Mutations in MTFMT Underlie a Human Disorder of Formylation Causing Impaired Mitochondrial Translation
| Autor: | Jinal Patel, David R. Thorburn, Steven A. Carr, Alison G. Compton, Caroline Köhrer, Matthew McKenzie, Jacob D. Jaffe, Sarah E. Calvo, Jonathon M. Silberstein, Uttam L. RajBhandary, Olga Goldberger, Steven G. Hershman, Vamsi K. Mootha, Michael T. Ryan, John Christodoulou, Elena J. Tucker, Casey A. Belcher-Timme |
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| Rok vydání: | 2011 |
| Předmět: |
Hydroxymethyl and Formyl Transferases
Mitochondrial DNA Heterozygote RNA Transfer Met Mitochondrial translation Physiology Immunoblotting Mitochondrion Biology DNA Mitochondrial Article Mitochondrial Proteins 03 medical and health sciences 0302 clinical medicine Eukaryotic translation Transduction Genetic medicine Protein biosynthesis Humans Leigh disease Child Molecular Biology Cells Cultured 030304 developmental biology Genetics 0303 health sciences Prokaryotic initiation factor-2 Lentivirus Virion Sequence Analysis DNA Cell Biology Fibroblasts medicine.disease Mitochondria Protein Biosynthesis Transfer RNA Mutation Cyclooxygenase 1 Leigh Disease 030217 neurology & neurosurgery |
| Zdroj: | Cell Metabolism. 14(3):428-434 |
| ISSN: | 1550-4131 |
| DOI: | 10.1016/j.cmet.2011.07.010 |
| Popis: | The metazoan mitochondrial translation machinery is unusual in having a single tRNA(Met) that fulfills the dual role of the initiator and elongator tRNA(Met). A portion of the Met-tRNA(Met) pool is formylated by mitochondrial methionyl-tRNA formyltransferase (MTFMT) to generate N-formylmethionine-tRNA(Met) (fMet-tRNA(met)), which is used for translation initiation; however, the requirement of formylation for initiation in human mitochondria is still under debate. Using targeted sequencing of the mtDNA and nuclear exons encoding the mitochondrial proteome (MitoExome), we identified compound heterozygous mutations in MTFMT in two unrelated children presenting with Leigh syndrome and combined OXPHOS deficiency. Patient fibroblasts exhibit severe defects in mitochondrial translation that can be rescued by exogenous expression of MTFMT. Furthermore, patient fibroblasts have dramatically reduced fMet-tRNA(Met) levels and an abnormal formylation profile of mitochondrially translated COX1. Our findings demonstrate that MTFMT is critical for efficient human mitochondrial translation and reveal a human disorder of Met-tRNA(Met) formylation. |
| Databáze: | OpenAIRE |
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