期刊论文详细信息
EMBO Molecular Medicine
Human mitochondrial leucyl tRNA synthetase can suppress non cognate pathogenic mt‐tRNA mutations
Hue Tran Hornig-Do2  Arianna Montanari1  Agata Rozanska2  Helen A Tuppen2  Abdulraheem A Almalki2  Dyg P Abg-Kamaludin2  Laura Frontali1  Silvia Francisci1  Robert N Lightowlers3 
[1] Department of Biology and Biotechnologies “C. Darwin”, Pasteur Institute-Cenci Bolognetti Foundation, Sapienza University of Rome, Rome, Italy;The Wellcome Trust Centre for Mitochondrial Research, Institute for Ageing and Health, The Medical School, Newcastle University, Newcastle upon Tyne, UK;The Wellcome Trust Centre for Mitochondrial Research, Institute for Cell and Molecular Biosciences, The Medical School, Newcastle University, Newcastle upon Tyne, UK
关键词: aminoacyl tRNA synthetase;    disease;    mitochondria;    protein synthesis;    therapy;   
DOI  :  10.1002/emmm.201303202
来源: Wiley
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【 摘 要 】

Abstract

Disorders of the mitochondrial genome cause a wide spectrum of disease, these present mainly as neurological and/or muscle related pathologies. Due to the intractability of the human mitochondrial genome there are currently no effective treatments for these disorders. The majority of the pathogenic mutations lie in the genes encoding mitochondrial tRNAs. Consequently, the biochemical deficiency is due to mitochondrial protein synthesis defects, which manifest as aberrant cellular respiration and ATP synthesis. It has previously been reported that overexpression of mitochondrial aminoacyl tRNA synthetases has been effective, in cell lines, at partially suppressing the defects resulting from mutations in their cognate mt-tRNAs. We now show that leucyl tRNA synthetase is able to partially rescue defects caused by mutations in non-cognate mt-tRNAs. Further, a C terminal peptide alone can enter mitochondria and interact with the same spectrum of mt-tRNAs as the entire synthetase, in intact cells. These data support the possibility that a small peptide could correct at least the biochemical defect associated with many mt-tRNA mutations, inferring a novel therapy for these disorders.

Synopsis

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A non-cognate mitochondrial aminoacyl tRNA synthetase can overcome the respiratory defect caused by an mt-tRNA mutation. The pathogenic mutation can be suppressed by a short peptide corresponding to the C-terminus of leucyl tRNA synthetase.

  • Human mitochondrial leucyl tRNA synthetase (LARS2) can bind many species of mt-tRNAs, not exclusively mt-tRNAleu(UUR) or mt-tRNAleu(CUN)
  • Binding can stabilize mt-tRNAs that carry pathogenic destabilizing mutations such as that generated from the m.1624C>T in the gene encoding mt-tRNAVal
  • A C-terminal peptide of LARS2 is able to access the mitochondrial matrix and bind a similar spectrum of mt-tRNAs to the complete LARS2 protein
  • This short peptide has potential to be a therapeutic molecule for many pathogenic mt-tRNA mutations.

【 授权许可】

CC BY   
© 2014 The Authors.

Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

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