2. Academic Validation
  3. PINK1 deficiency alleviates bleomycin-induced pulmonary fibrosis in mice

PINK1 deficiency alleviates bleomycin-induced pulmonary fibrosis in mice

  • Cell Signal. 2025 Sep:133:111868. doi: 10.1016/j.cellsig.2025.111868.
Yu-Qing Gu 1,  Jing Wu 1,  Tong Wang 2,  Yi-Fan Yu 3,  Jia Han 3,  Ya-Ling Chen 2,  Xiao-Long Hu 3,  Ming Wu 3,  Hu Hu 4,  Wei-Ping Zhang 2,  Yun-Bi Lu 5,  Bo Jiang 6
Affiliations

Affiliations

  • 1 Department of Pharmacology, School of Pharmacy, Zhejiang University, Hangzhou, Zhejiang Province, China; Department of Clinical Pharmacology, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang Province, China.
  • 2 Department of Pharmacology, School of Basic Medical Sciences, Zhejiang University, Hangzhou, Zhejiang Province, China.
  • 3 Department of Thoracic Surgery, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang Province, China.
  • 4 Department of Pathology and Pathophysiology and Bone Marrow Transplantation Center of the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China; Institute of Hematology, Zhejiang University & Zhejiang Engineering Laboratory for Stem Cell and Immunotherapy, Hangzhou, China.
  • 5 Department of Pharmacology, School of Basic Medical Sciences, Zhejiang University, Hangzhou, Zhejiang Province, China. Electronic address: yunbi@zju.edu.cn.
  • 6 Department of Pharmacology, School of Pharmacy, Zhejiang University, Hangzhou, Zhejiang Province, China; Department of Clinical Pharmacology, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang Province, China. Electronic address: Jiangbo@zju.edu.cn.
PMID: 40373838 DOI: 10.1016/j.cellsig.2025.111868
Abstract

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive lung disorder marked by deteriorating dyspnea and declining pulmonary function. Despite its rising prevalence and incidence, therapeutic options remain limited. PTEN-induced kinase 1 (PINK1), known for its role in PINK1/Parkin-dependent Mitophagy, contributes to the pathogenesis of various lung diseases. In this study, we elucidate a previously unrecognized mechanism of PINK1, beyond its canonical Mitophagy function, during pulmonary fibrosis. We established a bleomycin (BLM)-induced pulmonary fibrosis model in Pink1 knockout (Pink1-/-) mice and treated BEAS-2B cells with transforming growth factor-beta 1 (TGF-β1) to simulate the microenvironment of pulmonary fibrosis. A significant elevation in PINK1 expression was observed in vivo and in vitro systems. While PINK1/Parkin-dependent Mitophagy was activated, Mitophagy mediated by BCL2-interacting protein 3 (BNIP3) and FUN14 domain-containing 1 (FUNDC1) was suppressed. Further experiments in carbonyl cyanide m-chlorophenyl hydrazone (CCCP)-treated PINK1 knockout (KO) HEK293 cells and YFP-Parkin-expressing HeLa cells demonstrated that PINK1 deficiency enhanced BNIP3- and FUNDC1-mediated Mitophagy, whereas PINK1 overexpression inhibited it. Moreover, dual BNIP3/FUNDC1 knockdown significantly reversed the anti-apoptotic effect of PINK1 KO. We conclude that PINK1 deficiency promotes the clearance of damaged mitochondria via BNIP3/FUNDC1 upregulation, preserving mitochondrial homeostasis, mitigating alveolar epithelial injury, and attenuating fibrosis. Thus, PINK1 may inhibit BNIP3- and FUNDC1-mediated Mitophagy besides driving PINK1-dependent Mitophagy during pulmonary fibrosis.

Keywords

Apoptosis; Lung epithelial cell; Mitophagy; PINK1; Pulmonary fibrosis.

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