The isolated carboxy-terminal domain of human mitochondrial leucyl-tRNA synthetase rescues the pathological phenotype of mitochondrial tRNA mutations in human cells

Elena Perli, Carla Giordano, Annalinda Pisano, Arianna Montanari, Antonio F. Campese, Aurelio Reyes, Daniele Ghezzi, Alessia Nasca, Helen A. Tuppen, Maurizia Orlandi, Patrizio Di Micco, Elena Poser, Robert W. Taylor, Gianni Colotti, Silvia Francisci, Veronica Morea, Laura Frontali, Massimo Zeviani, Giulia d'Amati

Research output: Contribution to journalArticle

28 Citations (Scopus)

Abstract

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-tRNAIle 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-tRNALeu(UUR) gene. Furthermore, we provide evidence that this small, non-catalytic domain is able to directly and specifically interact in vitro with human mt-tRNALeu(UUR) with high affinity and stability and, with lower affinity, with mt-tRNAIle. 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.

Original languageEnglish
Pages (from-to)169-182
Number of pages14
JournalEMBO Molecular Medicine
Volume6
Issue number2
DOIs
Publication statusPublished - Feb 2014

Fingerprint

Amino Acyl-tRNA Synthetases
Transfer RNA
Phenotype
RNA, Transfer, Ile
Mutation
RNA, Transfer, Leu
Genes
Mitochondrial Diseases
Mitochondrial Genes
Mitochondrial DNA
Energy Metabolism
mitochondrial RNA

Keywords

  • Aminoacyl-tRNA synthetases
  • Mitochondrial disease
  • Mitochondrial tRNA mutations
  • Molecular therapy

ASJC Scopus subject areas

  • Molecular Medicine

Cite this

The isolated carboxy-terminal domain of human mitochondrial leucyl-tRNA synthetase rescues the pathological phenotype of mitochondrial tRNA mutations in human cells. / 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.

In: EMBO Molecular Medicine, Vol. 6, No. 2, 02.2014, p. 169-182.

Research output: Contribution to journalArticle

Perli, E, Giordano, C, Pisano, A, Montanari, A, Campese, AF, Reyes, A, Ghezzi, D, Nasca, A, Tuppen, HA, Orlandi, M, Di Micco, P, Poser, E, Taylor, RW, Colotti, G, Francisci, S, Morea, V, Frontali, L, Zeviani, M & d'Amati, G 2014, 'The isolated carboxy-terminal domain of human mitochondrial leucyl-tRNA synthetase rescues the pathological phenotype of mitochondrial tRNA mutations in human cells', EMBO Molecular Medicine, vol. 6, no. 2, pp. 169-182. https://doi.org/10.1002/emmm.201303198
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. / The isolated carboxy-terminal domain of human mitochondrial leucyl-tRNA synthetase rescues the pathological phenotype of mitochondrial tRNA mutations in human cells. In: EMBO Molecular Medicine. 2014 ; Vol. 6, No. 2. pp. 169-182.
@article{117e51ed50314ee0a28eb085fe7b753a,
title = "The isolated carboxy-terminal domain of human mitochondrial leucyl-tRNA synthetase rescues the pathological phenotype of mitochondrial tRNA mutations in human cells",
abstract = "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-tRNAIle 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-tRNALeu(UUR) gene. Furthermore, we provide evidence that this small, non-catalytic domain is able to directly and specifically interact in vitro with human mt-tRNALeu(UUR) with high affinity and stability and, with lower affinity, with mt-tRNAIle. 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.",
keywords = "Aminoacyl-tRNA synthetases, Mitochondrial disease, Mitochondrial tRNA mutations, Molecular therapy",
author = "Elena Perli and Carla Giordano and Annalinda Pisano and Arianna Montanari and Campese, {Antonio F.} and Aurelio Reyes and Daniele Ghezzi and Alessia Nasca and Tuppen, {Helen A.} and Maurizia Orlandi and {Di Micco}, Patrizio and Elena Poser and Taylor, {Robert W.} and Gianni Colotti and Silvia Francisci and Veronica Morea and Laura Frontali and Massimo Zeviani and Giulia d'Amati",
year = "2014",
month = "2",
doi = "10.1002/emmm.201303198",
language = "English",
volume = "6",
pages = "169--182",
journal = "EMBO Molecular Medicine",
issn = "1757-4676",
publisher = "Wiley-Blackwell",
number = "2",

}

TY - JOUR

T1 - The isolated carboxy-terminal domain of human mitochondrial leucyl-tRNA synthetase rescues the pathological phenotype of mitochondrial tRNA mutations in human cells

AU - Perli, Elena

AU - Giordano, Carla

AU - Pisano, Annalinda

AU - Montanari, Arianna

AU - Campese, Antonio F.

AU - Reyes, Aurelio

AU - Ghezzi, Daniele

AU - Nasca, Alessia

AU - Tuppen, Helen A.

AU - Orlandi, Maurizia

AU - Di Micco, Patrizio

AU - Poser, Elena

AU - Taylor, Robert W.

AU - Colotti, Gianni

AU - Francisci, Silvia

AU - Morea, Veronica

AU - Frontali, Laura

AU - Zeviani, Massimo

AU - d'Amati, Giulia

PY - 2014/2

Y1 - 2014/2

N2 - 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-tRNAIle 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-tRNALeu(UUR) gene. Furthermore, we provide evidence that this small, non-catalytic domain is able to directly and specifically interact in vitro with human mt-tRNALeu(UUR) with high affinity and stability and, with lower affinity, with mt-tRNAIle. 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.

AB - 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-tRNAIle 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-tRNALeu(UUR) gene. Furthermore, we provide evidence that this small, non-catalytic domain is able to directly and specifically interact in vitro with human mt-tRNALeu(UUR) with high affinity and stability and, with lower affinity, with mt-tRNAIle. 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.

KW - Aminoacyl-tRNA synthetases

KW - Mitochondrial disease

KW - Mitochondrial tRNA mutations

KW - Molecular therapy

UR - http://www.scopus.com/inward/record.url?scp=84893777996&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84893777996&partnerID=8YFLogxK

U2 - 10.1002/emmm.201303198

DO - 10.1002/emmm.201303198

M3 - Article

C2 - 24413190

AN - SCOPUS:84893777996

VL - 6

SP - 169

EP - 182

JO - EMBO Molecular Medicine

JF - EMBO Molecular Medicine

SN - 1757-4676

IS - 2

ER -