Exploring the Ability of LARS2 Carboxy-Terminal Domain in Rescuing the MELAS Phenotype

Life

Paola Loguercio Polosa¹  Francesco Bruni¹  Francesco Capriglia¹  Marina Roberti¹  Francesca Rizzo¹  Palmiro Cantatore¹  Giulia d’Amati²  Giuseppe Petrosillo³  Veronica Morea⁴ 

[1] Department of Biosciences, Biotechnologies and Biopharmaceutics, University of Bari Aldo Moro, 70125 Bari, Italy;Department of Radiological, Oncological and Pathological Sciences, Sapienza University of Rome, 00185 Rome, Italy;Institute of Biomembranes, Bioenergetics and Molecular Biotechnologies (IBIOM), National Research Council (CNR), 70125 Bari, Italy;Institute of Molecular Biology and Pathology (IMBP), National Research Council (CNR), 00185 Rome, Italy;

关键词: Cterm;    MELAS;    transmitochondrial cybrids;    aminoacyl-tRNA synthetases;    LARS2;    mitochondrial disease;   

DOI  :  10.3390/life11070674

来源: DOAJ

【 摘 要 】

The m.3243A>G mutation within the mitochondrial mt-tRNALeu^(UUR) gene is the most prevalent variant linked to mitochondrial encephalopathy with lactic acidosis and stroke-like episodes (MELAS) syndrome. This pathogenic mutation causes severe impairment of mitochondrial protein synthesis due to alterations of the mutated tRNA, such as reduced aminoacylation and a lack of post-transcriptional modification. In transmitochondrial cybrids, overexpression of human mitochondrial leucyl-tRNA synthetase (LARS2) has proven effective in rescuing the phenotype associated with m.3243A>G substitution. The rescuing activity resides in the carboxy-terminal domain (Cterm) of the enzyme; however, the precise molecular mechanisms underlying this process have not been fully elucidated. To deepen our knowledge on the rescuing mechanisms, we demonstrated the interactions of the Cterm with mutated mt-tRNALeu^(UUR) and its precursor in MELAS cybrids. Further, the effect of Cterm expression on mitochondrial functions was evaluated. We found that Cterm ameliorates de novo mitochondrial protein synthesis, whilst it has no effect on mt-tRNALeu^(UUR) steady-state levels and aminoacylation. Despite the complete recovery of cell viability and the increase in mitochondrial translation, Cterm-overexpressing cybrids were not able to recover bioenergetic competence. These data suggest that, in our MELAS cell model, the beneficial effect of Cterm may be mediated by factors that are independent of the mitochondrial bioenergetics.

【 授权许可】

Unknown