1. Academic Validation
  2. HUWE1-Mediated Degradation of MUTYH Facilitates DNA Damage and Mitochondrial Dysfunction to Promote Acute Kidney Injury

HUWE1-Mediated Degradation of MUTYH Facilitates DNA Damage and Mitochondrial Dysfunction to Promote Acute Kidney Injury

  • Adv Sci (Weinh). 2025 Feb 8:e2412250. doi: 10.1002/advs.202412250.
Yunwen Yang 1 2 3 Peipei Wang 1 2 3 Kaiqian Zhou 1 2 3 Wen Zhang 4 Suwen Liu 5 Jing Ouyang 1 2 3 Mi Bai 1 2 3 Guixia Ding 1 2 3 Songming Huang 1 2 3 Zhanjun Jia 1 2 3 Aihua Zhang 1 2 3
Affiliations

Affiliations

  • 1 Department of Nephrology, Children's Hospital of Nanjing Medical University, 72 Guangzhou Road, Nanjing, 210008, P. R. China.
  • 2 Nanjing Key Laboratory of Pediatrics, Children's Hospital of Nanjing Medical University, Nanjing, 210008, P. R. China.
  • 3 Jiangsu Key Laboratory of Early Development and Chronic Diseases Prevention in Children, Nanjing Medical University, Nanjing, 210029, P. R. China.
  • 4 Department of Nephrology, Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, 210028, P. R. China.
  • 5 Department of Pediatrics, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, 250021, P. R. China.
Abstract

The role of MUTYH, a DNA repair glycosylase in the pathogenesis of acute kidney injury (AKI) is unclear. In this study, it is found that MUTYH protein levels are significantly decreased in the kidneys of cisplatin- or folic acid (FA)-induced mouse AKI models and patients with AKI. MUTYH deficiency aggravates renal dysfunction and tubular injury following cisplatin and FA treatment, along with the accumulation of 7, 8-dihydro-8-oxoguanine (8-oxoG) and impairs mitochondrial function. Importantly, the overexpression of type 2 MUTYH (nuclear) significantly ameliorates cisplatin-induced Apoptosis, oxidative stress, mitochondrial dysfunction, and DNA damage in vivo and in vitro. In contrast, overexpression of type 1 MUTYH (mitochondrial) shows a marginal effect against cisplatin-induced injury, indicating the chief role of type 2 MUTYH in antagonizing AKI. Interestingly, the results also indicate that the upregulation of the E3 Ligase HUWE1 causes the ubiquitination and degradation of MUTYH in tubular epithelial cells. HUWE1 knockout or treatment with the HUWE1 inhibitor BI8622 significantly protect against cisplatin-induced AKI. Taken together, these results suggest that the ubiquitin E3 Ligase HUWE1-mediates ubiquitination and degradation of MUTYH can aggravate DNA damage in the nucleus and mitochondria and promote AKI. Targeting the HUWE1/MUTYH pathway may be a potential strategy for AKI treatment.

Keywords

DNA damage; HUWE1; MUTYH; acute kidney injury; base excision repair.

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