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

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 alt...

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Bibliographic Details
Published in:Life (Basel, Switzerland) Switzerland), 2021-07, Vol.11 (7), p.674
Main Authors: Capriglia, Francesco, Rizzo, Francesca, Petrosillo, Giuseppe, Morea, Veronica, d’Amati, Giulia, Cantatore, Palmiro, Roberti, Marina, Loguercio Polosa, Paola, Bruni, Francesco
Format: Article
Language:English
Subjects:
Acidosis
aminoacyl-tRNA synthetases
Aminoacylation
Bioenergetics
Cell viability
Cterm
Cybrids
Domains
Encephalopathy
Lactic acidosis
LARS2
Leucine-tRNA ligase
MELAS
MELAS syndrome
Mitochondria
mitochondrial disease
Mitochondrial DNA
Molecular modelling
Mutation
Peptides
Phenotypes
Post-transcription
Protein biosynthesis
Protein synthesis
Proteins
Stroke-like episodes
transmitochondrial cybrids
tRNA
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Summary: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.
ISSN:2075-1729
2075-1729
DOI:10.3390/life11070674