SLC39A1 sustains mitochondrial integrity in alveolar epithelium during acute lung injury

Acute respiratory distress syndrome (ARDS) is a devastating lung condition in which injury to the alveolar epithelium and loss of mitochondrial fitness are central. The zinc transporter SLC39A1 is known to engage with mitochondria and modulate intraorganellar zinc levels. How this interaction translates into functional organelle protection, however, has not been resolved. Using an in vitro model of LPS-induced alveolar epithelial injury, we combined high-resolution imaging, biochemical assays, and mitochondrial functional analyses to investigate this relationship. These findings were extended in vivo using a murine model of LPS-induced lung injury. We found that inflammatory stress selectively recruits SLC39A1 to mitochondria. Functional studies demonstrated that SLC39A1 overexpression preserves mitochondrial integrity by maintaining ultrastructure, membrane potential, and ATP synthesis while mitigating oxidative stress. This cytoprotective role of SLC39A1 was further substantiated in an in vivo model of acute lung injury. Conversely, SLC39A1 depletion exacerbates LPS-induced damage. Mechanistically, we show that SLC39A1 is responsible for stress-triggered zinc accumulation within mitochondria. This zinc flux correlates with enhanced PINK1 protein stability, linking it to a PINK1-associated quality control mechanism. Our study thus reveals an organelle-specific defense mechanism in which inflammation-induced translocation of SLC39A1 to mitochondria facilitates zinc delivery, thereby engaging a PINK1-mediated quality control program that promotes cell survival. These insights extend our understanding of cellular adaptation in ARDS and nominate zinc transport as a potential target for mitochondrial therapy.