Mutations in MTFMT Underlie a Human Disorder of Formylation Causing Impaired Mitochondrial Translation
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Tucker-2011-Mutations in MTFMT U.pdf
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Author(s)
Tucker, Elena J.
Hershman, Steven G.
Belcher-Timme, Casey A.
Patel, Jinal
Goldberger, Olga A.
Christodoulou, John
Silberstein, Jonathon M.
McKenzie, Matthew
Ryan, Michael T.
Compton, Alison G.
Date Issued
September 2011
Journal
Cell Metabolism
Publisher
Elsevier
Citation
Tucker, Elena J., Steven G. Hershman, Caroline Kohrer, Casey A. Belcher-Timme, Jinal Patel, Olga A. Goldberger, John Christodoulou, et al. “Mutations in MTFMT Underlie a Human Disorder of Formylation Causing Impaired Mitochondrial Translation.” Cell Metabolism 14, no. 3 (September 2011): 428–434. © 2011 Elsevier Inc.
Version
Final published version
Abstract
The metazoan mitochondrial translation machinery is unusual in having a single tRNA[superscript Met] that fulfills the dual role of the initiator and elongator tRNA[superscript Met]. A portion of the Met-tRNA[superscript Met] pool is formylated by mitochondrial methionyl-tRNA formyltransferase (MTFMT) to generate N-formylmethionine-tRNA[superscript Met] (fMet-tRNA[superscript 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[superscript 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[superscript Met] formylation.
MIT Department
Massachusetts Institute of Technology. Department of Biology
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DOI of Published Version
https://doi.org/10.1016/j.cmet.2011.07.010
