CUL3 induces mitochondrial dysfunction via MRPL12 ubiquitination in renal tubular epithelial cells

Diabetic kidney disease (DKD) is the leading cause of chronic kidney disease worldwide and the strongest predictor of mortality in patients with diabetes. Despite its significance, the pathological mechanism underlying the onset and progression of DKD remains incompletely understood. In this study, we have shown that mitochondrial ribosomal protein L12 (MRPL12) plays a significant role in DKD by modulating mitochondrial function. We demonstrated that MRPL12 was mainly ubiquitinated at K150 in renal tubular epithelial cells. We have found that Cullin3 (CUL3), an E3 ubiquitin ligase, directly interacts with MRPL12 and induces the K63-linked ubiquitination of MRPL12, resulting in mitochondrial biosynthesis dysfunction. Moreover, under high-glucose (HG) conditions in renal tubular epithelial cells, we observed up-regulation of CUL3 expression, significant increase in CUL3-mediated ubiquitination of MRPL12 and dysregulation of mitochondrial biosynthesis. Notably, CUL3 knockdown stabilised the MRPL12 protein and protected mitochondrial biosynthesis under HG conditions. Our findings provide novel insight into how CUL3 affects mitochondrial biosynthesis in renal tubular epithelial cells through MRPL12 ubiquitination and suggest a potential therapeutic strategy for DKD in the future.