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

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

PROVIDER: PRJNA985594 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR24968063_1.fastq.gz	Fastqsanger.gz
	SRR24968063_2.fastq.gz	Fastqsanger.gz
	SRR24968064_1.fastq.gz	Fastqsanger.gz
	SRR24968064_2.fastq.gz	Fastqsanger.gz

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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

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

| S-SCDT-10_15252-EMBR_202356958 | biostudies-other

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

Project description: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.

2015-01-19 | GSE42442 | GEO

Obesity by High-Fat Diet Increases Pain Sensitivity by Reprogramming Branched-Chain Amino Acid Catabolism in Dorsal Root Ganglia.

Project description:Obesity is a significant health concern as a result of poor-quality diet, for example, high-fat diet (HFD). Although multiple biological and molecular changes have been identified to contribute to HFD-induced pain susceptibility, the mechanisms are not fully understood. Here, we show that mice under 8 weeks of HFD were sensitive to mechanical and thermal stimuli, which was coupled with an accumulation of branched-chain amino acids (BCAAs) in lumbar dorsal root ganglia (DRG) due to local BCAA catabolism deficiency. This HFD-induced hyperalgesic phenotype could be exacerbated by supply of excessive BCAAs or mitigated by promotion of BCAA catabolism via BT2 treatment. In addition, our results suggested that HFD-related pain hypersensitivity was associated with a pro-inflammatory status in DRG, which could be regulated by BCAA abundance. Therefore, our study demonstrates that defective BCAA catabolism in DRG facilitates HFD-induced pain hypersensitivity by triggering inflammation. These findings not only reveal metabolic underpinnings for the pathogenesis of HFD-related hyperalgesia but also offer potential targets for developing diet-based therapy of chronic pain.

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MicroRNA-mediated attenuation of branched-chain amino acid catabolism promotes ferroptosis in chronic kidney disease.

Project description:MicroRNA-mediated attenuation of branched-chain amino acid catabolism promotes ferroptosis in chronic kidney disease.

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Mitochondrial Calcium Signaling Regulates Branched-Chain Amino Acid Catabolism in Fibrolamellar Carcinoma

Project description:Metabolic adaptations in response to changes in energy supply and demand are essential for survival. The mitochondrial calcium uniporter plays a key role in coordinating metabolic homeostasis by regulating TCA cycle activation, mitochondrial fatty acid oxidation and cellular calcium signaling. However, a comprehensive analysis of uniporter-regulated mitochondrial metabolic pathways has remained unexplored. Here, we investigate metabolic consequences of uniporter loss- and gain-of-function using uniporter knock out cells and the liver cancer fibrolamellar carcinoma (FLC), which we demonstrate to have elevated mitochondrial calcium levels. Our results reveal that branched chain amino acid (BCAA) catabolism and the urea cycle are uniporter-regulated metabolic pathways. Reduced uniproter function increases expression of BCAA catabolism genes, and the urea cycle enzyme ornithine transcarbamylase (OTC). In contrast, high uniporter activity in FLC suppresses their expression. This suppression happens via the transcription factor KLF15, a master regulator of liver metabolism, suggesting that calcium signaling plays a central role in FLC-associated metabolic changes, including hyperammonemia. Consistent with this, activation of BCAA catabolism in FLC cells impairs their growth. Collectively, our study identifies an important role for mitochondrial calcium signaling in metabolic adaptation through transcriptional regulation of metabolism and elucidates its importance for BCAA and ammonia metabolism in FLC.

2024-11-21 | MSV000096493 | MassIVE

Impaired Branched-Chain Amino Acid Catabolism is Associated with Chemotherapy-Induced Heart Failure and Rescued by Metformin

Project description:Impaired Branched-Chain Amino Acid Catabolism is Associated with Chemotherapy-Induced Heart Failure and Rescued by Metformin

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

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

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

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

| PRJNA1014775 | ENA

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

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

| PRJNA1014776 | ENA

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