Slc25a38, a mitochondrial solute carrier, is crucial for mitochondrial glycine transport [1,4,8,9]. It's involved in pathways like heme biosynthesis, as glycine is a key precursor for heme production. Additionally, it plays a role in regulating mitochondrial pyridoxal 5'-phosphate (PLP) levels, which is essential for numerous enzymatic reactions within the mitochondria [3]. Genetic models, such as mouse models, have been valuable in studying Slc25a38's functions.

Mutations in Slc25a38 cause the most common recessive form of congenital sideroblastic anemia (CSA), characterized by pathologic iron deposits in erythroblast mitochondria [1,5,6,8,10]. A mouse model of SLC25A38-CSA demonstrated extreme hypersensitivity to pyridoxine deficiency, uncovering a conditional synthetic lethality between heme synthesis-related CSAs and pyridoxine deficiency [5]. In uveal melanoma, low expression of SLC25A38 promotes angiogenesis and metastasis, acting as a novel biomarker for predicting metastatic risk and survival [2]. Also, in acute lymphoblastic leukemia cells, SLC25A38 is highly expressed, potentially serving as a diagnostic biomarker and therapeutic target [7].

In summary, Slc25a38 is essential for mitochondrial function, especially in processes related to heme synthesis and PLP regulation. Mouse models have been instrumental in understanding its role in diseases like congenital sideroblastic anemia, highlighting its significance in disease-related research and potentially paving the way for new therapeutic strategies in these disease areas.

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/