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ABHD11 mediated deglutarylation regulates the TCA cycle and T cell metabolism

ABSTRACT: ABHD11 mediated deglutarylation regulates the TCA cycle and T cell metabolism

PROVIDER: PRJNA1240100 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR32804437_1.fastq.gz	Fastqsanger.gz
	SRR32804437_2.fastq.gz	Fastqsanger.gz
	SRR32804438_1.fastq.gz	Fastqsanger.gz
	SRR32804438_2.fastq.gz	Fastqsanger.gz
	SRR32804439_1.fastq.gz	Fastqsanger.gz

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ABHD11 mediated deglutarylation regulates the TCA cycle and T cell metabolism

Project description:Glutarate is an intermediate of amino acid catabolism and an important metabolite for reprogramming T cell immunity, exerting its effects by inhibition of histone demethylase enzymes or through glutarylation. However, how distinct glutarate modifications are regulated is unclear. Here, we uncover a deglutarylation pathway that couples amino acid catabolism to tricarboxylic acid (TCA) cycle function. By examining how glutarate can form conjugates with lipoate, an essential mitochondrial modification for the TCA cycle, we find that Alpha Beta Hydrolase Domain 11 (ABHD11) protects against the formation of glutaryl-lipoyl adducts. Mechanistically, ABHD11 acts as a thioesterase to selectively remove glutaryl adducts from lipoate, maintaining integrity of the TCA cycle. Functionally, ABHD11 influences the metabolic reprogramming of human T cells, increasing central memory T cell formation and attenuating oxidative phosphorylation. These results uncover ABHD11 as a selective deglutarylating enzyme and highlight that targeting ABHD11 offers a potential approach to metabolically reprogramme cytotoxic T cells.

2025-05-23 | GSE292544 | GEO

TCA metabolism regulates DNA hypermethylation in LPS and Mycobacterium tuberculosis–induced immune tolerance

Project description:Severe and chronic infections, including pneumonia, sepsis, and tuberculosis (TB), induce long-lasting epigenetic changes that are associated with an increase in all cause post-infectious morbidity and mortality. We show that TCA cycle also regulates epigenetics, specifically DNA methylation, after infection induced immune tolerance. The following data is DNA methylation from lipopolysaccharide (LPS) in presence of by inhibitors of cellular metabolism (rapamycin, everolimus, metformin) and the TCA cycle (IDH inhibitors). DNA methylation profiles were also generated from exogenous supplementation with TCA metabolites (succinate and itaconate) in Monocyte derived Macrophages

2024-09-12 | GSE276988 | GEO

Gene expression analysis of a double knockout of TCA cycle enzymes IDH and KDH

Project description:New antimalarial drugs are urgently needed to control drug resistant forms of the malaria parasite, Plasmodium falciparum. Although mitochondrial metabolism is the target of both existing drugs and new lead compounds, the role of the mitochondrial tricarboxylic acid (TCA) cycle remains poorly understood. Herein, we describe 11 genetic knockout parasite lines that delete six of the eight TCA cycle enzymes. Although all TCA knockouts grew normally in asexual blood stages, these metabolic deficiencies halted lifecycle progression in later stages. Specifically, aconitase knockout parasites arrested as late gametocytes, whereas α-ketoglutarate dehydrogenase deficient parasites failed to develop oocysts in the mosquitoes. Mass-spectrometry analysis of 13C isotope-labeled TCA mutant parasites showed that P. falciparum has significant flexibility in TCA metabolism. This flexibility manifested itself through changes in pathway fluxes and through altered exchange of substrates between cytosolic and mitochondrial pools. Our findings suggest that mitochondrial metabolic plasticity is essential for parasite development . Two parallel timecourses resulting in a total of 16 samples (8 wildtype, Isocitrate Dehydrogenase/alpha-Ketogluterate Dehydrogenase double knockout) were hybridized against a Cy3-labeled reference pool of 3D7 mixed stage parasites on a two-color array.

2014-08-01 | E-GEOD-59015 | biostudies-arrayexpress

Identification of non-specific phosphatases in TCA cycle regulation

Project description:Protein phosphorylation is a well-established post-translational mechanism that regulates protein functions and metabolic pathways. It has been shown that several plant mitochondrial proteins are phosphorylated in a reversible manner. However, the identity of the phosphatases/kinases involved in this mechanism and their role in the regulation of the TCA cycle remains unclear. Here, we isolated and characterized plants lacking two mitochondrially targeted phosphatases (Sal2 and PP2c63) alongside pyruvate dehydrogenase kinase (PDK). Protein-protein interaction, quantitative phosphoproteomics and enzymatic analyses revealed that PDK specifically regulates pyruvate dehydrogenase (PDH), whilst Sal2 and PP2c63 regulate PDHand fumarase. Alongside with the recombinant protein complemented the purified mitochondria, the PP2c63 directly regulate the PDH and fumarase while the Sal2 indirectly regulated. Characterization of steady-state metabolite levels and fluxes in the corresponding mutants revealed that these phosphatases regulate the fluxes through the TCA cycle, with altered metabolism compromising growth of the sal2/pp2c63 double. The combined data are collectively discussed in the context of current models of the control of respiration in plants.

2021-04-01 | PXD018412 | JPOST Repository

TCA metabolism regulates DNA hypermethylation in LPS and Mycobacterium tuberculosis–induced immune tolerance

Project description:Severe and chronic infections, including pneumonia, sepsis, and tuberculosis (TB), induce long-lasting epigenetic changes that are associated with an increase in all cause post-infectious morbidity and mortality. We show that TCA cycle also regulates epigenetics, specifically DNA methylation, after infection induced immune tolerance. This data from TB patients who received everolimus with standard of care antibiotics, and have less DNA hypermethylation demonstrating proof of concept that metabolic manipulation can mitigate epigenetic scars.

2024-09-12 | GSE277003 | GEO

TCA metabolism regulates DNA hypermethylation in LPS and Mycobacterium tuberculosis–induced immune tolerance

Project description:TCA metabolism regulates DNA hypermethylation in LPS and Mycobacterium tuberculosis–induced immune tolerance

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TCA metabolism regulates DNA hypermethylation in LPS and Mycobacterium tuberculosis–induced immune tolerance

Project description:TCA metabolism regulates DNA hypermethylation in LPS and Mycobacterium tuberculosis–induced immune tolerance

| PRJNA1159897 | ENA

Gene expression analysis of a double knockout of TCA cycle enzymes IDH and KDH

2014-08-01 | GSE59015 | GEO

S-Nitrosylation-mediated dysfunction of TCA cycle enzymes in synucleinopathy studied in postmortem human brains and hiPSC-derived neurons

Project description:A causal relationship between mitochondrial metabolic dysfunction and neurodegeneration has been strongly implicated in synucleinopathies, including Parkinson’s disease (PD) and Lewy body dementia (LBD), but the underlying molecular basis is not fully understood. Here, using human induced pluripotent stem cell (hiPSC)-derived neurons bearing a pathological point mutation in the gene encoding α-synuclein (αSyn) protein, we report that the presence of many aberrantly S-nitrosylated proteins, including multiple tricarboxylic acid (TCA) cycle enzymes, which results in inhibition of their activity, as assessed by carbon-labeled metabolic flux experiments. The block in the TCA cycle principally affects the step at -ketoglutarate dehydrogenase/succinyl coenzyme-A synthetase, metabolizing -ketoglutarate to succinate. Notably, human LBD brain manifests a similar pattern of aberrantly S-nitrosylated TCA enzymes, indicating the pathophysiological relevance of these results. Inhibition of mitochondrial energy metabolism in neurons is known to compromise dendritic length and synaptic integrity, eventually leading to neuronal cell death, with consequent neurodegenerative phenotypes. Our new evidence indicates that redox-mediated inhibition of the TCA cycle via aberrant protein S-nitrosylation contributes to this bioenergetic failure.

2024-10-17 | PXD036797 | Pride

O-GlcNAcylation regulates c-Myc/PDK2 axis to rewire TCA cycle and promote colorectal tumor growth

Project description:O-GlcNAcylation regulates c-Myc/PDK2 axis to rewire TCA cycle and promote colorectal tumor growth

| PRJNA971495 | ENA