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The mitochondrial tRNA(Leu)(UUR)) mutation in MELAS: a model for pathogenesis
E A Schon1, Y Koga, M Davidson
1Department of Genetics and Development, College of Physicians and Surgeons, Columbia University, New York, NY 10032.
Biochimica Et Biophysica Acta
|July 17, 1992
Summary
A mitochondrial DNA mutation causing MELAS (mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes) leads to impaired mitochondrial protein production and function. A novel RNA species (RNA 19) may interfere with mitochondrial ribosomes, explaining MELAS symptoms.
Area of Science:
- Molecular Biology
- Genetics
- Cell Biology
Background:
- Mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) is a maternally inherited mitochondrial disorder.
- A specific mutation, A-G transition at nucleotide 3243 in the mitochondrial tRNA(Leu)(UUR) gene, is strongly associated with MELAS.
Purpose of the Study:
- To investigate the functional consequences of the MELAS-associated mtDNA mutation.
- To elucidate the molecular mechanisms underlying MELAS pathogenesis.
Main Methods:
- Mitochondria harboring the A3243G mtDNA mutation were transferred into rho(0) human cells (lacking endogenous mtDNA).
- Analysis of mitochondrial protein synthesis, respiratory chain function, and RNA species was performed.
Main Results:
- Transferred mitochondria showed reduced synthesis and steady-state levels of mitochondrial translational products.
- Respiratory chain function was significantly impaired in the mutated cells.
- A novel unprocessed RNA species, termed RNA 19, was found in increased amounts, transcribed from the 16S rRNA + tRNA(Leu)(UUR) + ND 1 region.
Conclusions:
- The A3243G mtDNA mutation disrupts mitochondrial translation and respiratory function.
- RNA 19, containing rRNA sequences, is proposed to incorporate into mitochondrial ribosomes.
- RNA 19 may disproportionately interfere with mitochondrial translation, contributing to MELAS phenotypes.