Sfxn1, a multipass inner mitochondrial membrane protein, functions as a mitochondrial serine transporter essential for one-carbon metabolism [1]. One-carbon metabolism generates crucial metabolites like nucleotides, and Sfxn1 enables the entry of serine into mitochondria for its conversion into glycine and formate. It is also associated with multiple biological processes and diseases.

In genetic studies, SFXN1-null human cells show defects in glycine and purine synthesis, similar to cells lacking other mitochondrial components of one-carbon metabolism [1]. In zebrafish, both knockdown and knockout of sfxn1 result in hypochromic anemia due to hemoglobin biosynthetic deficiency, revealing its importance in erythrocyte maturation [3]. In lung adenocarcinoma (LUAD), SFXN1 is upregulated and associated with poor prognosis. RNA-seq and scRNA-seq analyses show increased SFXN1 expression in tumor cells accompanied by decreased infiltration of NK and cytotoxic T cells. Knockdown of SFXN1 reduces cell proliferation and migration in vitro and inhibits tumor growth in vivo [2]. In non-viral hepatocellular carcinoma, loss of SFXN1 expression suppresses lipid accumulation and ROS generation, and predicts clinical outcome [4].

In summary, Sfxn1 is vital for one-carbon metabolism, erythrocyte maturation, and is involved in multiple cancer-related processes. Gene-knockout models in different organisms have been crucial in revealing its functions in these biological processes and disease conditions, providing insights into potential therapeutic targets for related diseases.

References:

1. Kory, Nora, Wyant, Gregory A, Prakash, Gyan, Guo, Yang Eric, Sabatini, David M. . SFXN1 is a mitochondrial serine transporter required for one-carbon metabolism. In Science (New York, N.Y.), 362, . doi:10.1126/science.aat9528. https://pubmed.ncbi.nlm.nih.gov/30442778/

2. Li, Yanjun, Yang, Wenke, Liu, Chaojun, Zhang, Jiaqiang, Chang, Enqiang. 2024. SFXN1-mediated immune cell infiltration and tumorigenesis in lung adenocarcinoma: A potential therapeutic target. In International immunopharmacology, 132, 111918. doi:10.1016/j.intimp.2024.111918. https://pubmed.ncbi.nlm.nih.gov/38537539/

3. Bao, Binghao, An, Wenbin, Lu, Qunwei, Zhu, Xiaofan, Jia, Haibo. 2021. Sfxn1 is essential for erythrocyte maturation via facilitating hemoglobin production in zebrafish. In Biochimica et biophysica acta. Molecular basis of disease, 1867, 166096. doi:10.1016/j.bbadis.2021.166096. https://pubmed.ncbi.nlm.nih.gov/33524530/

4. Yagi, Kohei, Shimada, Shu, Akiyama, Yoshimitsu, Tanabe, Minoru, Tanaka, Shinji. 2023. Loss of SFXN1 mitigates lipotoxicity and predicts poor outcome in non-viral hepatocellular carcinoma. In Scientific reports, 13, 9449. doi:10.1038/s41598-023-36660-w. https://pubmed.ncbi.nlm.nih.gov/37296228/