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METTL3-mediated m6A modification regulates D-galactose-induced skin fibroblast senescence through miR-208a-5p

Gaoxiang Huang1,2,3, Sainan Sun1, Mingde Liao4

  • 1School of Basic Medical, Guangxi Medical University, Nanning, Guangxi, China.

Frontiers in Immunology
|June 23, 2025
PubMed
Abstract

Insights

This study reveals how N6-methyladenosine (m6A) modification, via METTL3, regulates microRNA-208a-5p and OPA1 to control skin cell aging and mitochondrial function.

Area of Science:

  • Epitranscriptomics
  • Molecular Biology
  • Aging Research

Background:

  • N6-methyladenosine (m6A) is a key epitranscriptomic mark influencing aging.
  • The role of m6A and microRNAs (miRNAs) in skin aging is not fully understood.

Purpose of the Study:

  • To elucidate the regulatory network of m6A, miRNAs, and mitochondrial function in skin aging.
  • To investigate the METTL3/miR-208a-5p/OPA1 axis in the context of senescence.

Main Methods:

  • D-galactose-induced senescence models in mouse skin fibroblasts and mice.
  • Manipulation of METTL3 and miR-208a-5p levels.
  • Assessment of m6A dynamics, gene expression, and mitochondrial function, including mitophagy.
  • Pharmacological intervention with GSK to induce mitophagy.

Main Results:

  • Reduced METTL3 and global RNA hypomethylation were observed in aging models.
  • METTL3 depletion increased miR-208a-5p, which targets OPA1 and suppresses mitophagy.
  • METTL3 overexpression ameliorated senescence, while its knockdown induced it.
  • Senescent phenotypes were reversed by pharmacological mitophagy induction.

Conclusions:

  • An m6A-dependent pathway involving METTL3, miR-208a-5p, and OPA1 regulates mitophagy and skin aging.
  • Restoring mitophagy offers a therapeutic strategy for age-related skin conditions.
Keywords:
M6AMETTL3agingmiR-208a-5psenescence

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