2. Academic Validation
  3. Serine Catabolism by SHMT2 Is Required for Proper Mitochondrial Translation Initiation and Maintenance of Formylmethionyl-tRNAs

Serine Catabolism by SHMT2 Is Required for Proper Mitochondrial Translation Initiation and Maintenance of Formylmethionyl-tRNAs

  • Mol Cell. 2018 Feb 15;69(4):610-621.e5. doi: 10.1016/j.molcel.2018.01.024.
Denise R Minton 1,  Minwoo Nam 1,  Daniel J McLaughlin 1,  Jong Shin 1,  Erol C Bayraktar 2,  Samantha W Alvarez 1,  Vladislav O Sviderskiy 1,  Thales Papagiannakopoulos 1,  David M Sabatini 3,  Kıvanç Birsoy 4,  Richard Possemato 5
Affiliations

Affiliations

  • 1 Department of Pathology, NYU School of Medicine, New York, NY 10016, USA; Laura and Isaac Perlmutter Cancer Center, NYU School of Medicine, New York, NY 10016, USA.
  • 2 Laboratory of Metabolic Regulation and Genetics, The Rockefeller University, 1230 York Avenue, New York, NY 10065, USA.
  • 3 Whitehead Institute for Biomedical Research, Nine Cambridge Center, Cambridge, MA 02142, USA; Howard Hughes Medical Institute, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; David H. Koch Institute for Integrative Cancer Research at MIT, 77 Massachusetts Avenue, Cambridge, MA 02139, USA; Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Broad Institute of Harvard and MIT, Seven Cambridge Center, Cambridge, MA 02142, USA.
  • 4 Laboratory of Metabolic Regulation and Genetics, The Rockefeller University, 1230 York Avenue, New York, NY 10065, USA. Electronic address: [email protected].
  • 5 Department of Pathology, NYU School of Medicine, New York, NY 10016, USA; Laura and Isaac Perlmutter Cancer Center, NYU School of Medicine, New York, NY 10016, USA. Electronic address: [email protected].
PMID: 29452640 DOI: 10.1016/j.molcel.2018.01.024
Abstract

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; formylmethionine; metabolism; one-carbon metabolism; serine.

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