2. Academic Validation
  3. Loss of PTPN21 disrupted mitochondrial metabolic homeostasis and aggravated experimental pulmonary fibrosis

Loss of PTPN21 disrupted mitochondrial metabolic homeostasis and aggravated experimental pulmonary fibrosis

  • Respir Res. 2024 Dec 4;25(1):426. doi: 10.1186/s12931-024-03041-4.
Hui Lian 1 2,  Kai Xu 1,  Airu Chang 1,  Yaxuan Wang 1,  Shuaichen Ma 1,  Lianhui Cheng 1,  Wenyu Zhao 1,  Cong Xia 1,  Lan Wang 3,  Guoying Yu 4
Affiliations

Affiliations

  • 1 State Key Laboratory of Cell Differentiation and Regulation, Henan International Joint Laboratory of Pulmonary Fibrosis, Henan Center for Outstanding Overseas Scientists of Organ Fibrosis, Pingyuan Laboratory, College of Life Science, Henan Normal university, Xinxiang, 453007, China.
  • 2 Department of Human Anatomy and Histoembryology, School of Basic Medical Sciences, Xinxiang Medical University, Xinxiang, China.
  • 3 State Key Laboratory of Cell Differentiation and Regulation, Henan International Joint Laboratory of Pulmonary Fibrosis, Henan Center for Outstanding Overseas Scientists of Organ Fibrosis, Pingyuan Laboratory, College of Life Science, Henan Normal university, Xinxiang, 453007, China. wanglan@htu.edu.cn.
  • 4 State Key Laboratory of Cell Differentiation and Regulation, Henan International Joint Laboratory of Pulmonary Fibrosis, Henan Center for Outstanding Overseas Scientists of Organ Fibrosis, Pingyuan Laboratory, College of Life Science, Henan Normal university, Xinxiang, 453007, China. guoyingyu@htu.edu.cn.
PMID: 39633451 DOI: 10.1186/s12931-024-03041-4
Abstract

Idiopathic pulmonary fibrosis (IPF) is a high-mortality lung disease with unclear pathogenesis. Convincing evidence suggests that an imbalance in mitochondrial homeostasis resulting from repeated injury to alveolar epithelial type 2 cells (AEC2) underlies IPF. Non-receptor protein tyrosine Phosphatase 21 (PTPN21) performs various functions in cancer; however, its role in IPF has not been studied. This study aimed to investigate the role of PTPN21 in lung fibrosis. The experimental results showed that loss of PTPN21 exacerbated lung fibrosis by increasing cell numbers in bronchoalveolar lavage fluid, lung hydroxyproline content, and extracellular matrix protein expression of fibronectin and α-smooth muscle actin (α-SMA) in bleomycin-challenged mouse lungs. In A549 cells (AEC2), knockdown of PTPN21 suppressed focal adhesion and migration, reduced mitochondrial fission and increased fusion, increased the level of mitochondrial superoxide, decreased mitochondrial membrane potential and ATP levels. Simultaneously, knockdown of PTPN21 impaired Autophagy, and increased intracellular Reactive Oxygen Species levels. Treatment of fibroblasts (MRC-5) and primary human lung fibroblasts (PHLF)) with the supernatant from PTPN21-knockdown A549 cells increased the expression of fibronectin, collagen 1 and α-SMA. Conversely, overexpression of PTPN21 in A549 cells produced opposite effects. However, treatment of MRC-5 and PHLF with the supernatant from PTPN21-overexpressing A549 cells only slightly reduced the expression of fibronectin, collagen 1 in MRC-5 cells, but did not change the expression of α-SMA. In summary, this study revealed that the loss of PTPN21 in epithelial cells disrupted mitochondrial metabolic homeostasis, leading to epithelial cell inactivation and increased the deposition of extracellular matrix proteins in fibroblasts, thereby exacerbating experimental pulmonary fibrosis.

Keywords

Alveolar epithelial cells; Autophagy; Idiopathic pulmonary fibrosis; Mitochondrial homeostasis; PTPN21.

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