2. Academic Validation
  3. Mitochondrial one-carbon metabolism is required for TGF-β-induced glycine synthesis and fibrotic responses

Mitochondrial one-carbon metabolism is required for TGF-β-induced glycine synthesis and fibrotic responses

  • Nat Commun. 2025 Oct 20;16(1):9250. doi: 10.1038/s41467-025-64320-2.
Angelo Y Meliton 1,  Kun Woo D Shin 1,  Rengül Cetin-Atalay 1,  M Volkan Atalay 2,  Yufeng Tian 1,  Jennifer C Houpy Szafran 1,  Takugo Cho 1,  Kaitlyn A Sun 1,  Parker S Woods 1,  Obada R Shamaa 1,  Bohao Chen 1,  Nickolai O Dulin 1,  Aliya N Husain 3,  Alexander Muir 4,  Hardik Shah 5,  Gökhan M Mutlu 1,  Robert B Hamanaka 6
Affiliations

Affiliations

  • 1 Department of Medicine, Section of Pulmonary and Critical Care Medicine, The University of Chicago, Chicago, IL, USA.
  • 2 Department of Information Systems and Supply Chain Management, Loyola University Chicago, Chicago, IL, USA.
  • 3 Department of Pathology, The University of Chicago, Chicago, IL, USA.
  • 4 Ben May Department for Cancer Research, The University of Chicago, Chicago, IL, USA.
  • 5 Metabolomics Platform, Comprehensive Cancer Center, The University of Chicago, Chicago, IL, USA.
  • 6 Department of Medicine, Section of Pulmonary and Critical Care Medicine, The University of Chicago, Chicago, IL, USA. rhamanaka@bsd.uchicago.edu.
PMID: 41115888 DOI: 10.1038/s41467-025-64320-2
Abstract

TGF-β-dependent activation of lung fibroblasts is a hallmark of Idiopathic Pulmonary Fibrosis (IPF) which results in excessive Collagen deposition and progressive scarring. Collagen production by lung fibroblasts is supported by de novo synthesis of glycine, the most abundant amino acid in Collagen protein. SHMT2 produces glycine by transferring a one-carbon (1 C) unit from serine to tetrahydrofolate (THF), producing 5,10-methylene-THF (meTHF). meTHF is then converted back to THF in the mitochondrial 1 C pathway. It is unknown how 1 C metabolism contributes to Collagen protein production and fibrosis. Here, we demonstrate that TGF-β induces the expression of mitochondrial 1 C pathway Enzymes, including MTHFD2, in human lung fibroblasts. MTHFD2 was required for TGF-β-induced cellular glycine accumulation and Collagen protein production in lung fibroblasts. Pharmacologic inhibition of MTHFD2 ameliorated fibrotic responses after intratracheal bleomycin instillation in vivo. Our findings suggest that mitochondrial 1 C metabolism is a therapeutic target for IPF and Other fibrotic diseases.

Figures
Products