Article Dans Une Revue Biochemical Journal Année : 2013

Multilevel functional and structural defects induced by two pathogenic mitochondrial tRNA mutations

Résumé

Point mutations in hmtRNAs (human mitochondrial tRNAs) can cause various disorders, such as CPEO (chronic progressive external ophthalmoplegia) and MM (mitochondrial myopathy). Mitochondrial tRNA$^{Leu}$, especially the UUR codon isoacceptor, is recognized as a hot spot for pathogenic mtDNA point mutations. Thus far, 40 mutations have been reported in hmtRNA$^{Leu}$. In the present paper, we describe the wide range of effects of two substitutions found in the TYC arms of two hmtRNA$^{Leu}$ isoacceptors. The G52A substitution, corresponding to the pathogenic G12315A mutation in tRNA$^{Leu}$(CUN), and G3283A in tRNA$^{Leu}$(UUR) exhibited structural changes in the outer corner of the tRNA shape as shown by RNase probing. These mutations also induced reductions in aminoacylation, 3'-end processing and base modification processes. The main effects of the A57G substitution, corresponding to mutations A12320G in tRNA$^{Leu}$(CUN) and A3288G in tRNA$^{Leu}$(UUR), were observed on the aminoacylation activity and binding to hmEF-Tu (human mitochondrial elongation factor Tu). These observations suggest that the wide range of effects may amplify the deleterious impact on mitochondrial protein synthesis in vivo. The findings also emphasize that an exact understanding of tRNA dysfunction is critical for the future development of therapies for mitochondrial diseases.

Fichier principal
Vignette du fichier
HAL Meng Wang 2023.pdf (3.87 Mo) Télécharger le fichier
Origine Fichiers produits par l'(les) auteur(s)
Licence

Dates et versions

hal-04705574 , version 1 (23-09-2024)

Licence

Identifiants

Citer

Meng Wang, Xiao-Long Zhou, Ru-Juan Liu, Zhi-Peng Fang, Mi Zhou, et al.. Multilevel functional and structural defects induced by two pathogenic mitochondrial tRNA mutations. Biochemical Journal, 2013, 453, pp.455 - 465. ⟨10.1042/bj20130294⟩. ⟨hal-04705574⟩
44 Consultations
115 Téléchargements

Altmetric

Partager

  • More