METTL3-mediated m6A modification of SIRT1 mRNA affects the progression of diabetic cataracts through cellular autophagy and senescence
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Su Dong1, Jiajia Zhang1, Yushan Fu1
1Department of Ophthalmology, The Second Affiliated Hospital of Harbin Medical University, Harbin, 150086, China.
Background:
The increasing incidence of diabetes mellitus has established diabetic cataracts (DC) as a significant worldwide public health issue. The mechanisms underlying DC remain unknown, and effective prevention and treatment strategies are lacking. Accordingly, we aimed to explore the role and mechanism behind N6-methyladenosine (m6A) in DC progression.
Methods:
Methyltransferase-like 3 (METTL3), p21, Beclin1, LC3, and p62 expression levels were measured in human tissues. This study assessed total m6A levels and common m6A-regulated biomarkers in both in vitro and in vivo DC models. Autophagy flux was detected in vitro through Ad-mCherry-GFP-LC3B and Monodansylcadaverine (MDC) staining. Cellular senescence was assessed utilizing the senescence-associated β-galactosidase (SA-β-Gal) assay. Furthermore, the effect of METTL3 on SIRT1 mRNA modification was demonstrated, and its mechanism was elucidated using RT-qPCR, western blot, RNA stability assays, and RIP analysis.
Results:
METTL3, p21, and p62 expression levels were elevated in lens epithelial cells (LECs) from DC patients, while Beclin1 and LC3 levels were reduced. Silencing METTL3-mediated m6A modifications restored high-glucose-induced autophagy inhibition and prevented premature senescence in LECs. Notably, SIRT1720 and Metformin significantly enhanced autophagosome generation and delayed cellular senescence. The m6A-reading protein YTHDF2 bound to m6A modifications, and YTHDF2 silencing significantly reduced METTL3-mediated SIRT1 inactivation.
Conclusions:
METTL3 induces senescence in DC by destabilizing SIRT1 mRNA in an m6A-YTHDF2-dependent manner. The METTL3-YTHDF2-SIRT1 axis is a key target and potential pathogenic mechanism in DC.
Insights
N6-methyladenosine (m6A) modification, driven by METTL3, promotes diabetic cataract (DC) progression by destabilizing SIRT1 mRNA. Targeting the METTL3-YTHDF2-SIRT1 pathway offers a potential strategy for DC prevention and treatment.
Area of Science:
- Molecular Biology
- Epigenetics
- Ophthalmology
Background:
- Diabetic cataracts (DC) are a growing global health concern due to rising diabetes mellitus incidence.
- Current understanding of DC pathogenesis is limited, hindering effective prevention and treatment strategies.
Purpose of the Study:
- To investigate the role and mechanism of N6-methyladenosine (m6A) in the progression of diabetic cataracts.
- To explore potential therapeutic targets within the m6A regulatory pathway for DC.
Main Methods:
- Assessed expression of METTL3, p21, Beclin1, LC3, and p62 in human DC tissues.
- Utilized in vitro and in vivo DC models to evaluate m6A levels and biomarkers.
- Analyzed autophagy flux, cellular senescence, and METTL3's effect on SIRT1 mRNA using molecular biology techniques.
Main Results:
- Elevated METTL3, p21, and p62, with reduced Beclin1 and LC3, were observed in DC patient lens epithelial cells (LECs).
- METTL3 inhibition reversed high-glucose-induced autophagy suppression and prevented premature senescence in LECs.
- The METTL3-YTHDF2 interaction was crucial for SIRT1 mRNA destabilization and inactivation, contributing to DC pathogenesis.
Conclusions:
- METTL3 promotes cellular senescence in diabetic cataracts by destabilizing SIRT1 mRNA via an m6A-YTHDF2-dependent mechanism.
- The METTL3-YTHDF2-SIRT1 axis represents a key pathogenic pathway and a potential therapeutic target for diabetic cataracts.
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