SFXN1 is a mitochondrial serine transporter required for one-carbon metabolism

Science. 2018 Nov 16;362(6416):eaat9528. doi: 10.1126/science.aat9528.

Nora Kory ¹ ² ³ ⁴, Gregory A Wyant ^# ¹ ² ³ ⁴, Gyan Prakash ^# ¹, Jelmi Uit de Bos ¹, Francesca Bottanelli ⁵, Michael E Pacold ¹ ² ³ ⁴ ⁶, Sze Ham Chan ¹, Caroline A Lewis ¹, Tim Wang ¹ ² ³ ⁴, Heather R Keys ¹, Yang Eric Guo ¹, David M Sabatini ⁷ ² ³ ⁴

Affiliations

1 Whitehead Institute for Biomedical Research, 455 Main Street, Cambridge, MA 02142, USA.
2 Howard Hughes Medical Institute, Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
3 Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Department of Biology, 77 Massachusetts Avenue, Cambridge, MA 02139, USA.
4 Broad Institute of Harvard and Massachusetts Institute of Technology, 415 Main Street, Cambridge, MA 02142, USA.
5 Department of Cell Biology, Yale University School of Medicine, New Haven, CT 06520, USA.
6 Department of Radiation Oncology at NYU Langone Medical Center, New York, NY 10016, USA.
7 Whitehead Institute for Biomedical Research, 455 Main Street, Cambridge, MA 02142, USA. sabatini@wi.mit.edu.
# Contributed equally.

PMID: 30442778 DOI: 10.1126/science.aat9528

Abstract

One-carbon metabolism generates the one-carbon units required to synthesize many critical metabolites, including nucleotides. The pathway has cytosolic and mitochondrial branches, and a key step is the entry, through an unknown mechanism, of serine into mitochondria, where it is converted into glycine and formate. In a CRISPR-based genetic screen in human cells for genes of the mitochondrial pathway, we found sideroflexin 1 (SFXN1), a multipass inner mitochondrial membrane protein of unclear function. Like cells missing mitochondrial components of one-carbon metabolism, those null for SFXN1 are defective in glycine and purine synthesis. Cells lacking SFXN1 and one of its four homologs, SFXN3, have more severe defects, including being auxotrophic for glycine. Purified SFXN1 transports serine in vitro. Thus, SFXN1 functions as a mitochondrial serine transporter in one-carbon metabolism.

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