TOMM7 Alleviates Diabetic Kidney Disease by Regulating PINK1/Parkin-Mediated Mitophagy via Intracellular Redistribution of PLA2G6

Background: Accumulating evidence showed that renal tubular injury is crucial for the development of diabetic kidney disease (DKD), and mitophagy is a pivotal event to maintain mitochondrial homeostasis especially in renal tubular cells, which are rich in mitochondria. However, the underlying mechanisms of mitophagy regulation remain largely unknown. This study aims to investigate the role of translocase of outer mitochondrial membrane subunit 7 (TOMM7), a critical regulator of mitophagy, in the pathogenesis of DKD. Methods: TOMM7 expression was determined in the kidney sections of DKD patients. Subcellular fractions of mice kidney were isolated, and mitochondrial proteomics was used to explore the underlying mechanism, which was further validated in HK-2 cells. Results: Here, we found that the expression of TOMM7 was significantly downregulated in renal specimens of DKD patients and db/db mice as well as high glucose/palmitic acid (HG/PA) treated HK-2 cells accompanied by impaired PINK1/Parkin-mediated mitophagy. TOMM7 overexpression in db/db mice significantly alleviated renal injury and restored PINK1/Parkin-mediated mitophagy. Mechanistically, TOMM7 regulated PINK1/Parkin recruitment through modulating intracellular redistribution of PLA2G6 between nucleus and mitochondria in renal tubular cells. Moreover, we identified zinc finger and BTB domain containing 12 (ZBTB12) as a transcription repressor of TOMM7 and developed renal tubular cells targeted small interfering RNA (siRNA) to achieve specific upregulation of TOMM7 in the kidney. In addition, treatment with Zbtb12 siRNA could relieve tubular injury and improve mitophagy by increasing TOMM7 expression in db/db mice. Conclusion: In conclusion, this study highlighted that TOMM7 improved PINK1/Parkin-mediated mitophagy through intracellular redistribution of PLA2G6 in renal tubular cells in DKD models, and Zbtb12 siRNA could be a potential treatment strategy targeting renal tubular cells for DKD. Funding: Government Support – Non-U.S.Graphical Abstract