Abstract: TH-OR016
Tip60 Downregulation Induces Cell Cycle Arrest and Z-mtDNA-Dependent Necroptosis by Impairing Aurora-B Kinase Activity in CKD Progression
Session Information
- CKD: Exploring Intertwined Mechanisms of Disease Progression
November 06, 2025 | Location: Room 362A, Convention Center
Abstract Time: 05:30 PM - 05:40 PM
Category: CKD (Non-Dialysis)
- 2303 CKD (Non-Dialysis): Mechanisms
Authors
- Xu, Yanfang, Department of Nephrology, Blood Purification Research Center, the First Affiliated Hospital, Fujian Medical University, Fuzhou, Fujian, China
- Wang, Yujia, Department of Nephrology, Blood Purification Research Center, the First Affiliated Hospital, Fujian Medical University, Fuzhou, Fujian, China
- Chen, Zhimin, Department of Nephrology, Blood Purification Research Center, the First Affiliated Hospital, Fujian Medical University, Fuzhou, Fujian, China
- Ma, Huabin, Central Laboratory, the First Affiliated Hospital, Fujian Medical University, Fuzhou, Fujian, China
- Yuan, Ying, Department of Nephrology, Blood Purification Research Center, the First Affiliated Hospital, Fujian Medical University, Fuzhou, Fujian, China
Background
Chronic kidney disease (CKD) progression is driven by persistent tubular epithelial cell injury and death, with cell cycle arrest playing a central role. However, the molecular mechanisms remain poorly understood. Tip60, a histone acetyltransferase of the MYST family, is a key regulator of cell cycle progression. Single-cell RNA sequencing revealed a progressive decline in Tip60 expression in tubular cells during the transition from acute kidney injury (AKI) to CKD, suggesting its involvement in disease pathogenesis.
Methods
To investigate the role of Tip60 in CKD, we generated mice with renal tubule-specific deletion of Tip60 and assessed tubular cell death, fibrosis, cell cycle progression, mitochondrial function, and DNA integrity. Proteomic and functional analyses were conducted to evaluate the cellular consequences of Tip60 loss. Additionally, gene deletion of Ripk3 was used to examine the role of necroptosis in CKD progression, while restoration of Aurora B acetylation was tested to evaluate its potential to mitigate the effects of Tip60 deficiency.
Results
Tip60 expression was downregulated in renal biopsies from CKD patients, and its progressive decline in tubular cells was observed during AKI-to-CKD transition. Tip60-deficient mice exhibited marked tubular cell death and fibrosis. Loss of Tip60 induced G2/M cell cycle arrest, mitochondrial oxidative stress, DNA damage, and release of Z-mtDNA. Mechanistically, Tip60 acetylated Aurora B kinase at lysine 220, enhancing its activity and ensuring mitotic fidelity. Tip60 loss reduced Aurora B acetylation, causing spindle defects, G2/M arrest, and mitochondrial dysfunction. Z-mtDNA release activated the ZBP1-RIPK3-MLKL necroptosis pathway, exacerbating tubular injury and fibrosis. Notably, Ripk3 deletion alleviated tubular cell death and slowed CKD progression. Restoration of Aurora B acetylation mitigated mitochondrial dysfunction and cell cycle arrest caused by Tip60 loss.
Conclusion
Tip60 is a critical regulator linking cell cycle dysregulation to necroptotic cell death in CKD. These findings underscore its role in maintaining mitochondrial and genomic integrity, suggesting that targeting Tip60 or its downstream effectors could offer a novel therapeutic strategy to halt CKD progression.