primary cortical neurons, DJ-1 KO mouse primary lymphoblasts, H1299 [192] DJ-1 KO mouse embryonic fibroblasts, primary human fibroblast from DJ-1 mutated patients (E46D homozygous mutation) [186] Mitochondrial homeostasis DJ-1 KO mouse embryonic fibroblasts, DJ-1 KO mouse primary cortical neurons, DJ-1 KO mouse primary lymphoblasts, H1299 [187] N9 (mouse microglia cell line), primary mouse microglia [71] SN4741 (mouse dopaminergic neuron cell line) [188] Controls metabolic pathways Promote pyruvate dehydrogenase (PDH) activity by binding to PDHE1-β, a component of the PDH complex, inhibiting phosphorylation and thereby promoting oxidative phosphorylation Drosophila melanogaster, DJ-1 deficient SH-SY5Y [189] Aged DJ-1 KO mice [32] Acts as a protease H1299, HEK293, HEK293T [96] DJ-1 crystallography (in silico prediction), (Flp-In)NIH3T3 [99] D2 (mouse mammary gland tumor cell line), HEK293T [190] Lind-Holm Mogensen et al Journal of Neuroinflammation (2023) 20 :95 described in this post-mortem study, which is also similar in iPD post-mortem studies and is in line with the notion that microglia are highly activated by α-syn leading to secretion of neurotoxic substances, including TNF and ROS [105].…”

“…This review will recapitulate the role of microglia in PD and specifically the genetic form of PD associated with the loss of DJ-1, an important protein involved in protection against oxidative stress. Recent advances have led to the discovery of a large variety of functions of DJ-1, both in the CNS [ 30 ] and peripheral immune functions [ 31 , 32 ]. However, the large majority of studies have focused on DJ-1’s involvement in PD pathogenesis and the demise of dopaminergic neurons.…”

Cuproptosis and cuproptosis–related genes in rheumatoid arthritis: Implication, prospects, and perspectives

“…PDHB has been identified as a susceptibility gene for RA and its expression is downregulated in various tissues and cells ( 28 ). Deglycase DJ-1 was found to bind PDHB in Tregs, inhibit PDHA phosphorylation, and promote PDH activity and oxidative phosphorylation to maintain Treg cell differentiation and the functional integrity of T cells ( 29 ). In addition, PDHB has also been studied in various tumor cells.…”