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

Angelo Y. Meliton, Kun Woo D. Shin, Rengül Cetin-Atalay, M. Volkan Atalay, Yufeng Tian, Jennifer C. Houpy Szafran, Takugo Cho, Kaitlyn A. Sun, Parker S. Woods, Obada R. Shamaa, Bohao Chen, Nickolai O. Dulin, Aliya N. Husain, Alexander Muir, Hardik Shah, Gökhan M. Mutlu and Robert B. Hamanaka ()
Additional contact information
Angelo Y. Meliton: The University of Chicago
Kun Woo D. Shin: The University of Chicago
Rengül Cetin-Atalay: The University of Chicago
M. Volkan Atalay: Loyola University Chicago
Yufeng Tian: The University of Chicago
Jennifer C. Houpy Szafran: The University of Chicago
Takugo Cho: The University of Chicago
Kaitlyn A. Sun: The University of Chicago
Parker S. Woods: The University of Chicago
Obada R. Shamaa: The University of Chicago
Bohao Chen: The University of Chicago
Nickolai O. Dulin: The University of Chicago
Aliya N. Husain: The University of Chicago
Alexander Muir: The University of Chicago
Hardik Shah: The University of Chicago
Gökhan M. Mutlu: The University of Chicago
Robert B. Hamanaka: The University of Chicago

Nature Communications, 2025, vol. 16, issue 1, 1-16

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-025-64320-2

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