Dataset Information

Mitochondrial One-Carbon Metabolism is Required for TGF-β-Induced Glycine Synthesis and Collagen Protein Production

ABSTRACT: A hallmark of Idiopathic Pulmonary Fibrosis is the TGF-β-dependent activation of lung fibroblasts, leading to excessive deposition of collagen proteins and progressive scarring. We have previously shown that synthesis of collagen by lung fibroblasts requires de novo synthesis of glycine, the most abundant amino acid in collagen protein. TGF-β upregulates the expression of the enzymes of the de novo serine/glycine synthesis pathway in lung fibroblasts through mTORC1 and ATF4-dependent transcriptional programs. SHMT2, the final enzyme of the de novo serine/glycine synthesis pathway, transfers a one-carbon unit from serine to tetrahydrofolate (THF), producing glycine and 5,10-methylene-THF (meTHF). meTHF is converted back to THF in the mitochondrial one-carbon (1C) pathway through the sequential actions of MTHFD2 (which converts meTHF to 10-formyl-THF), and either MTHFD1L, which produces formate, or ALDH1L2, which produces CO2. It is unknown how the mitochondrial 1C pathway contributes to glycine biosynthesis or collagen protein production in fibroblasts, or fibrosis in vivo. Here, we demonstrate that TGF-β induces the expression of MTHFD2, MTHFD1L, and ALDH1L2 in human lung fibroblasts. MTHFD2 expression was required for TGF-β-induced cellular glycine accumulation and collagen protein production.

ORGANISM(S): Homo sapiens

PROVIDER: GSE302114 | GEO | 2025/07/16

REPOSITORIES: GEO

ACCESS DATA

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

Project description:Purpose: We examined the impact of niacin on muscle gene expression in mitochondrial myopathy patients and healthy controls. Methods: Muscle transcriptomics profiles were generated using global transcriptomics analysis by RNA sequencing which was performed by the Beijing Genomic Institute (BGI) using their standard protocols Results: The pathway enrichment analysis of RNA-sequencing data indicated that phagosome formation, serine/glycine/one-carbon pathways (de novo serine biosynthesis, purine degradation, glutathione metabolism), LXR/RXR activation, eicosanoid, glycoprotein 6, atherosclerosis, iron homeostasis and cAMP-mediated signalling pathways were among the most significantly changed in patients. Only five and two of the disease associated pathways remained significantly changed after 4- and 10-month supplementation, respectively, in patients as compared to controls. The most prominent niacin-related transcriptomic change in patients’ muscle (patient 10-months on niacin vs patient baseline) was wide-spread downregulation of mTOR-dependent cytoplasmic translation, involving a large number of cytoplasmic ribosome subunits as well as translation initiation factor eIF1. In patients, niacin activated also the peroxisome proliferator-activated receptor signaling pathway, known to induce mitochondrial biogenesis. Niacin also led to decreased atherosclerosis signaling including lowered apolipoprotein expression in patients. The healthy control muscles showed only few changes after 4-months of niacin. To examine in detail the effects of NAD-booster niacin in the mitochondrial integrated stress response (ISRmt), we studied the effects NAD+ boosting for the expression of 24 ISRmt target genes in the patients’ muscle. The analysis confirmed wide-spread induction of these genes, but their expression was unaffected by niacin (ATF5 and its targets ASNS, TRIB3, FGF21, GDF15, MTHFD2, and MTHFD1L; de novo synthesis of serine, PSAT1, PHGDH and SHMT2; glutathione metabolism GPX3 and GSR; and unfolded protein response ER CHOP). Conclusions: These results showed that niacin modulated the expression of disease associated pathways and suppressed mTOR signalling in patients but niacin did not affect disease-related ISRmt signalling.

Dataset Information

Mitochondrial One-Carbon Metabolism is Required for TGF-β-Induced Glycine Synthesis and Collagen Protein Production

Dataset's files

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets