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  3. Mitochondrial folate pathway regulates myofibroblast differentiation and silica-induced pulmonary fibrosis

Mitochondrial folate pathway regulates myofibroblast differentiation and silica-induced pulmonary fibrosis

  • J Transl Med. 2023 Jun 6;21(1):365. doi: 10.1186/s12967-023-04241-0.
Yaqian Qu # 1 2,  Ruonan Zhai # 1 3 4,  Dandan Wang 3 4,  Zheng Wang 3 4,  Guangjie Hou 1,  Chenchen Wu 1,  Meian Tang 5,  Xiongbin Xiao 5,  Jie Jiao 6,  Yue Ba 1,  Fang Zhou 1,  Jian Qiu 7 8 9,  Wu Yao 10
Affiliations

Affiliations

  • 1 Department of Occupational and Environmental Health, College of Public Health, Zhengzhou University, Zhengzhou, Henan, China.
  • 2 Public Health and Preventive Medicine Teaching and Research Center, Henan University of Chinese Medicine, Zhengzhou, Henan, China.
  • 3 Hunan Key Laboratory of Molecular Precision Medicine, Department of Neurology, Xiangya Hospital, Central South University, Changsha, Hunan, China.
  • 4 National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan, China.
  • 5 Hunan Prevention and Treatment Institute for Occupational Diseases, Changsha, Hunan, China.
  • 6 Henan Institute for Occupational Health, Zhengzhou, Henan, China.
  • 7 Hunan Key Laboratory of Molecular Precision Medicine, Department of Neurology, Xiangya Hospital, Central South University, Changsha, Hunan, China. qiujian@sklmg.edu.cn.
  • 8 Hunan Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha, Hunan, China. qiujian@sklmg.edu.cn.
  • 9 National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan, China. qiujian@sklmg.edu.cn.
  • 10 Department of Occupational and Environmental Health, College of Public Health, Zhengzhou University, Zhengzhou, Henan, China. yaowu@zzu.edu.cn.
  • # Contributed equally.
PMID: 37280614 DOI: 10.1186/s12967-023-04241-0
Abstract

Background: Silica-induced pulmonary fibrosis (silicosis) is a diffuse interstitial fibrotic disease characterized by the massive deposition of extracellular matrix in lung tissue. Fibroblast to myofibroblast differentiation is crucial for the disease progression. Inhibiting myofibroblast differentiation may be an effective way for pulmonary fibrosis treatment.

Methods: The experiments were conducted in TGF-β treated human lung fibroblasts to induce myofibroblast differentiation in vitro and silica treated mice to induce pulmonary fibrosis in vivo.

Results: By quantitative mass spectrometry, we revealed that proteins involved in mitochondrial folate metabolism were specifically upregulated during myofibroblast differentiation following TGF-β stimulation. The expression level of proteins in mitochondrial folate pathway, MTHFD2 and SLC25A32, negatively regulated myofibroblast differentiation. Moreover, plasma folate concentration was significantly reduced in patients and mice with silicosis. Folate supplementation elevated the expression of MTHFD2 and SLC25A32, alleviated oxidative stress and effectively suppressed myofibroblast differentiation and silica-induced pulmonary fibrosis in mice.

Conclusion: Our study suggests that mitochondrial folate pathway regulates myofibroblast differentiation and could serve as a potential target for ameliorating silica-induced pulmonary fibrosis.

Keywords

Folate; MTHFD2; Mitochondria; Oxidative stress; SLC25A32; Silicosis.

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