2. Academic Validation
  3. Targeting renal tubular WWP2 to restore mitochondrial OXPHOS integrity retards the AKI-to-CKD transition

Targeting renal tubular WWP2 to restore mitochondrial OXPHOS integrity retards the AKI-to-CKD transition

  • Mol Ther. 2025 Nov 17:S1525-0016(25)00961-X. doi: 10.1016/j.ymthe.2025.11.022.
Mengqiu Wu 1,  Mengqiu Miao 1,  Yuting Li 1,  Jiaojiao Fan 1,  Wenping Zhu 1,  Yujia Niu 1,  Ruotian Liu 2,  Weiyi Chen 3,  Ran Zou 2,  Songming Huang 1,  Yue Zhang 1,  Mi Bai 4,  Ran You 5,  Zhanjun Jia 6,  Aihua Zhang 7
Affiliations

Affiliations

  • 1 Department of Nephrology, State Key Laboratory of Reproductive Medicine, Children's Hospital of Nanjing Medical University, Nanjing 211166, China; Jiangsu Key Laboratory of Pediatrics, Nanjing Medical University, Nanjing 210029, China; Nanjing Key Laboratory of Pediatrics, Children's Hospital of Nanjing Medical University, Nanjing 210008, China.
  • 2 Jiangsu Key Laboratory of Pediatrics, Nanjing Medical University, Nanjing 210029, China; Nanjing Key Laboratory of Pediatrics, Children's Hospital of Nanjing Medical University, Nanjing 210008, China.
  • 3 Department of Nephrology, State Key Laboratory of Reproductive Medicine, Children's Hospital of Nanjing Medical University, Nanjing 211166, China; Jiangsu Key Laboratory of Pediatrics, Nanjing Medical University, Nanjing 210029, China; Nanjing Key Laboratory of Pediatrics, Children's Hospital of Nanjing Medical University, Nanjing 210008, China; Department of Emergency/Critical Medicine, Children's Hospital of Nanjing Medical University, Nanjing 210008, China.
  • 4 Department of Nephrology, State Key Laboratory of Reproductive Medicine, Children's Hospital of Nanjing Medical University, Nanjing 211166, China; Jiangsu Key Laboratory of Pediatrics, Nanjing Medical University, Nanjing 210029, China; Nanjing Key Laboratory of Pediatrics, Children's Hospital of Nanjing Medical University, Nanjing 210008, China. Electronic address: [email protected].
  • 5 Department of Nephrology, State Key Laboratory of Reproductive Medicine, Children's Hospital of Nanjing Medical University, Nanjing 211166, China; Jiangsu Key Laboratory of Pediatrics, Nanjing Medical University, Nanjing 210029, China; Nanjing Key Laboratory of Pediatrics, Children's Hospital of Nanjing Medical University, Nanjing 210008, China. Electronic address: [email protected].
  • 6 Department of Nephrology, State Key Laboratory of Reproductive Medicine, Children's Hospital of Nanjing Medical University, Nanjing 211166, China; Jiangsu Key Laboratory of Pediatrics, Nanjing Medical University, Nanjing 210029, China; Nanjing Key Laboratory of Pediatrics, Children's Hospital of Nanjing Medical University, Nanjing 210008, China. Electronic address: [email protected].
  • 7 Department of Nephrology, State Key Laboratory of Reproductive Medicine, Children's Hospital of Nanjing Medical University, Nanjing 211166, China; Jiangsu Key Laboratory of Pediatrics, Nanjing Medical University, Nanjing 210029, China; Nanjing Key Laboratory of Pediatrics, Children's Hospital of Nanjing Medical University, Nanjing 210008, China. Electronic address: [email protected].
PMID: 41254942 DOI: 10.1016/j.ymthe.2025.11.022
Abstract

Defects in mitochondrial energy metabolism in injured tubular epithelial cells (TECs) are a well-recognized hallmark of kidney injury pathogenesis; however, the key target leading to this defect during the acute kidney injury (AKI)-to-chronic kidney disease (CKD) transition remains elusive. Here, we found that during the AKI-to-CKD transition, the increased WW domain containing E3 ubiquitin protein Ligase 2 (WWP2) was shuttled to the mitochondria and disabled TEC mitochondrial energy metabolism by ubiquitinating and degrading complex II subunit Succinate Dehydrogenase complex subunit C (SDHC), leading to Oxidative Phosphorylation (OXPHOS) disability and aggravated TEC maladaptive repair. Preemptive and late depletion of Wwp2 both ameliorated unilateral ischemia-reperfusion (UIR) injury-induced AKI-to-CKD transition, and tubular-specific Wwp2 depletion resulted in the same protective phenotype. Furthermore, Sdhc knockdown abolished the protective effects of Wwp2 deletion in UIR mice. Conversely, SDHC overexpression attenuated OXPHOS impairment and TEC injury following WWP2 overexpression. Finally, we leveraged high-throughput virtual screening, enzyme activity assays, and binding affinity assays to identify two candidate WWP2 inhibitors. Both inhibitors significantly improved TEC maladaptive repair and deferred the AKI-to-CKD transition. Overall, we identified WWP2 as a critical regulator of mitochondrial OXPHOS integrity in maladaptive repairing TECs and identified two WWP2 inhibitors as potential drug candidates for interrupting the AKI-to-CKD transition.

Keywords

AKI-to-CKD transition; H111-H7; H36-E4; OXPHOS; SDHC; TCA cycle; WWP2; maladaptive repair of TECs; mitochondrion; ubiquitin.

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