BCKDK-Phosphorylated Pyruvate Dehydrogenase Impairs Mitochondrial Function, Leading to Tubular Epithelial Senescence and Aggravated Diabetic Kidney Disease

Background: In diabetic kidney disease (DKD), renal tubulointerstitial cells undergo premature senescence, yet the functional significance of upregulated BCKDK in this pathological process has not been fully elucidated. Methods: Renal tissue specimens from DKD patients, diabetic mouse models, and cell experiments under high-glucose conditions were employed. Mouse models with renal tubule-specific knockout of BCKDK were generated. Mitochondrial functions were validated using oxidative respiration rate and ATP production. Results: We found that renal tubular epithelial cells exhibited premature senescence phenotypes in DKD, with increased BCKDK expression positively correlated with urinary protein levels. Downregulation of BCKDK through inducible knockout in proximal tubular cells and administration of the BCKDK inhibitor BT2 alleviated proteinuria and ameliorated tubular senescence during DKD progression. In proximal tubular cells (PTCs), we observed an interaction between BCKDK and pyruvate dehydrogenase (PDH). Under hyperglycemic conditions, BCKDK-mediated phosphorylation of PDH induced mitochondrial dysfunction. In BCKDK-knockout HEK293 cell lines, deletion of BCKDK effectively mitigated high glucose-induced mitochondrial dysfunction and cellular senescence, accompanied by a reduction in PDH phosphorylation levels. Conclusion: Elevated BCKDK levels in DKD phosphorylate mitochondrial PDH, leading to mitochondrial dysfunction and subsequent premature tubular senescence. Downregulating BCKDK expression can preserve mitochondrial function and ameliorate tubular senescence during DKD progression. This study elucidates a potential mechanism underlying premature aging in DKD and suggests that targeting BCKDK levels may offer a promising strategy for delaying the aging process. Funding: Government Support – Non-U.S.