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Short peptides from leucyl-tRNA synthetase rescue disease-causing mitochondrial tRNA point mutations

Lookup NU author(s): Dr Helen Tuppen, Professor Robert Taylor



This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License (CC BY-NC 4.0).


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). Herewe 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, beta 30_31 and beta 32_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.

Publication metadata

Author(s): Perli E, Fiorillo A, Giordano C, Pisano A, Montanari A, Grazioli P, Campese AF, Di Micco P, Tuppen HA, Genovese I, Poser E, Preziuso C, Taylor RW, Morea V, Colotti G, d'Amati G

Publication type: Article

Publication status: Published

Journal: Human Molecular Genetics

Year: 2016

Volume: 25

Issue: 5

Pages: 903-915

Print publication date: 01/03/2016

Online publication date: 31/12/2015

Acceptance date: 18/12/2015

Date deposited: 16/05/2016

ISSN (print): 0964-6906

ISSN (electronic): 1460-2083

Publisher: Oxford University Press


DOI: 10.1093/hmg/ddv619


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Funder referenceFunder name
Associazione Serena Talarico per i giovani nel mondo
Istituto Pasteur-Fondazione Cenci Bolognetti
Lily Foundation
National Research Council of Italy (CNR) Interomics Flagship Project
UK NHS Highly Specialised 'Rare Mitochondrial Disorders of Adults and Children' Service in Newcastle upon Tyne
AFM Telethon
096919/Z/11/ZWellcome Trust
GGP13097Telethon - Italy
G0601943MRC Centre for Neuromuscular Diseases