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<p>Alveolar repair and regeneration are critical for resolving lung ischemia-reperfusion injury (LIRI); however, the molecular mechanisms that restrain this process remain unclear. Here, we identify PTEN-induced kinase 1 (PINK1) as a critical regulator of alveolar regeneration via Hippo-YAP signaling in LIRI. Wild-type and <i>Pink1</i><sup><i>-/-</i></sup> mice, as well as mice with adeno-associated virus type 6-mediated alveolar epithelium-specific knockdown or overexpression of PINK1, were subjected to left lung ischemia-reperfusion. In vitro, murine alveolar epithelial MLE-12 cells were exposed to oxygen-glucose deprivation/recovery (OGD/R) with PINK1 modulated genetically. We demonstrated that PINK1 deficiency markedly enhanced, while PINK1 overexpression attenuated, type II alveolar epithelial cell (AT2) proliferation, nuclear translocation of YAP, and the expression of YAP target genes in LIRI. Pharmacologic inhibition of YAP abrogated, whereas YAP activation potentiated, the pro-regenerative phenotype induced by OGD/R under PINK1 knockdown. Mechanistically, PINK1 directly phosphorylated YAP at Ser127, promoting YAP cytoplasmic retention and stabilization. PINK1 deficiency reduced YAP phosphorylation, leading to increased nuclear translocation of YAP and enhanced regenerative signaling. Meanwhile, PINK1 deficiency induced alveolar basement membrane thickening and lung function decline. Collectively, our findings reveal PINK1 as a kinase-dependent brake on YAP-driven alveolar regeneration. However, PINK1 deficiency facilitates alveolar repair while simultaneously precipitating maladaptive remodeling and functional deterioration in murine LIRI, suggesting that balanced regulation of the PINK1-YAP pathway is essential during LIRI repair.</p>

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PINK1 deficiency enhances alveolar regeneration and basement membrane remodeling by reducing YAP phosphorylation during lung ischemia-reperfusion injury

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年8月5日

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  • Yifan Yu,
  • Xiaolong Hu,
  • Jinsheng Li,
  • Jinghao Huang,
  • Zhiheng Ji,
  • Qiuyu Fang,
  • Yongchao Wang,
  • Zhiling Lou,
  • Weiping Zhang,
  • Fuxiang Liang,
  • Ming Wu

摘要

Alveolar repair and regeneration are critical for resolving lung ischemia-reperfusion injury (LIRI); however, the molecular mechanisms that restrain this process remain unclear. Here, we identify PTEN-induced kinase 1 (PINK1) as a critical regulator of alveolar regeneration via Hippo-YAP signaling in LIRI. Wild-type and Pink1-/- mice, as well as mice with adeno-associated virus type 6-mediated alveolar epithelium-specific knockdown or overexpression of PINK1, were subjected to left lung ischemia-reperfusion. In vitro, murine alveolar epithelial MLE-12 cells were exposed to oxygen-glucose deprivation/recovery (OGD/R) with PINK1 modulated genetically. We demonstrated that PINK1 deficiency markedly enhanced, while PINK1 overexpression attenuated, type II alveolar epithelial cell (AT2) proliferation, nuclear translocation of YAP, and the expression of YAP target genes in LIRI. Pharmacologic inhibition of YAP abrogated, whereas YAP activation potentiated, the pro-regenerative phenotype induced by OGD/R under PINK1 knockdown. Mechanistically, PINK1 directly phosphorylated YAP at Ser127, promoting YAP cytoplasmic retention and stabilization. PINK1 deficiency reduced YAP phosphorylation, leading to increased nuclear translocation of YAP and enhanced regenerative signaling. Meanwhile, PINK1 deficiency induced alveolar basement membrane thickening and lung function decline. Collectively, our findings reveal PINK1 as a kinase-dependent brake on YAP-driven alveolar regeneration. However, PINK1 deficiency facilitates alveolar repair while simultaneously precipitating maladaptive remodeling and functional deterioration in murine LIRI, suggesting that balanced regulation of the PINK1-YAP pathway is essential during LIRI repair.