Mitochondrial complex III is essential for regulatory T cell suppressive function. [gene expression/RNA-seq]
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ABSTRACT:
PROVIDER: PRJNA493086 | ENA |
REPOSITORIES: ENA
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Project description:Mitochondrial complex III is essential for regulatory T cell suppressive function
| PRJNA493083 | ENA
Project description:Regulatory T cells (Treg cells), a distinct subset of CD4+ T cells, are necessary for the maintenance of immune self-tolerance and homeostasis. Recent studies have demonstrated that Treg cells display a unique metabolic profile characterized by an increase in mitochondrial metabolism relative to other CD4+ effector subsets. Furthermore, the Treg cell lineage-defining transcription factor, Foxp3, has been shown to promote respiration; however, it remains unknown whether the mitochondrial respiratory chain is required for Treg cell suppressive capacity, stability, and survival. Here we report that Treg cell-specific ablation of mitochondrial respiratory chain complex III results in the development of a fatal inflammatory disease early in life, without impacting Treg cell number. Mice lacking complex III specifically in Treg cells displayed a loss of Treg cell suppressive capacity without altering Treg cell proliferation and survival. Treg cells deficient in complex III display decreased expression of genes associated with Treg function while maintaining stable FOXP3 expression. Complex III-null Treg cells displayed increased DNA methylation at the loci of differentially down-regulated genes without a global increase in DNA methylation. Loss of complex III in Treg cells resulted in buildup of the metabolites 2-hydroxyglutarate (2-HG) and succinate that can function as inhibitors of α-ketoglutarate (α−KG)-dependent dioxygenase reactions such as the ten-eleven translocation (TET) family of DNA demethylases. Thus, Treg cells require mitochondrial respiration to maintain immune regulatory gene expression and suppressive function.
2018-12-18 | GSE120451 | GEO
Project description:Regulatory T cells (Treg cells), a distinct subset of CD4+ T cells, are necessary for the maintenance of immune self-tolerance and homeostasis. Recent studies have demonstrated that Treg cells display a unique metabolic profile characterized by an increase in mitochondrial metabolism relative to other CD4+ effector subsets. Furthermore, the Treg cell lineage-defining transcription factor, Foxp3, has been shown to promote respiration; however, it remains unknown whether the mitochondrial respiratory chain is required for Treg cell suppressive capacity, stability, and survival. Here we report that Treg cell-specific ablation of mitochondrial respiratory chain complex III results in the development of a fatal inflammatory disease early in life, without impacting Treg cell number. Mice lacking complex III specifically in Treg cells displayed a loss of Treg cell suppressive capacity without altering Treg cell proliferation and survival. Treg cells deficient in complex III display decreased expression of genes associated with Treg function while maintaining stable FOXP3 expression. Complex III-null Treg cells displayed increased DNA methylation at the loci of differentially down-regulated genes without a global increase in DNA methylation. Loss of complex III in Treg cells resulted in buildup of the metabolites 2-hydroxyglutarate (2-HG) and succinate that can function as inhibitors of α-ketoglutarate (α−KG)-dependent dioxygenase reactions such as the ten-eleven translocation (TET) family of DNA demethylases. Thus, Treg cells require mitochondrial respiration to maintain immune regulatory gene expression and suppressive function.
2018-12-18 | GSE120449 | GEO
Project description:Mitochondrial complex III is essential for regulatory T cell suppressive function. [DNA methylation/RRBS]
| PRJNA493088 | ENA
Project description:Regulatory T cells (Treg cells), a distinct subset of CD4+ T cells, are necessary for the maintenance of immune self-tolerance and homeostasis1,2. Recent studies have demonstrated that Treg cells exhibit a unique metabolic profile, characterized by an increase in mitochondrial metabolism relative to other CD4+ effector subsets3,4. Furthermore, the Treg cell lineage-defining transcription factor, Foxp3, has been shown to promote respiration5,6; however, it remains unknown whether the mitochondrial respiratory chain is required for the T cell-suppression capacity, stability and survival of Treg cells. Here we report that Treg cell-specific ablation of mitochondrial respiratory chain complex III in mice results in the development of fatal inflammatory disease early in life, without affecting Treg cell number. Mice that lack mitochondrial complex III specifically in Treg cells displayed a loss of T cell-suppression capacity without altering Treg cell proliferation and survival. Treg cells deficient in complex III showed decreased expression of genes associated with Treg function, whereas Foxp3 expression remained stable. Loss of complex III in Treg cells increased DNA methylation as well as the metabolites 2-hydroxyglutarate (2-HG) and succinate that inhibit the ten-eleven translocation (TET) family of DNA demethylases7. Thus, Treg cells require mitochondrial complex III to maintain immune regulatory gene expression and suppressive function.
| S-EPMC6345596 | biostudies-literature
Project description:This SuperSeries is composed of the SubSeries listed below.
2018-12-18 | GSE120452 | GEO
Project description:The emergence of small open reading frame (sORF)-encoded peptides (SEPs) is rapidly expanding the known proteome at the lower end of the size distribution. Here, we show that the mitochondrial proteome is enriched for proteins smaller than 100 a.a. (defined as SEPs). Using a prediction and validation pipeline for small open-reading-frame (sORF)-encoded peptides (SEPs), we report the discovery of 16 endogenous nuclear encoded, mitochondrial-localized SEPs (mito-SEPs). Through functional prediction, proteomics, metabolomics and metabolic flux modeling, we demonstrate that BRAWNIN (BR), a 71 amino acid peptide encoded by the C12orf73 gene, is essential for respiratory chain complex III (CIII) assembly. In human cells, BR is induced by the energy-sensing AMPK pathway, and its depletion impairs mitochondrial ATP production. In vivo, BR is enriched in muscle tissues and its maternal zygotic deletion in zebrafish causes complete CIII loss, resulting in severe growth retardation, lactic acidosis and early death. Our findings demonstrate that BR is essential for oxidative phosphorylation across vertebrate species. We propose that mito-SEPs are an untapped resource for essential regulators of oxidative metabolism. The dataset included in this entry is for the Zebrafish and MEF BR knockouts.
2020-03-18 | PXD016718 | Pride
Project description:Regulatory T cells (Tregs) negatively regulate immune-mediated inflammation that is essential for preventing autoimmunity, but which can be detrimental in cancer. Central to Treg activation are changes in lipid metabolism to support their survival and function. Fatty acid binding proteins (FABPs) are a family of lipid chaperones required to facilitate the uptake and trafficking of intracellular lipids. One family member, FABP5, is expressed in certain T cell subsets, but its function remains elusive. We show here that in Tregs, FABP5 inhibition causes mitochondrial defects, underscored by decreased OXPHOS, lipid elongation and desaturation, and loss of cristae structure, which augment their suppressive function. Mitochondrial dysfunction after FABP5 inhibition results in mtDNA release and consequent cGAS/STING-dependent type I IFN signaling, which induces increased production of the regulatory cytokine IL-10, promoting Treg cell suppressive activity. Together these data reveal that FABP5 acts as a gatekeeper of mitochondrial health to control Treg cell function.
2019-12-26 | GSE126245 | GEO
Project description:The mitochondria play a vital role in controlling cell metabolism and regulating crucial cellular outcomes. We previously demonstrated that chronic inhibition of the mitochondrial complex III in rats by Antimycin A (AA) induced pulmonary vasoconstriction. On the metabolic level, AA-induced mitochondrial dysfunction resulted in a glycolytic shift that was reported as the primary contributor to pulmonary hypertension pathogenesis. However, the regulatory proteins driving this metabolic shift with complex III inhibition are yet to be explored. Therefore, to delineate the mechanisms, we followed the rat lung mitochondrial proteomics. Rats treated with the complex III inhibitor, Antimycin-A for up to 24 days, showed a disturbed mitochondrial proteome with significant changes in 28 proteins (p<0.05). We observe a time-dependent decrease in the expression of key proteins that regulate fatty acid oxidation, the tricarboxylic acid cycle, electron transport chain, and amino acid metabolism, indicating diminished mitochondrial function. We also found a significant dysregulation in proteins that control protein import, and the clearance and detoxification of oxidatively damaged peptides via proteolysis and mitophagy. This could lead to the onset of mitochondrial toxicity due to the misfolded protein's stress. We conclude that chronic inhibition of the mitochondrial complex III attenuates mitochondrial function by disruption of global mitochondrial metabolism. This potentially aggravates cellular proliferation by initiating a glycolytic switch and thereby leading to pulmonary hypertension.
2021-09-09 | PXD020551 | Pride
Project description:Conventional T cell fate and function are determined by coordination between cellular signaling and metabolism. Invariant natural killer T (iNKT) cells are a subset of “innate-like” pre-activated T cells whose dependence on mitochondrial metabolism remains elusive. Here, we showed that mature iNKT cells have reduced mitochondrial respiratory reserve and iNKT cell development was highly sensitive to perturbation of mitochondrial function. Mice with T cell-specific ablation of Rieske Iron-Sulphur protein (T-Uqcrfs1-/-), an essential subunit of mitochondrial complex III, had a dramatic reduction of iNKT cells in the thymus and periphery, but minimal effects on conventional T cell development. Residual iNKT cells in T-Uqcrfs1-/- mice retained ability to proliferate but exhibited increased apoptosis, decreased TCR signaling and impaired responses to TCR and IL-15 stimulation. Furthermore, knocking down RISP in mature iNKT cells diminished their cytokine production, correlating with reduced NFATC2 activity. Collectively, our data demonstrate a critical role for mitochondrial metabolism in iNKT cell development and activation outside of supporting bioenergetic demands.
2021-03-12 | GSE157283 | GEO