甜菜碱可恢复肺泡上皮II型细胞中OPA1介导的线粒体融合功能，并减轻新生小鼠高氧肺损伤

Abstract

Introduction Bronchopulmonary dysplasia (BPD) is a common chronic respiratory disease in preterm infants, characterized by impaired lung development. Mitochondrial dysfunction of alveolar type II epithelial (AT2) cells plays a critical role in the pathogenesis of BPD. Betaine is an endogenous methyl donor with anti-inflammatory and antioxidant properties. Our previous study demonstrated that plasma betaine levels were significantly decreased in preterm infants with BPD. The aim of this study was to investigate the effect of betaine on mitochondrial dysfunction of AT2 cells in BPD. Methods Hyperoxia-induced BPD mouse models and hyperoxia-exposed MLE-12 cells were used. Proteomic analysis was performed on lung tissues from BPD and control mice. Mitochondrial structure and function were assessed by transmission electron microscopy, immunofluorescence, Western blotting, flow cytometry, and related assays. The OPA1 inhibitor MYLS22 was used to evaluate the role of OPA1 in the protective effect of betaine. Results Hyperoxia exposure induced mitochondrial structural damage in AT2 cells and impaired lung development in BPD mice. Proteomic analysis revealed that differentially expressed proteins were significantly enriched in mitochondrial dysfunction pathways in the lungs of BPD mice. Family with sequence similarity 162 member A (FAM162A), a mitochondria-associated protein involved in mitochondrial homeostasis, was prominently downregulated. Betaine significantly increased the expression of FAM162A and optic atrophy 1 (OPA1), suppressed the activating transcription factor 4 (ATF4) and C/EBP homologous protein (CHOP) mediated integrated stress response, and alleviated cell apoptosis in AT2 cells in BPD mice. In vitro, betaine increased the expression of FAM162A and OPA1, improved mitochondrial dysfunction and decreased cell apoptosis, and the effect was abolished by the OPA1 inhibitor MYLS22 in MLE-12 cells exposed to hyperoxia. Discussion Our findings revealed that bet