DNA-binding protein-A promotes renal ischemia/reperfusion injury and participates in mitochondrial function

DNA-binding protein-A (DbpA; gene: Ybx3) belongs to the cold shock protein family with known functions in cell cycling, transcription, translation and tight junction communication. In chronic nephritis DbpA is upregulated, however its activities in acute injury models, such as renal ischemia/reperfusion injury (IRI), are unclear. Mice harboring Ybx3+/+, Ybx3+/- or Ybx3-/- genotype were characterized over a period of 24 months and following experimental renal IRI. Mitochondrial function, number and integrity were analyzed by mito stress tests, MitoTracker staining and electron microscopy. Immunohistochemistry, Western blotting and flow cytometry were performed to quantify tubular cell damage and immune cell infiltration. DbpA is dispensable for kidney development and tissue homeostasis under healthy conditions. Furthermore, endogenous DbpA protein localizes within mitochondria in primary tubular epithelial cells (TECs). Genetic deletion of Ybx3 elevates the mitochondrial membrane potential, the lipid uptake and metabolism, the oxygen consumption rates (OCR) and glycolytic activities of TECs. Ybx3-/- mice demonstrate protection from IRI with less immune cell infiltration, ER stress and tubular cell damage. A putative protective mechanism is identified via upregulated antioxidant activities and reduced ferroptosis, when Ybx3 is deleted. Here, experimental evidences reveal DbpA acts as a mitochondrial protein with profound adverse effects on cell metabolism and highlights a protective effect against IRI when Ybx3 is genetically deleted.