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Drosophila miR-277 controls branched-chain amino acid catabolism and affects lifespan

ABSTRACT: Development, growth and adult survival are coordinated with available metabolic resources. The insulin/IGF and TOR signaling pathways relay nutritional status, thereby ascertaining that the organism responds appropriately to environmental conditions. MicroRNAs are short (21-23 nt) regulatory RNAs that confer specificity on the RNA-induced silencing complex (RISC) to inhibit a given set of mRNA targets. We profiled changes in miRNA expression during adult life in Drosophila melanogaster and determined that miR-277 is down-regulated with age. This miRNA controls branched-chain amino acid (BCAA) catabolism and the activity of the TOR kinase, a central growth regulator. Metabolite analysis suggests that the mechanistic basis may be an accumulation of BCKAs, rather than BCAAs, thus avoiding potentially detrimental consequences of increased branched chain amino acid levels on e.g. translational fidelity. Constitutive miR-277 expression as well as transgenic inhibition with a miRNA sponge construct shortens lifespan. Furthermore, constitutive miR-277 expression is synthetically lethal with reduced insulin signaling. Thus, optimal metabolic adaptation requires tuning of cellular BCAA catabolism by miR-277 to be concordant with systemic growth signaling.

ORGANISM(S): Drosophila melanogaster

PROVIDER: GSE42442 | GEO | 2015/01/19

SECONDARY ACCESSION(S): PRJNA181983

REPOSITORIES: GEO

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Drosophila melanogaster

Project description:Drosophila miR-277 controls branched-chain amino acid catabolism and affects lifespan

| PRJNA181983 | ENA

RNA sequencing of human marcrophages treated with lipopolysaccharide (LPS) for 8 hours, with or without BCAT1 inhibitor (ERG240)

Project description:Branched-chain aminotransferases (BCAT) are enzymes that initiate the catabolism of branched-chain amino acids (BCAA), such as leucine, thereby providing macromolecule precursors. In order to study the effect of BCAT1 inhibitor (ERG240) on LPS-polarized macrophage transcriptome, we stimulated monocyte derived macrophages (MDMs) with LPS for 8 hours, with or without the presence of ERG240. We then performed whole-genome transcriptome sequencing by RNA-sequencing (RNA-seq).

2020-11-23 | GSE148701 | GEO

Defective Branched-Chain Amino Acid Catabolism in Dorsal Root Ganglia Contributes to Mechanical Pain

Project description:Impaired branched-chain amino acid (BCAA) catabolism has recently been implicated in the development of mechanical pain, but the underlying molecular mechanisms are unclear. Here we report that defective BCAA catabolism in dorsal root ganglion (DRG) neurons sensitizes mice to mechanical pain by increasing lactate production and expression of the mechanotransduction channel Piezo2. In high-fat diet-fed obese mice, we observe downregulation of PP2Cm, a key regulator of the BCAA catabolic pathway, in DRG neurons. Mice with conditional knockout of PP2Cm in DRG neurons exhibit mechanical allodynia under normal or SNI-induced neuropathic injury conditions. Furthermore, the VAS scores in the plasma of patients with peripheral neuropathic pain are positively correlated with BCAA contents. Mechanistically, defective BCAA catabolism in DRG neurons promotes lactate production through glycolysis, which increases H3K18la modification and drives Piezo2 expression. Inhibition of lactate production or Piezo2 silencing attenuates the pain phenotype of knockout mice in response to mechanical stimuli. Therefore, our study demonstrates a causal role of defective BCAA catabolism in mechanical pain by enhancing metabolite-mediated epigenetic regulation.

2023-08-27 | GSE235230 | GEO

Decreased adipose tissue oxygenation is associated with insulin resistance in people with obesity

Project description:We evaluated the potential importance of adipose tissue (AT) oxygenation on AT biology and insulin sensitivity in people. AT oxygen partial pressure (pO2), branched chain amino acid (BCAA) catabolism and marker of inflammation were determined in three groups stratified by adiposity and insulin sensitivity: 1) metabolically-healthy lean (MHL); 2) metabolically-healthy obese (MHO); and 3) metabolically-unhealthy obese (MUO). AT pO2 progressively declined from the MHL to the MHO to the MUO group, and was positively associated with hepatic and whole-body insulin sensitivity. AT pO2 was positively associated with AT expression of genes involved in BCAA catabolism and negatively associated with plasma BCAA concentrations. Although AT pO2 was negatively associated with AT markers of inflammation, it was not associated with plasma adipokine concentrations. These results support the notion that reduced AT pO2 in people with obesity contributes to insulin resistance by decreasing AT BCAA catabolism and thereby increasing plasma BCAA concentrations.

2020-12-07 | GSE152991 | GEO

The BCKDH kinase and phosphatase integrate BCAA and lipid metabolism via regulation of ATP-citrate lyase

Project description:Strong associations exist between branched chain amino acids (BCAA) and dysregulated glucose and lipid metabolism, but the underlying mechanisms are not well understood. Here we report that inhibition of the kinase (BDK) or overexpression of the phosphatase (PPM1K) that regulate branched-chain ketoacid dehydrogenase (BCKDH), the committed step of BCAA catabolism, lowers circulating BCAA, reduces hepatic steatosis and improves glucose tolerance in the absence of weight loss in Zucker fatty rats. Phosphoproteomics analysis identified ATP-citrate lyase (ACL) as an alternate substrate of BDK and PPM1K. Overexpression of BDK in liver of lean rats increased ACL phosphorylation and activated de novo lipogenesis. Moreover, BDK and PPM1K transcript levels were increased and repressed, respectively, in response to fructose feeding and expression of the ChREBP transcription factor. These studies identify BDK and PPM1K as a regulatory node that integrates BCAA, glucose, and lipid metabolism via reciprocal regulation of BCKDH and ACL. Modulation of this node relieves key disease phenotypes in a genetic model of severe obesity and metabolic dysfunction.

2018-05-18 | PXD009122 | Pride

MicroRNA-mediated attenuation of branched-chain amino acid catabolism promotes ferroptosis in chronic kidney disease [miRNA-seq]

Project description:Chronic kidney disease (CKD) complicates cisplatin-based chemotherapy of cancer patients. Here we investigate microRNA (miRNA)-regulated transcriptomic activity to unveil biological processes associated with cisplatin-induced kidney injury. Implementing chimeric-eCLIP-seq approach to a mouse model for cisplatin-induced CKD, we identify direct pairs of miRNA and their target messenger RNA in the injured kidney. We find a dedicated transcriptomic program directed by a group of miRNAs that alter metabolic pathways centered on mitochondria in the injured kidneys. Specifically, cisplatin-induced miRNA, miR-429-3p suppresses the mitochondria pathway that catalyzes branched-chain amino acid (BCAA), eventually leading to lipid peroxidation-dependent cell death, called ferroptosis. Thus, the identification of miRNA-429-3p-mediated stimulation of ferroptosis suggests a therapeutic potential for BCAA pathway modulation in ameliorating CKD and cisplatin-associated nephrotoxicity.

2023-11-01 | GSE242807 | GEO

MicroRNA-mediated attenuation of branched-chain amino acid catabolism promotes ferroptosis in chronic kidney disease [CLIP-seq]

2023-11-01 | GSE242806 | GEO

MicroRNA-mediated attenuation of branched-chain amino acid catabolism promotes ferroptosis in chronic kidney disease [RNA-seq]

2023-11-01 | GSE242808 | GEO

Effect of Mut heterozygosity in skeletal muscle gene expression

Project description:Branched-chain amino acids (BCAA) have emerged as predictors of type 2 diabetes (T2D). However, their potential role in the pathogenesis of insulin resistance and T2D remains unclear. By integrating data from skeletal muscle gene expression and metabolomic analyses, we demonstrate evidence for perturbation in BCAA metabolism and fatty acid oxidation in skeletal muscle from insulin-resistant humans. Experimental modulation of BCAA flux in cultured cells alters fatty acid oxidation in parallel. Furthermore, heterozygosity for the BCAA metabolic enzyme methylmalonyl-CoA mutase (MUT) alters muscle lipid metabolism in vivo, resulting in increased muscle triacylglycerol (TAG) accumulation and increased body weight after high-fat feeding. Together, our results demonstrate that impaired muscle BCAA catabolism may contribute to the development of insulin resistance by reducing fatty acid oxidation and increasing TAG accumulation.

2017-02-09 | GSE66766 | GEO

expression changes due to constitutive expression of Drosophila miR-277

Project description:Drosophila miR-277 is down-regulated during adult life. To infer the transcripts regulated by miR-277, we transgenically expressed the miRNA from a heterologous promotor. RNA was extracted at an age when 50% of the population had died, then we compared the transgenic strain with constitutive expression to the corresponding ywbackground.

2013-11-25 | E-MEXP-3785 | biostudies-arrayexpress

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