N1-methylation of adenosine (mA) in ND5 mRNA leads to complex I dysfunction in Alzheimer's disease.
Fiche publication
Date publication
janvier 2024
Journal
Molecular psychiatry
Auteurs
Membres identifiés du Cancéropôle Est :
Pr MOTORINE Iouri
Tous les auteurs :
Jörg M, Plehn JE, Kristen M, Lander M, Walz L, Lietz C, Wijns J, Pichot F, Rojas-Charry L, Wirtz Martin KM, Ruffini N, Kreim N, Gerber S, Motorin Y, Endres K, Rossmanith W, Methner A, Helm M, Friedland K
Lien Pubmed
Résumé
One mechanism of particular interest to regulate mRNA fate post-transcriptionally is mRNA modification. Especially the extent of mA mRNA methylation is highly discussed due to methodological differences. However, one single mA site in mitochondrial ND5 mRNA was unanimously reported by different groups. ND5 is a subunit of complex I of the respiratory chain. It is considered essential for the coupling of oxidation and proton transport. Here we demonstrate that this mA site might be involved in the pathophysiology of Alzheimer's disease (AD). One of the pathological hallmarks of this neurodegenerative disease is mitochondrial dysfunction, mainly induced by Amyloid β (Aβ). Aβ mainly disturbs functions of complex I and IV of the respiratory chain. However, the molecular mechanism of complex I dysfunction is still not fully understood. We found enhanced mA methylation of ND5 mRNA in an AD cell model as well as in AD patients. Formation of this mA methylation is catalyzed by increased TRMT10C protein levels, leading to translation repression of ND5. As a consequence, here demonstrated for the first time, TRMT10C induced mA methylation of ND5 mRNA leads to mitochondrial dysfunction. Our findings suggest that this newly identified mechanism might be involved in Aβ-induced mitochondrial dysfunction.
Référence
Mol Psychiatry. 2024 01 29;: