Mettl3-m6A-YTHDF1 axis promotion of mitochondrial dysfunction in metabolic dysfunction-associated steatotic liver...

Area of Science:

• * Molecular Biology
• * Hepatology
• * Epigenetics

Background:

• * Metabolic dysfunction-associated steatotic liver disease (MASLD) is a growing health concern linked to N6-methyladenosine (m6A) mRNA modification and mitochondrial dysfunction.
• * Understanding the interplay between m6A and mitochondrial health is crucial for MASLD pathogenesis.

Purpose of the Study:

• * To investigate the role of m6A modification in hepatic mitochondrial dysfunction in MASLD.
• * To identify key molecular players and pathways involved in m6A-mediated mitochondrial regulation in MASLD.
• * To offer a novel perspective on MASLD pathogenesis and potential therapeutic targets.

Main Methods:

• * Utilized high-throughput screening to analyze transcriptome and proteome changes in MASLD model mice.
• * Employed Western blotting, blue native gel electrophoresis (BNGE), dot blot, and Seahorse analyses for validation.
• * Investigated the effects of methyltransferase like 3 (Mettl3) and YTH N6-methyladenosine RNA binding protein 1 (YTHDF1) on mitochondrial function in vitro.

Main Results:

• * High-fat diets induced abnormal m6A modification in MASLD by upregulating Mettl3 and downregulating YTHDF1.
• * Mettl3 knockdown impaired hepatic oxidative phosphorylation (OXPHOS) and mitochondrial respiratory chain (MRC) function, while Mettl3 overexpression promoted these processes.
• * YTHDF1 knockout counteracted Mettl3's effects and suppressed mitochondrial OXPHOS, highlighting its critical role as an m6A reader.

Conclusions:

• * The Mettl3-m6A-YTHDF1 axis, particularly YTHDF1, regulates mitochondrial respiratory chain damage in MASLD.
• * Modulating this axis offers a promising therapeutic strategy to enhance mitochondrial function.
• * Targeting the Mettl3-m6A-YTHDF1 pathway may alleviate MASLD symptoms and reduce disease progression.