TitleMitochondrial translation requires folate-dependent tRNA methylation.
Publication TypeJournal Article
Year of Publication2018
AuthorsMorscher, RJ, Ducker, GS, Li, SHsin-Jung, Mayer, JA, Gitai, Z, Sperl, W, Rabinowitz, JD
Date Published2018 02 01
KeywordsAminohydrolases, Biocatalysis, Carrier Proteins, Codon, Electron Transport, Folic Acid, Folic Acid Antagonists, Glycine Hydroxymethyltransferase, GTP-Binding Proteins, Guanosine, HCT116 Cells, HEK293 Cells, Humans, Leucine, Lysine, Methylation, Methylenetetrahydrofolate Dehydrogenase (NADP), Mitochondria, Multifunctional Enzymes, Oxidative Phosphorylation, Protein Biosynthesis, Ribosomes, RNA, Transfer, Sarcosine, Tetrahydrofolates, Thymine Nucleotides

Folates enable the activation and transfer of one-carbon units for the biosynthesis of purines, thymidine and methionine. Antifolates are important immunosuppressive and anticancer agents. In proliferating lymphocytes and human cancers, 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 metabolism. 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.

Alternate JournalNature
PubMed ID29364879
PubMed Central IDPMC6020024
Grant ListDP1 DK113643 / DK / NIDDK NIH HHS / United States
F31 DK113653 / DK / NIDDK NIH HHS / United States
DP1 AI124669 / AI / NIAID NIH HHS / United States
R01 CA163591 / CA / NCI NIH HHS / United States
R01 GM107384 / GM / NIGMS NIH HHS / United States