Your browser doesn't support javascript.
loading
METTL3-mediated m6A modification of SIRT1 mRNA affects the progression of diabetic cataracts through cellular autophagy and senescence.
Dong, Su; Zhang, Jiajia; Fu, Yushan; Tang, Gege; Chen, Jianfeng; Sun, Dawei; Qi, Yanhua; Zhou, Nan.
Afiliação
  • Dong S; Department of Ophthalmology, The Second Affiliated Hospital of Harbin Medical University, Harbin, 150086, China.
  • Zhang J; Department of Ophthalmology, The Second Affiliated Hospital of Harbin Medical University, Harbin, 150086, China.
  • Fu Y; Department of Ophthalmology, The Second Affiliated Hospital of Harbin Medical University, Harbin, 150086, China.
  • Tang G; Department of Ophthalmology, The Second Affiliated Hospital of Harbin Medical University, Harbin, 150086, China.
  • Chen J; Laboratory Animal Center, The Second Affiliated Hospital of Harbin Medical University, Harbin, 150086, China.
  • Sun D; Department of Ophthalmology, The Second Affiliated Hospital of Harbin Medical University, Harbin, 150086, China. sundawei@hrbmu.edu.cn.
  • Qi Y; Department of Ophthalmology, The Second Affiliated Hospital of Harbin Medical University, Harbin, 150086, China. qyh86605643@126.com.
  • Zhou N; Department of Ophthalmology, The Second Affiliated Hospital of Harbin Medical University, Harbin, 150086, China. nzhou_hmu@126.com.
J Transl Med ; 22(1): 865, 2024 Sep 27.
Article em En | MEDLINE | ID: mdl-39334185
ABSTRACT

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 ß-galactosidase (SA-ß-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.
Assuntos
Palavras-chave
Texto completo
Adicionar na Minha BVS
Imprimir
XML
PubMed Links
Buscar no Google

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Autofagia / Catarata / RNA Mensageiro / Adenosina / Senescência Celular / Progressão da Doença / Sirtuína 1 / Metiltransferases Limite: Animals / Female / Humans / Male / Middle aged Idioma: En Revista: J Transl Med Ano de publicação: 2024 Tipo de documento: Article País de afiliação: China País de publicação: Reino Unido
Texto completo
Adicionar na Minha BVS
Imprimir
XML
PubMed Links
Buscar no Google

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Autofagia / Catarata / RNA Mensageiro / Adenosina / Senescência Celular / Progressão da Doença / Sirtuína 1 / Metiltransferases Limite: Animals / Female / Humans / Male / Middle aged Idioma: En Revista: J Transl Med Ano de publicação: 2024 Tipo de documento: Article País de afiliação: China País de publicação: Reino Unido