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J Biol Chem, Vol. 274, Issue 42, 29744-29748, October 15, 1999

The Diabetes-associated 3243 Mutation in the Mitochondrial tRNA^Leu(UUR) Gene Causes Severe Mitochondrial Dysfunction without a Strong Decrease in Protein Synthesis Rate

From the Department of Molecular Cell Biology, Leiden University Medical Centre, Wassenaarseweg 72, 2333 AL Leiden, The Netherlands

Cells harboring patient-derived mitochondria with an A-to-G transition at nucleotide position 3243 of their mitochondrial DNA display severe loss of respiration when compared with cells containing the wild-type adenine but otherwise identical mitochondrial DNA sequence. The amount and degree of leucylation of tRNA^Leu(UUR) were both found to be highly reduced in mutant cells. Despite the low level of leucyl-tRNA^Leu(UUR), the rate of mitochondrial translation was not seriously affected by this mutation. Therefore, decrease of mitochondrial protein synthesis as such does not appear to be a necessary prerequisite for loss of respiration. Rather, the mitochondrially encoded proteins seem subject to elevated degradation, leading to a severe reduction in their steady state levels. Our results favor a scheme in which the 3243 mutation causes loss of respiration through accelerated protein degradation, leading to a disequilibrium between the levels of mitochondrial and nuclear encoded respiratory chain subunits and thereby a reduction of functional respiratory chain complexes. The possible mechanisms underlying the pathogenesis of mitochondrial diabetes is discussed.

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