Slc48a1, also known as Hrg1 (heme responsive gene-1), encodes a protein responsible for transporting heme. It plays a crucial role in heme-iron recycling and is associated with pathways related to iron homeostasis. This gene is important for maintaining normal cellular iron levels and is involved in various biological processes, such as erythrocyte recycling and myelination [2,3,4]. Genetic models, like knockout mouse models, have been valuable in studying its functions [2,4,5].

In SLC48A1 -deficient mice, visible hemozoin first appears in reticuloendothelial system macrophages at 8 days of age, indicating disrupted erythrocyte recycling. These mice accumulate heme in macrophages as hemozoin crystals, with reduced iron recycling equivalent to at least 10 parts per million of dietary iron, and they show impaired erythroid maturation and inability to respond to iron deficiency [2,5]. In zebrafish, genetic ablation of Hrg1a and Hrg1b (paralogs of Hrg1) leads to lower iron accumulation and higher amounts of heme sequestered in kidney macrophages, along with large-scale perturbation in genes related to heme, iron metabolism, and immune functions [4]. In Hrg1 null mutant mice, there are reduced myelin iron levels, decreased expression of myelin associated glycoprotein (Mag), and ultrastructural myelin defects, suggesting a role in myelin integrity [1].

In conclusion, Slc48a1 is essential for heme-iron recycling and myelin integrity. The study of Slc48a1 knockout mouse models has provided insights into its role in iron-related disorders and myelin-associated diseases, highlighting its significance in understanding these biological processes and potential disease mechanisms [1,2,4,5].

References:

1. Stockley, John H, Vaquie, Adrien M, Xu, Zhaoyang, Hamza, Iqbal, Rowitch, David H. 2024. Oligodendrocyte Slc48a1 (Hrg1) encodes a functional heme transporter required for myelin integrity. In Glia, 73, 399-421. doi:10.1002/glia.24641. https://pubmed.ncbi.nlm.nih.gov/39501820/

2. Simmons, William R, Wain, Lily, Toker, Joseph, Hamza, Iqbal, Bodine, David M. 2020. Normal Iron Homeostasis Requires the Transporter SLC48A1 for Efficient Heme-Iron Recycling in Mammals. In Frontiers in genome editing, 2, 8. doi:10.3389/fgeed.2020.00008. https://pubmed.ncbi.nlm.nih.gov/34713217/

3. Khan, Anwar A, Quigley, John G. . Heme and FLVCR-related transporter families SLC48 and SLC49. In Molecular aspects of medicine, 34, 669-82. doi:10.1016/j.mam.2012.07.013. https://pubmed.ncbi.nlm.nih.gov/23506900/

4. Zhang, Jianbing, Chambers, Ian, Yun, Sijung, Krause, Michael, Hamza, Iqbal. 2018. Hrg1 promotes heme-iron recycling during hemolysis in the zebrafish kidney. In PLoS genetics, 14, e1007665. doi:10.1371/journal.pgen.1007665. https://pubmed.ncbi.nlm.nih.gov/30248094/

5. Pek, Rini H, Yuan, Xiaojing, Rietzschel, Nicole, Bodine, David M, Hamza, Iqbal. 2019. Hemozoin produced by mammals confers heme tolerance. In eLife, 8, . doi:10.7554/eLife.49503. https://pubmed.ncbi.nlm.nih.gov/31571584/