Defective iA37 Modification of Mitochondrial and Cytosolic tRNAs Results from Pathogenic Mutations in TRIT1 and Its Substrate tRNA

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Mitochondrial disorders are clinically diverse, and identifying the underlying genetic mutations is technically challenging due to the large number of mitochondrial proteins. Using high-throughput sequencing technology, we identified a disease-causing mutation in the TRIT1 gene. This gene encodes an enzyme, tRNA isopentenyltransferase, that adds an N6-isopentenyl modification to adenosine-37 (i6A37) in a small number of tRNAs, enabling them to function correctly during the synthesis of essential mitochondrial proteins. We show that this mutation leads to severe deficiency of tRNA-i6A37 in the patient's cells that can be rescued by introduction of the wild-type TRIT1 protein. A deficiency in oxidative phosphorylation, the process by which energy (ATP) is generated in the mitochondria, leads to a mitochondrial disease presentation. Introducing the mutant protein into model yeast species and measuring the resulting impairment provided further evidence of the pathogenic effect of the mutation. Additional studies investigating a previously reported pathogenic mutation in a mitochondrial tRNA gene demonstrated that a mutation in a substrate of TRIT1 can also cause a loss of the modification, providing evidence of a new mechanism causing mitochondrial disease in humans.

Vyšlo v časopise: Defective iA37 Modification of Mitochondrial and Cytosolic tRNAs Results from Pathogenic Mutations in TRIT1 and Its Substrate tRNA. PLoS Genet 10(6): e32767. doi:10.1371/journal.pgen.1004424
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1004424

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