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

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

PROVIDER: PRJNA474438 | ENA |

REPOSITORIES: ENA

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

Project description: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.

2022-04-19 | GSE115269 | GEO

Pyruvate dehydrogenase complex integrates the metabolome and epigenome in memory T cell differentiation in vitro [ATAC-Seq]

Project description:The chromatin landscape was assessed in effector and memory T-cells obtained from wildtype and pyruvate dehydrogenase knockout mouse. Disruption of the metabolic processes involving pyruvate dehydrogenase can affect T-cell differentiation through epigenetic and metabolic mechanisms.

2023-08-07 | GSE231554 | GEO

Mitochondrial carrier homolog 2 (MTCH2) regulates the differentiation of AML cells by controlling pyruvate entry into the mitochondria, nuclear localization of pyruvate dehydrogenase complex and H3 and H4 histone acetylation

Project description:Inhibiting MTCH2 or the Mitochondrial Pyruvate Carrier increased levels of pyruvate and pyruvate dehydrogenase in the nucleus leading to differentiation and loss of stemness in AML.

2020-09-01 | GSE103834 | GEO

Activation of the pyruvate dehydrogenase complex dictates tumour progression in prostate cancer

Project description:Metabolism in cancer serves to provide energy and key biomolecules that sustain cell growth, a process that is frequently accompanied by decreased mitochondrial use of glucose. Importantly, metabolic intermediates including mitochondrial metabolites are central substrates for post-translational modifications at the core of cellular signalling and epigenetics. However, the molecular means that coordinate the use of mitochondrial metabolites for anabolism and nuclear protein modification are poorly understood. Here, we unexpectedly found that genetic and pharmacological inactivation of Pyruvate Dehydrogenase A1 (PDHA1), a subunit of pyruvate dehydrogenase complex (PDC) that regulates mitochondrial metabolism16 inhibits prostate cancer development in different mouse and human xenograft tumour models. Intriguingly, we found that lipid biosynthesis was strongly affected in prostate tumours upon PDC inactivation. Mechanistically, we found that nuclear PDC controls the expression of Sterol regulatory element-binding transcription factor (SREBF) target genes by mediating histone acetylation whereas mitochondrial PDC provides cytosolic citrate for lipid synthesis in a coordinated effort to sustain anabolism. In line with the oncogenic function of PDC in prostate cancer, we find that PDHA1 and the PDC activator, Pyruvate dehydrogenase phospatase 1 (PDP1), are frequently amplified and overexpressed at both gene and protein level in these tumours. Taken together, our findings demonstrate that both mitochondrial and nuclear PDC sustains prostate tumourigenesis by controlling lipid biosynthesis thereby pointing at this complex as a novel target for cancer therapy.

2018-02-21 | GSE74245 | GEO

Stimulation of glycolysis via the pyruvate dehydrogenase axis promotes cardiomyocyte proliferation after injury in adult zebrafish.

Project description:Cardiac metabolism plays a crucial role in producing sufficient energy to sustain cardiac contractions. However, the role of metabolism in cardiomyocyte proliferation remains unclear. Working with the adult zebrafish heart regeneration model, we first find an increase in the levels of mRNAs encoding enzymes regulating glucose and pyruvate metabolism, including pyruvate kinase M1/2 (Pkm) and pyruvate dehydrogenase kinases (Pdks), specifically in tissues bordering the damaged area. We proceed to show that impaired glycolysis decreases the number of proliferating cardiomyocytes following cardiac injury. These observations are further supported by analyses using loss-of-function models for the metabolic regulators Pkm2a and peroxisome proliferator-activated receptor gamma coactivator 1 alpha (Ppargc1a). Cardiomyocyte-specific loss- and gain-of-function manipulations of pyruvate metabolism using Pdk3 and a catalytic subunit of the pyruvate dehydrogenase complex (PDC) reveal its importance in cardiomyocyte dedifferentiation and proliferation. Furthermore, we find that PDK activity can modulate cell cycle progression and protrusive activity in mammalian cardiomyocytes in culture. Our findings reveal new roles for cardiac metabolism and the PDK-PDC axis in cardiomyocyte behavior following cardiac injury.

2020-06-04 | GSE147073 | GEO

Pyruvate dehydrogenase kinase is a metabolic checkpoint for polarization of macrophages to the M1 phenotype

Project description:Metabolic reprogramming during macrophage polarization supports the effector functions of these cells in health and disease. Although the importance of glycolytic and oxidative metabolism in M1 and M2 macrophages, respectively, is well established, our knowledge of metabolic checkpoints controlling these effector states is limited. Here we demonstrate that pyruvate dehydrogenase kinase (PDK), which inhibits the conversion of cytosolic pyruvate to mitochondrial acetyl-CoA by pyruvate dehydrogenase, functions as a metabolic checkpoint in M1 macrophages. Genetic deletion or pharmacological inhibition of PDK2/4 prevents polarization of macrophages to the M1 phenotype in response to inflammatory stimuli (lipopolysaccharide plus IFN-γ). The therapeutic potential of attenuation of pro-inflammatory responses by PDK inhibition was tested, both genetically and pharmacologically, in obesity-induced insulin resistance, a disease process in which M1 macrophages contribute to adipose tissue inflammation and insulin resistance. Taken together, these studies identify PDK2/4 as a metabolic checkpoint for M1 phenotype polarization of macrophages.

2019-05-11 | GSE112595 | GEO

Pyruvate dehydrogenase complex integrates the metabolome and epigenome in memory CD8+ T cell differentiation in vitro [ChIP-Seq]

Project description:Modulation of metabolic flux through pyruvate dehydrogenase complex (PDC) plays an important role in T cell activation and differentiation. PDC sits at the transition between glycolysis and the tricarboxylic acid cycle and is a major producer of acetyl-CoA, marking it as a potential metabolic and epigenetic node. To understand the role of pyruvate dehydrogenase complex in T cell differentiation, we generated mice deficient in T cell pyruvate dehydrogenase E1A (Pdha) subunit using a CD4-cre recombinase-based strategy. Herein, we show that genetic ablation of PDC activity in T cells (TPdh-/-) leads to marked perturbations in glycolysis, the tricarboxylic acid cycle, and OXPHOS. Due to depressed OXPHOS, TPdh-/- T cells became dependent upon substrate level phosphorylation via glycolysis. Due to the block of PDC activity, histone acetylation was reduced, including H3K27, a critical site for CD8+ T cell memory differentiation. Transcriptional and functional profiling revealed abnormal CD8+ memory T cell differentiation in vitro. Collectively, our data indicate that PDC integrates the metabolome and epigenome in memory T cell differentiation. Targeting this metabolic and epigenetic node can have widespread ramifications on cellular function.

2023-08-07 | GSE231433 | GEO

Pyruvate dehydrogenase complex integrates the metabolome and epigenome in memory CD8+ T cell differentiation in vitro [RNA-Seq]

2023-08-07 | GSE231553 | GEO

The pyruvate dehydrogenase complex regulates matrix protein phosphorylation and mitophagic selectivity

Project description:In this project, we study the influence of the pyruvate dehydrogenase complex on the phosphorylation status of mitochondrial matrix proteins.

2023-08-07 | PXD040964 | Pride

Nuclear Pyruvate Dehydrogenase Complex regulates EIN2-directed Histone Acetylation and Transcriptional Regulation in the Ethylene Response.[ChIP-Seq]

Project description:Next-generation sequencing (NGS) has been used to study the histone acetylation in Arabidopsis etiolated seedlings under air and ethylene treatment. The goal of this study is to investigate how pyruvate dehydrogenase complex is involved in histone acetylation changes in response to ethylene.

2023-12-01 | GSE212536 | GEO

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