Slc25a38-KO Mouse

Slc25a38, a member of the mitochondrial solute carrier family SLC25, is a mitochondrial inner membrane protein. It functions as a glycine carrier [1,4,8,9]. Many proteins require pyridoxal 5'-phosphate (PLP) as a cofactor, and SLC25A38 is involved in mitochondrial PLP accumulation, influencing enzymatic reactions like serine to glycine conversion and ornithine aminotransferase [3]. It is also associated with heme biosynthesis as it supplies mitochondrial glycine for ALAS2 [5].

Mutations in Slc25a38 cause the most common recessive form of congenital sideroblastic anemia (CSA) [1,5,6,8,10]. In a study of 31 individuals from 24 families, 11 novel mutations were identified [1]. In uveal melanoma, low expression of SLC25A38 promotes angiogenesis and metastasis, and is an independent predictive and prognostic factor [2]. In acute lymphoblastic leukemia cells, SLC25A38 is highly expressed and may be a biomarker and therapeutic target [7]. Knock-out of SLC25A38 in UM cells enhanced migration and promoted distant metastasis in mice [2]. Murine models of SLC25A38-CSA showed extreme hypersensitivity to pyridoxine deficiency, uncovering a conditional synthetic lethality between SLC25A38-related CSA and pyridoxine deficiency [5].

In summary, Slc25a38 is crucial for mitochondrial functions, especially in glycine transport and PLP accumulation. Its role in diseases like congenital sideroblastic anemia, uveal melanoma, and acute lymphoblastic leukemia has been revealed through various studies, with murine models providing insights into the pathophysiology and potential therapeutic approaches for SLC25A38-related congenital sideroblastic anemia [1-8,10].

References:

1. Heeney, Matthew M, Berhe, Simon, Campagna, Dean R, Bottomley, Sylvia S, Fleming, Mark D. 2021. SLC25A38 congenital sideroblastic anemia: Phenotypes and genotypes of 31 individuals from 24 families, including 11 novel mutations, and a review of the literature. In Human mutation, 42, 1367-1383. doi:10.1002/humu.24267. https://pubmed.ncbi.nlm.nih.gov/34298585/

2. Fan, Zhongyi, Duan, Jingjing, Luo, Pu, Zhang, Lei, Xu, Xiaojie. 2022. SLC25A38 as a novel biomarker for metastasis and clinical outcome in uveal melanoma. In Cell death & disease, 13, 330. doi:10.1038/s41419-022-04718-8. https://pubmed.ncbi.nlm.nih.gov/35411037/

3. Pena, Izabella A, Shi, Jeffrey S, Chang, Sarah M, Vander Heiden, Matthew G, Heiman, Myriam. 2025. SLC25A38 is required for mitochondrial pyridoxal 5'-phosphate (PLP) accumulation. In Nature communications, 16, 978. doi:10.1038/s41467-025-56130-3. https://pubmed.ncbi.nlm.nih.gov/39856062/

4. Tan, Sijie, Dengler, Alisa Susan, Darawsheh, Rami Zahi, Kory, Nora. 2024. The iAAA-mitochondrial protease YME1L1 regulates the degradation of the short-lived mitochondrial transporter SLC25A38. In bioRxiv : the preprint server for biology, , . doi:10.1101/2024.05.12.593764. https://pubmed.ncbi.nlm.nih.gov/38979268/

5. Ducamp, Sarah, Sendamarai, Anoop K, Campagna, Dean R, Schmidt, Paul J, Fleming, Mark D. . Murine models of erythroid 5ALA synthesis disorders and their conditional synthetic lethal dependency on pyridoxine. In Blood, 144, 1418-1432. doi:10.1182/blood.2023023078. https://pubmed.ncbi.nlm.nih.gov/38900972/

6. Ravindra, Niveditha, Athiyarath, Rekha, S, Eswari, George, Biju, Edison, Eunice Sindhuvi. 2020. Novel frameshift variant (c.409dupG) in SLC25A38 is a common cause of congenital sideroblastic anaemia in the Indian subcontinent. In Journal of clinical pathology, 74, 157-162. doi:10.1136/jclinpath-2020-206647. https://pubmed.ncbi.nlm.nih.gov/32605921/

7. Chen, Huaying, Lu, Quanyi, Zhang, Yunwu, Zhang, Han, Xu, Huaxi. 2014. Overexpression of SLC25A38 protein on acute lymphoblastic leukemia cells. In Oncology letters, 7, 1422-1426. doi:. https://pubmed.ncbi.nlm.nih.gov/24765149/

8. Kannengiesser, Caroline, Sanchez, Mayka, Sweeney, Marion, Grandchamp, Bernard, May, Alison. 2011. Missense SLC25A38 variations play an important role in autosomal recessive inherited sideroblastic anemia. In Haematologica, 96, 808-13. doi:10.3324/haematol.2010.039164. https://pubmed.ncbi.nlm.nih.gov/21393332/

9. Sha, Zhou, Benkovic, Stephen J. 2024. Purinosomes spatially co-localize with mitochondrial transporters. In The Journal of biological chemistry, 300, 107620. doi:10.1016/j.jbc.2024.107620. https://pubmed.ncbi.nlm.nih.gov/39098527/

10. Andolfo, Immacolata, Martone, Stefania, Ribersani, Michela, Iolascon, Achille, Russo, Roberta. 2020. Apparent recessive inheritance of sideroblastic anemia type 2 due to uniparental isodisomy at the SLC25A38 locus. In Haematologica, 105, 2883-2886. doi:10.3324/haematol.2020.258533. https://pubmed.ncbi.nlm.nih.gov/33256393/