Molecular Cell
Volume 69, Issue 4, 15 February 2018, Pages 610-621.e5
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Article
Serine Catabolism by SHMT2 Is Required for Proper Mitochondrial Translation Initiation and Maintenance of Formylmethionyl-tRNAs

https://doi.org/10.1016/j.molcel.2018.01.024Get rights and content
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Highlights

  • Cells lacking SHMT2 are sensitive to glucose restriction

  • The mitochondrial one-carbon pool supports respiration

  • SHMT2 loss disrupts proper translation of mitochondrially encoded proteins

  • Serine contributes to methionine formylation on mitochondrial initiator tRNAs

Summary

Upon glucose restriction, eukaryotic cells upregulate oxidative metabolism to maintain homeostasis. Using genetic screens, we find that the mitochondrial serine hydroxymethyltransferase (SHMT2) is required for robust mitochondrial oxygen consumption and low glucose proliferation. SHMT2 catalyzes the first step in mitochondrial one-carbon metabolism, which, particularly in proliferating cells, produces tetrahydrofolate (THF)-conjugated one-carbon units used in cytoplasmic reactions despite the presence of a parallel cytoplasmic pathway. Impairing cytoplasmic one-carbon metabolism or blocking efflux of one-carbon units from mitochondria does not phenocopy SHMT2 loss, indicating that a mitochondrial THF cofactor is responsible for the observed phenotype. The enzyme MTFMT utilizes one such cofactor, 10-formyl THF, producing formylmethionyl-tRNAs, specialized initiator tRNAs necessary for proper translation of mitochondrially encoded proteins. Accordingly, SHMT2 null cells specifically fail to maintain formylmethionyl-tRNA pools and mitochondrially encoded proteins, phenotypes similar to those observed in MTFMT-deficient patients. These findings provide a rationale for maintaining a compartmentalized one-carbon pathway in mitochondria.

Keywords

SHMT2
serine
one-carbon metabolism
formylmethionine
metabolism

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