N1-methylation of adenosine (m¹A) in ND5 mRNA leads to complex I dysfunction in Alzheimer's disease

Area of Science:

• Biochemistry
• Neuroscience
• Molecular Biology

Background:

• Post-transcriptional mRNA modification regulates gene expression.
• N⁶-methyladenosine (m⁶A) is a well-studied modification, but m¹A methylation is less understood.
• Mitochondrial dysfunction is a hallmark of Alzheimer's disease (AD), linked to Amyloid β (Aβ) peptide toxicity.

Purpose of the Study:

• Investigate the role of m¹A methylation in ND5 mRNA in AD pathophysiology.
• Elucidate the mechanism linking Aβ-induced mitochondrial dysfunction to ND5 mRNA.
• Identify potential therapeutic targets for AD.

Main Methods:

• Utilized an AD cell model and patient samples.
• Assessed m¹A methylation levels in ND5 mRNA.
• Quantified TRMT10C protein levels.
• Analyzed ND5 mRNA translation and mitochondrial function.

Main Results:

• Observed enhanced m¹A methylation of mitochondrial ND5 mRNA in AD models and patients.
• Demonstrated that increased TRMT10C protein levels catalyze this m¹A methylation.
• Showed that TRMT10C-induced m¹A methylation represses ND5 translation, causing mitochondrial dysfunction.
• Linked this mechanism to Aβ-induced mitochondrial impairment.

Conclusions:

• TRMT10C-mediated m¹A methylation of ND5 mRNA is a novel mechanism contributing to mitochondrial dysfunction in AD.
• This pathway represents a potential molecular link between Aβ pathology and neurodegeneration.
• Targeting TRMT10C or ND5 mRNA modification may offer therapeutic strategies for AD.