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Mutations in MTFMT underlie a human disorder of formylation causing impaired mitochondrial translation.

Publication TypeJournal Article
AuthorsTucker, EJ, Hershman SG, Köhrer C., Belcher-Timme CA, Patel J., Goldberger OA, Christodoulou J., Silberstein JM, McKenzie M., Ryan MT, Compton AG, Jaffe JD, Carr SA, Calvo SE, RajBhandary UL, Thorburn DR, and Mootha VK
AbstractThe 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.
Year of Publication2011
JournalCell metabolism
Volume14
Issue3
Pages428-34
Date Published (YYYY/MM/DD)2011/09/07
ISSN Number1550-4131
DOI10.1016/j.cmet.2011.07.010
PubMedhttp://www.ncbi.nlm.nih.gov/pubmed/21907147?dopt=Abstract