Mitochondrial translation requires folate-dependent tRNA methylation
- 24 January 2018
- journal article
- research article
- Published by Springer Science and Business Media LLC in Nature
- Vol. 554 (7690), 128-132
- https://doi.org/10.1038/nature25460
Abstract
Mammalian mitochondria use folate-bound one-carbon units generated by the enzyme SHMT2 to methylate tRNA, and this modification is required for mitochondrial translation and thus oxidative phosphorylation. Folates have an important role in intracellular metabolism, as they mediate the biosynthesis of purines, thymidine and methionine by exporting one-carbon units from mitochondria to the cytoplasm. The mitochondria-localized folate enzymes are strongly upregulated in human cancer cells, for reasons that have been unclear. Joshua Rabinowitz and colleagues provide an explanation for this observation by showing that, in addition to their role in cytoplasmic metabolism, folates are required for protein translation within mitochondria. Mammalian mitochondria use folate-bound one-carbon units to methylate transfer RNAs in a codon-specific manner. This modification is in turn required for the translation of respiratory chain proteins and, therefore, for oxidative phosphorylation. The authors further show that defects in folate-associated translation occur in certain human disorders characterized by inborn errors of mitochondrial metabolism—MERRF and MELAS. Folates enable the activation and transfer of one-carbon units for the biosynthesis of purines, thymidine and methionine1,2,3. Antifolates are important immunosuppressive4 and anticancer agents5. In proliferating lymphocytes6 and human cancers7,8, mitochondrial folate enzymes are particularly strongly upregulated. This in part reflects the need for mitochondria to generate one-carbon units and export them to the cytosol for anabolic metabolism2,9. The full range of uses of folate-bound one-carbon units in the mitochondrial compartment itself, however, has not been thoroughly explored. Here we show that loss of the catalytic activity of the mitochondrial folate enzyme serine hydroxymethyltransferase 2 (SHMT2), but not of other folate enzymes, leads to defective oxidative phosphorylation in human cells due to impaired mitochondrial translation. We find that SHMT2, presumably by generating mitochondrial 5,10-methylenetetrahydrofolate, provides methyl donors to produce the taurinomethyluridine base at the wobble position of select mitochondrial tRNAs. Mitochondrial ribosome profiling in SHMT2-knockout human cells reveals that the lack of this modified base causes defective translation, with preferential mitochondrial ribosome stalling at certain lysine (AAG) and leucine (UUG) codons. This results in the impaired expression of respiratory chain enzymes. Stalling at these specific codons also occurs in certain inborn errors of mitochondrial metabolism. Disruption of whole-cell folate metabolism, by either folate deficiency or antifolate treatment, also impairs the respiratory chain. In summary, mammalian mitochondria use folate-bound one-carbon units to methylate tRNA, and this modification is required for mitochondrial translation and thus oxidative phosphorylation.Keywords
This publication has 79 references indexed in Scilit:
- Ribosome profiling reveals pervasive and regulated stop codon readthrough in Drosophila melanogastereLife, 2013
- TopHat2: accurate alignment of transcriptomes in the presence of insertions, deletions and gene fusionsGenome Biology, 2013
- ALKBH5 Is a Mammalian RNA Demethylase that Impacts RNA Metabolism and Mouse FertilityMolecular Cell, 2013
- Mutations of the Mitochondrial-tRNA Modifier MTO1 Cause Hypertrophic Cardiomyopathy and Lactic AcidosisAmerican Journal of Human Genetics, 2012
- LC‐MS Data Processing with MAVEN: A Metabolomic Analysis and Visualization EngineCurrent Protocols in Bioinformatics, 2012
- Selective Ribosome Profiling Reveals the Cotranslational Chaperone Action of Trigger Factor In VivoCell, 2011
- Mutations in MTFMT Underlie a Human Disorder of Formylation Causing Impaired Mitochondrial TranslationCell Metabolism, 2011
- The AlkB Domain of Mammalian ABH8 Catalyzes Hydroxylation of 5‐Methoxycarbonylmethyluridine at the Wobble Position of tRNAAngewandte Chemie-International Edition, 2010
- Predicting transmembrane protein topology with a hidden markov model: application to complete genomesJournal of Molecular Biology, 2001
- An approach to correlate tandem mass spectral data of peptides with amino acid sequences in a protein databaseJournal of the American Society for Mass Spectrometry, 1994