Open AccessThe isolated carboxy‐terminal domain of human mitochondrial leucyl‐ tRNA synthetase rescues the pathological phenotype of mitochondrial tRNA mutations in human cells
Author(s) -
Perli Elena,
Giordano Carla,
Pisano Annalinda,
Montanari Arianna,
Campese Antonio F,
Reyes Aurelio,
Ghezzi Daniele,
Nasca Alessia,
Tuppen Helen A,
Orlandi Maurizia,
Di Micco Patrizio,
Poser Elena,
Taylor Robert W,
Colotti Gianni,
Francisci Silvia,
Morea Veronica,
Frontali Laura,
Zeviani Massimo,
d'Amati Giulia
Publication year - 2014
Publication title -
embo molecular medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.923
H-Index - 107
eISSN - 1757-4684
pISSN - 1757-4676
DOI - 10.1002/emmm.201303198
Subject(s) - transfer rna , biology , mutant , gene , mutation , mitochondrion , genetics , microbiology and biotechnology , mitochondrial dna , rna , phenotype , mitochondrial myopathy , biochemistry
Mitochondrial (mt) diseases are multisystem disorders due to mutations in nuclear or mtDNA genes. Among the latter, more than 50% are located in transfer RNA ( tRNA ) genes and are responsible for a wide range of syndromes, for which no effective treatment is available at present. We show that three human mt aminoacyl‐ tRNA syntethases, namely leucyl‐, valyl‐, and isoleucyl‐ tRNA synthetase are able to improve both viability and bioenergetic proficiency of human transmitochondrial cybrid cells carrying pathogenic mutations in the mt‐ tRNA Ile gene. Importantly, we further demonstrate that the carboxy‐terminal domain of human mt leucyl‐ tRNA synthetase is both necessary and sufficient to improve the pathologic phenotype associated either with these “mild” mutations or with the “severe” m.3243A>G mutation in the mt‐ tRNA L eu(UUR) gene. Furthermore, we provide evidence that this small, non‐catalytic domain is able to directly and specifically interact in vitro with human mt‐ tRNA Leu(UUR) with high affinity and stability and, with lower affinity, with mt‐ tRNA Ile . Taken together, our results sustain the hypothesis that the carboxy‐terminal domain of human mt leucyl‐ tRNA synthetase can be used to correct mt dysfunctions caused by mt‐ tRNA mutations.