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

Yunwen Yang1,2,3, Peipei Wang1,2,3, Kaiqian Zhou1,2,3

  • 1Department of Nephrology, Children's Hospital of Nanjing Medical University, 72 Guangzhou Road, Nanjing, 210008, P. R. China.

Advanced Science (Weinheim, Baden-Wurttemberg, Germany)
|February 8, 2025
PubMed

Insights

MUTYH, a DNA repair enzyme, is decreased in acute kidney injury (AKI). Its deficiency worsens kidney damage, but nuclear MUTYH protects against AKI by reducing DNA damage and improving mitochondrial function.

Area of Science:

  • Nephrology
  • Molecular Biology
  • Biochemistry

Background:

  • The role of MUTYH (a DNA repair glycosylase) in acute kidney injury (AKI) pathogenesis is not well understood.
  • MUTYH protein levels are reduced in AKI models and human patients.

Purpose of the Study:

  • To investigate the role of MUTYH in AKI.
  • To explore the mechanism by which MUTYH deficiency exacerbates AKI.
  • To identify potential therapeutic targets for AKI.

Main Methods:

  • Utilized cisplatin- and folic acid (FA)-induced mouse AKI models.
  • Assessed MUTYH protein levels in kidney tissues and patient samples.
  • Investigated the effects of MUTYH (types 1 and 2) overexpression on AKI.
  • Examined the role of E3 ligase HUWE1 in MUTYH degradation.
  • Evaluated the therapeutic potential of targeting the HUWE1/MUTYH pathway.

Main Results:

  • MUTYH levels are decreased in AKI, and its deficiency worsens renal dysfunction and tubular injury.
  • Nuclear MUTYH (type 2) significantly ameliorates cisplatin-induced apoptosis, oxidative stress, mitochondrial dysfunction, and DNA damage.
  • The E3 ligase HUWE1 promotes MUTYH ubiquitination and degradation, exacerbating AKI.
  • HUWE1 inhibition or knockout protects against cisplatin-induced AKI.

Conclusions:

  • MUTYH, particularly nuclear type 2, plays a protective role in AKI by mitigating DNA damage and mitochondrial dysfunction.
  • The HUWE1-mediated degradation of MUTYH contributes to AKI pathogenesis.
  • Targeting the HUWE1/MUTYH pathway presents a promising therapeutic strategy for AKI.
Keywords:
DNA damageHUWE1MUTYHacute kidney injurybase excision repair

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