Short peptides from leucyl-tRNA synthetase rescue disease-causing mitochondrial tRNA point mutations. (31st December 2015)

• Record Type: Journal Article
• Authors: Perli, Elena; Fiorillo, Annarita; Giordano, Carla; Pisano, Annalinda; Montanari, Arianna; Grazioli, Paola; Campese, Antonio F.; Di Micco, Patrizio; Tuppen, Helen A.; Genovese, Ilaria; Poser, Elena; Preziuso, Carmela; Taylor, Robert W.; Morea, Veronica; Colotti, Gianni; d'Amati, Giulia
• Is Part Of: Human molecular genetics. Volume 25:Number 5(2016:Mar. 01)
• Page Start: 903
• Page End: 915
• Publication Date: 2015-12-31
• Subjects: Human molecular genetics -- Periodicals; Human chromosome abnormalities -- Periodicals; 572.8
• DOI: 10.1093/hmg/ddv619
• Languages: English
• ISSNs: 0964-6906

Abstract

Abstract : Mutations in mitochondrial (mt) genes coding for mt-tRNAs are responsible for a range of syndromes, for which no effective treatment is available. We recently showed that the carboxy-terminal domain (Cterm) of human mt-leucyl tRNA synthetase rescues the pathologic phenotype associated either with the m.3243A>G mutation in mt-tRNA Leu(UUR) or with mutations in the mt-tRNA Ile, both of which are aminoacylated by Class I mt-aminoacyl-tRNA synthetases (mt-aaRSs). Here we show, by using the human transmitochondrial cybrid model, that the Cterm is also able to improve the phenotype caused by the m.8344A>G mutation in mt-tRNA Lys, aminoacylated by a Class II aaRS. Importantly, we demonstrate that the same rescuing ability is retained by two Cterm-derived short peptides, β30_31 and β32_33, which are effective towards both the m.8344A>G and the m.3243A>G mutations. Furthermore, we provide in vitro evidence that these peptides bind with high affinity wild-type and mutant human mt-tRNA Leu(UUR) and mt-tRNA Lys, and stabilize mutant mt-tRNA Leu(UUR) . In conclusion, we demonstrate that small Cterm-derived peptides can be effective tools to rescue cellular defects caused by mutations in a wide range of mt-tRNAs.