INTRODUCTION: Accumulating evidence indicates that kidney tubular injury is central to the pathogenesis of diabetic kidney disease (DKD). Mitophagy plays a pivotal role in maintaining mitochondrial homeostasis, particularly in kidney tubular cells since they are enriched with mitochondria. However, the molecular mechanisms regulating mitophagy in DKD remain poorly understood. Here, we investigated the role of translocase of outer mitochondrial membrane 7 (TOMM7), a key regulator of protein kinase/ubiquitin ligase PINK1/Parkin-mediated mitophagy, in the progression of DKD.
METHODS: Kidney tissue from patients with DKD and db/db mice, and high glucose/palmitic acid-treated HK-2 cells were employed to investigate TOMM7 expression and mitophagy activity. Regulatory mechanisms involving phospholipase PLA2G6 redistribution and zinc finger protein ZBTB12-mediated transcriptional repression were further explored, and a lithocholic acid-conjugated Zbtb12 small interfering (si)RNA was developed for targeted kidney therapy.
RESULTS: Expression of TOMM7 was significantly downregulated in kidney tissue of patients with DKD, db/db mice and high glucose/palmitic acid treated kidney tubular cells accompanied by impaired PINK1/Parkin-mediated mitophagy. Tomm7 overexpression in db/db mice significantly alleviated injury and restored PINK1/Parkin-mediated mitophagy. Mechanistically, TOMM7 regulated PINK1/Parkin recruitment by modulating the intracellular redistribution of PLA2G6 between the nucleus and mitochondria in kidney tubular cells. Moreover, we identified ZBTB12 as a transcription repressor of TOMM7 and developed a tubular cell-targeted siRNA for Zbtb12 to achieve specific upregulation of TOMM7 in the kidney. Furthermore, treatment with lithocholic acid-conjugated Zbtb12 siRNA attenuated tubular injury and enhanced mitophagy by increasing TOMM7 expression in db/db mice.
CONCLUSIONS: Our findings highlighted that TOMM7 enhanced PINK1/Parkin-mediated mitophagy through regulating intracellular redistribution of PLA2G6 in tubular cells in DKD models. Zbtb12 siRNA may be a potential treatment strategy targeting kidney tubular cells in DKD.
