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

Francesco Capriglia1, Francesca Rizzo1, Giuseppe Petrosillo2

  • 1Department of Biosciences, Biotechnologies and Biopharmaceutics, University of Bari Aldo Moro, 70125 Bari, Italy.

Life (Basel, Switzerland)
|August 6, 2021
PubMed
Summary

The carboxy-terminal domain of LARS2 partially rescues mitochondrial protein synthesis in MELAS syndrome models by interacting with mutated mitochondrial tRNA. However, it does not restore full mitochondrial bioenergetic function.

Keywords:
CtermLARS2MELASaminoacyl-tRNA synthetasesmitochondrial diseasetherapeutic peptidestransmitochondrial cybrids

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Area of Science:

  • Mitochondrial genetics
  • Molecular biology
  • Cellular pathophysiology

Background:

  • The m.3243A>G mutation in mitochondrial DNA is a primary cause of MELAS syndrome, severely impacting mitochondrial protein synthesis.
  • Overexpression of leucyl-tRNA synthetase (LARS2) can rescue MELAS phenotypes, with the carboxy-terminal domain (Cterm) being crucial for this effect.
  • The exact molecular mechanisms of Cterm-mediated rescue in MELAS remain unclear.

Purpose of the Study:

  • To investigate the interaction between the LARS2 Cterm and mutated mitochondrial tRNA in MELAS cybrids.
  • To evaluate the impact of Cterm expression on mitochondrial functions and cellular viability in a MELAS model.
  • To elucidate the specific molecular pathways involved in Cterm's rescuing activity.

Main Methods:

  • Utilized transmitochondrial cybrid models carrying the m.3243A>G MELAS mutation.
  • Demonstrated interactions between the LARS2 Cterm and mutated mt-tRNALeu(UUR) and its precursor.
  • Assessed mitochondrial protein synthesis, tRNA levels, aminoacylation, cell viability, and bioenergetic competence in Cterm-overexpressing cybrids.

Main Results:

  • The LARS2 Cterm interacts with mutated mt-tRNALeu(UUR) and its precursor in MELAS cybrids.
  • Cterm expression ameliorates de novo mitochondrial protein synthesis and fully recovers cell viability.
  • Cterm does not affect mt-tRNALeu(UUR) steady-state levels or aminoacylation and fails to restore full bioenergetic competence.

Conclusions:

  • The LARS2 Cterm exhibits a beneficial effect on mitochondrial protein synthesis and cell viability in MELAS models, independent of tRNA levels or aminoacylation.
  • The rescuing mechanism of Cterm in MELAS cybrids involves factors not directly linked to restoring mitochondrial bioenergetic function.
  • Further research is needed to fully understand the non-bioenergetic pathways mediating Cterm's therapeutic potential in MELAS syndrome.