The phenotypic expression of mitochondrial tRNA-mutations can be modulated by mitochondrial leucyl-tRNA synthetase and the C-terminal domain thereof.

Frontiers in Genetics

Veronica eMorea¹  Carla eGiordano²  Elena ePerli²  Giulia ed'Amati² 

[1] National Research Council of Italy, Institute of Molecular Biology and Pathology, c/o Department of Biological Sciences, Sapienza University of Rome, Italy;Sapienza, Università di Roma;

关键词: Mitochondria;    Molecular Therapy;    mitochondrial disease;    aminoacyl-tRNA synthetase;    mt-tRNA;   

DOI  :  10.3389/fgene.2015.00113

来源: DOAJ

【 摘 要 】

Mutations in mitochondrial (mt) DNA determine important human diseases. The majority of the known pathogenic mutations are located in transfer RNA (tRNA) genes and are responsible for a wide range of currently untreatable disorders. Experimental evidence both in yeast and in human cells has shown that the detrimental effects of mt-tRNA point mutations can be attenuated by increasing the expression of the cognate mt-aminoacyl-tRNA synthetases (aaRSs). In addition, constitutive high levels of isoleucyl-tRNA syntethase have been shown to reduce the penetrance of a homoplasmic mutation in mt-tRNAIle in a small kindred. More recently, we showed that the isolated carboxy-terminal domain of human mt-leucyl tRNA synthetase (LeuRS-Cterm) localizes to mitochondria and ameliorates the energetic defect in transmitochondrial cybrids carrying mutations either in the cognate mt-tRNALeu(UUR) or in the non cognate mt-tRNAIle gene. Since the mt-LeuRS-Cterm does not possess catalytic activity, its rescuing ability is most likely mediated by a chaperon-like effect, consisting in the stabilization of the tRNA structure altered by the mutation. All together, these observations open potential therapeutic options for mt-tRNA mutations-associated disease

【 授权许可】

Unknown