ATF4 and mTOR regulate metabolic reprogramming in TGF-β-treated lung fibroblasts

Area of Science:

• Cellular metabolism
• Fibrotic diseases
• Molecular biology

Background:

• Idiopathic pulmonary fibrosis (IPF) is a fatal lung disease driven by fibroblast activation and collagen deposition.
• Fibroblast activation in IPF is linked to metabolic reprogramming, including enhanced glycine synthesis.
• The precise regulation of fibroblast metabolism by TGF-β, mTOR, and ATF4 remains incompletely understood.

Purpose of the Study:

• To investigate the roles of mTOR and ATF4 in regulating gene expression and metabolic pathways in human lung fibroblasts stimulated by TGF-β.
• To identify novel ATF4- and mTOR-dependent pathways involved in fibroblast metabolic reprogramming relevant to IPF.

Main Methods:

• RNA sequencing of human lung fibroblasts treated with TGF-β to assess gene expression changes regulated by ATF4 and mTOR.
• Analysis of cellular metabolite levels to confirm the impact of ATF4 and mTOR on metabolic pathways.
• Bioinformatic analysis of publicly available single-cell RNA sequencing datasets from IPF patient lungs.

Main Results:

• ATF4 primarily regulates genes involved in amino acid homeostasis and aminoacyl-tRNA synthetases.
• mTOR inhibition reduced ATF4 target gene expression and also downregulated glycolytic enzymes and mitochondrial electron transport chain subunits.
• Both ATF4 and mTOR influence distinct metabolic pathways, including amino acid, glycolysis, and TCA cycles, with their targets upregulated in IPF fibroblasts.

Conclusions:

• ATF4 and mTOR are key regulators of metabolic reprogramming in lung fibroblasts during TGF-β activation.
• These findings elucidate novel ATF4- and mTOR-dependent metabolic pathways contributing to fibroblast activation in IPF.
• Targeting these identified ATF4 and mTOR pathways presents a potential therapeutic strategy for inhibiting fibrotic processes in IPF.