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.
journal_name
Mol Celljournal_title
Molecular cellauthors
Minton DR,Nam M,McLaughlin DJ,Shin J,Bayraktar EC,Alvarez SW,Sviderskiy VO,Papagiannakopoulos T,Sabatini DM,Birsoy K,Possemato Rdoi
10.1016/j.molcel.2018.01.024subject
Has Abstractpub_date
2018-02-15 00:00:00pages
610-621.e5issue
4eissn
1097-2765issn
1097-4164pii
S1097-2765(18)30053-4journal_volume
69pub_type
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