SLC25A28 Ameliorates Hyperoxic Lung Injury by Improving Mitochondrial Oxidative Phosphorylation in Alveolar Epithelial Cells.

Abstract

Mitochondrial dysfunction plays a central role in the pathogenesis of bronchopulmonary dysplasia (BPD). Solute carrier family 25 member 28 (SLC25A28) is an iron transporter located in the inner mitochondrial membrane. In this study, we aimed to explore the role and underlying molecular mechanisms of SLC25A28 in BPD. Hyperoxia (85% O) was used to establish a neonatal murine model of BPD, and mouse lung epithelial cells (MLE-12 cells) were used in vitro. SLC25A28 expression and activity were downregulated under hyperoxic conditions, both in vivo and in vitro. SLC25A28 overexpression restored hyperoxia-induced mitochondrial oxidative phosphorylation (OXPHOS) dysfunction, and further enhanced the proportion of Ki67-positive cells by 37% (< 0.05) and increased migration by 33% (< 0.01) in MLE-12 cells. In contrast, SLC25A28 knockdown exacerbated these impairments in MLE-12 cells, with reduced the proportion of Ki67 positive cells by 71% (< 0.01) and a 35% reduction in the migration rate. SLC25A28 was also knocked down in vivo, which further aggravated alveolar simplification in BPD mice. Furthermore, the mitochondrial-targeted peptide SS-31 could potentially interact with SLC25A28 and preserve its protein abundance. SS-31 administration mitigated hyperoxia-induced alveolar simplification, with the radical alveolar count (RAC) increasing by 28% (< 0.05) and the mean linear intercept (MLI) decreasing by 20% (< 0.001). In summary, this study revealed that SLC25A28 ameliorated hyperoxic lung injury by improving mitochondrial OXPHOS in alveolar epithelial cells, suggesting that it may serve as a potential therapeutic target for BPD.