Slc3a1, also known as solute carrier family 3 (cystine, basic and) neutral amino acid transporter, member 1, codes for the protein related to the system bo,+ amino-acid transporter (rBAT) [3]. It is a crucial component of the b0,+ transporter system, which is involved in the reabsorption of cystine, ornithine, lysine, and arginine in the renal proximal tubule [2,3,4,6]. Mutations in Slc3a1 are associated with cystinuria, a genetic disorder leading to high concentrations of cystine in the urine and recurrent nephrolithiasis [2,3,4,5,6,7]. Genetic models, such as knockout mice, are valuable for studying its functions.

In Slc3a1 knockout male mice, more severe stone formation and renal injuries were observed compared to females, suggesting its role in the sexual dimorphism of cystinuria [1]. Further investigations revealed that higher SLC3A1 levels in male kidneys enhance mitochondrial functions through modulation of mitochondrial NAD+ uptake, primarily in proximal tubule cells. This aberrant mitochondrial function was the primary factor contributing to the severity of cystinuria in Slc3a1 knockout male mice [1].

In conclusion, Slc3a1 is essential for the normal reabsorption of certain amino acids in the renal proximal tubule. Its deficiency in male mice models reveals its role in the sexual dimorphism of cystinuria, mainly through its impact on mitochondrial functions. These findings from Slc3a1 knockout mouse models provide novel insights into the potential interventions for cystinuria [1].

References:

1. Su, Jingyi, Pan, Yongdong, Zhong, Fengbo, Guan, Yuting, Xu, Guofeng. 2024. Mitochondrial SLC3A1 regulates sexual dimorphism in cystinuria. In Genes & diseases, 12, 101472. doi:10.1016/j.gendis.2024.101472. https://pubmed.ncbi.nlm.nih.gov/40110490/

2. D'Ambrosio, Viola, Capolongo, Giovanna, Goldfarb, David, Gambaro, Giovanni, Ferraro, Pietro Manuel. 2021. Cystinuria: an update on pathophysiology, genetics, and clinical management. In Pediatric nephrology (Berlin, Germany), 37, 1705-1711. doi:10.1007/s00467-021-05342-y. https://pubmed.ncbi.nlm.nih.gov/34812923/

3. Breuning, M H, Hamdy, N A T C. . [From gene to disease; SLC3A1, SLC7A9 and cystinuria]. In Nederlands tijdschrift voor geneeskunde, 147, 245-7. doi:. https://pubmed.ncbi.nlm.nih.gov/12621979/

4. Mattoo, Aditya, Goldfarb, David S. . Cystinuria. In Seminars in nephrology, 28, 181-91. doi:10.1016/j.semnephrol.2008.01.011. https://pubmed.ncbi.nlm.nih.gov/18359399/

5. Liu, Danhua, Zhao, Yongli, Xue, Xia, Guo, Jiancheng, Xu, Changbao. 2023. Novel compound heterozygous pathogenic variants in the SLC3A1 gene in a Chinese family with cystinuria. In BMC medical genomics, 16, 333. doi:10.1186/s12920-023-01767-6. https://pubmed.ncbi.nlm.nih.gov/38114997/

6. Dello Strologo, Luca, Rizzoni, Gianfranco. . Cystinuria. In Acta paediatrica (Oslo, Norway : 1992). Supplement, 95, 31-3. doi:. https://pubmed.ncbi.nlm.nih.gov/16801163/

7. Bai, Peide, Zhang, WenZhao, Lai, Longhui, Wang, Tao, Chen, Bin. 2023. Declaration: Novel SLC3A1 mutation in a cystinuria patient with xanthine stones: a case report. In BMC urology, 23, 130. doi:10.1186/s12894-023-01300-y. https://pubmed.ncbi.nlm.nih.gov/37525149/