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DCLRE1 downregulated by SYVN1-mediated ubiquitination and degradation, weakening mitochondrial homeostasis protection

Tianyu Cheng1, Pengfei Li2, Jiancen Tang1

  • 1Department of Ophthalmology, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, 200120, China.

Experimental Eye Research
|December 20, 2025
PubMed

Insights

DNA repair protein DCLRE1A protects against age-related cataract (ARC) by maintaining mitochondrial health. Its degradation by SYVN1 worsens cataract formation, suggesting SYVN1 as a therapeutic target for oxidative stress-related eye diseases.

Area of Science:

  • Molecular Biology
  • Ophthalmology
  • Genetics

Background:

  • Age-related cataract (ARC) is linked to DNA oxidative damage in lens epithelium cells (LECs).
  • DCLRE1A is involved in DNA repair but its role in mitochondrial health and ARC is unexplored.
  • Mitochondrial dysfunction contributes to cataract pathogenesis.

Purpose of the Study:

  • To investigate the role of DCLRE1A in mitochondrial homeostasis within LECs.
  • To explore the regulatory mechanism of DCLRE1A by E3 ubiquitin ligase SYVN1.
  • To determine the impact of SYVN1 on H2O2-induced lens opacity and ARC progression.

Main Methods:

  • Assessed DCLRE1A's effect on mitochondrial oxidative damage and function.
  • Investigated the interaction between SYVN1 and DCLRE1A, including ubiquitination and degradation.
  • Utilized ex-vivo rat lenses and an ARC mouse model to study SYVN1 knockdown effects on lens opacity.

Main Results:

  • DCLRE1A was found to alleviate mitochondrial DNA oxidative damage and dysfunction.
  • The E3 ubiquitin ligase SYVN1 interacts with DCLRE1A, promoting its ubiquitination and degradation.
  • SYVN1 knockdown exacerbated H2O2-induced lens opacity in both ex-vivo and in-vivo models, worsening ARC.

Conclusions:

  • DCLRE1A ubiquitination by SYVN1 plays a critical role in modulating mitochondrial homeostasis.
  • These findings provide novel insights into the pathogenesis of age-related cataract.
  • Targeting SYVN1 presents a potential therapeutic strategy for treating cataracts using antioxidative approaches.
Keywords:
Age-related cataractDCLRE1AMitochondrial homeostasisSYVN1

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