MRPL12 regulates high glucose-induced ferroptosis in renal tubular epithelial cells via GPX4

Diabetic kidney disease (DKD) is a severe chronic complication of diabetes and one of the major causes of end-stage renal disease (ESRD). Increasing evidence implicates ferroptosis in pathological cell death associated with metabolic diseases, carcinogenesis, and ischemia-reperfusion injury, which is also thought to be involved in kidney tubular cell death under diabetic conditions; however, the underlying pathogenic mechanism remains unclear. We found increased iron level and cellular lipid peroxidation in streptozotocin (STZ)-induced DKD mice and high glucose-stimulated renal tubular cells, accompanied by mitochondrial morphological and functional damages. Further research showed that the expression of mitochondrial ribosomal protein L12 (MRPL12) was downregulated in high glucose conditions. Overexpression of MRPL12 alleviated the damages caused by high glucose-induced ferroptosis in renal tubular cells. MRPL12 interacts with murine double minute 2 (MDM2), an E3 ubiquitin-protein ligase involved in the ubiquitination degradation pathway of several proteins. MRPL12 plays a crucial regulatory role in high glucose-induced ferroptosis of renal tubular epithelial cells by modulating glutathione peroxidase 4 (GPX4), which is a potential novel therapeutic target in improving mitochondrial homeostasis and promoting renal function.