title: Mutations in MTFMT underlie a human disorder of formylation causing impaired mitochondrial translation.
abstract: 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.
authors: Murdoch Childrens Research Institute, Royal Children's Hospital, Melbourne, VIC 3052, Australia.
authors: Elena J
authors: EJ
authors: Tucker
authors: Steven G
authors: SG
authors: Hershman
authors: Caroline
authors: C
authors: Köhrer
authors: Casey A
authors: CA
authors: Belcher-Timme
authors: Jinal
authors: J
authors: Patel
authors: Olga A
authors: OA
authors: Goldberger
authors: John
authors: J
authors: Christodoulou
authors: Jonathon M
authors: JM
authors: Silberstein
authors: Matthew
authors: M
authors: McKenzie
authors: Michael T
authors: MT
authors: Ryan
authors: Alison G
authors: AG
authors: Compton
authors: Jacob D
authors: JD
authors: Jaffe
authors: Steven A
authors: SA
authors: Carr
authors: Sarah E
authors: SE
authors: Calvo
authors: Uttam L
authors: UL
authors: RajBhandary
authors: David R
authors: DR
authors: Thorburn
authors: Vamsi K
authors: VK
authors: Mootha
mesh_terms: D002478:Cells, Cultured; D002648:Child; D051545:Cyclooxygenase 1 / Q000235:genetics / Q000378:metabolism*; D004272:DNA, Mitochondrial / Q000737:chemistry* / Q000235:genetics; D005347:Fibroblasts / Q000378:metabolism* / Q000473:pathology; D006579:Heterozygote; D006801:Humans; D019877:Hydroxymethyl and Formyl Transferases; D015151:Immunoblotting; D007888:Leigh Disease / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D016086:Lentivirus; D008928:Mitochondria / Q000235:genetics* / Q000378:metabolism; D024101:Mitochondrial Proteins / Q000235:genetics* / Q000378:metabolism; D009154:Mutation; D014176:Protein Biosynthesis / Q000235:genetics; D012358:RNA, Transfer, Met / Q000378:metabolism*; D017422:Sequence Analysis, DNA; D014161:Transduction, Genetic; D014771:Virion
chemical_list: D004272:DNA, Mitochondrial; D024101:Mitochondrial Proteins; D012358:RNA, Transfer, Met; C024988:tRNA, formylmethionine-; D051545:Cyclooxygenase 1; C496511:PTGS1 protein, human; D019877:Hydroxymethyl and Formyl Transferases; C021561:methionyl-tRNA formyltransferase