Sfxn3-KO Mouse

Sfxn3, also known as citrate transporter protein-like protein (CTPL), is a mitochondrial protein. It functions as a serine transporter in one-carbon metabolism, which is crucial for the synthesis of critical metabolites like nucleotides [2]. It is also involved in iron entry into mitochondria through the PCBP2-TOM20-SFXN3 axis [5]. Sfxn3 is enriched in neurons and is developmentally expressed [6].

In non-M3 acute myeloid leukemia (AML) patients, high SFXN3 levels are associated with poor clinical outcomes, frequent blast cells, and DNA hypermethylation at transcription start sites. Non-M3 AML patients with high SFXN3 levels show a higher complete remission (CR) ratio when receiving hypomethylating therapy [1]. In AML, knockdown of SFXN3 enhances cell apoptosis, reduces cell proliferation, and decreases the expression of CCND1 and NFKB1 [4]. In neurodegenerative disease models, overexpression of SFXN3 orthologues in Drosophila models of Parkinson's disease significantly reduced dopaminergic neuron loss, while Sfxn3-KO mice did not show neurodegeneration, indicating an anti-neurodegeneration role for SFXN3 [3]. In mice, Sfxn3 mutations lead to progressive outer retinal degeneration, disrupting synapses and synaptic ribbons in the outer plexiform layer [7].

In conclusion, Sfxn3 plays essential roles in one-carbon metabolism, iron entry into mitochondria, and is important in neurons. Through gene-knockout models, its functions in diseases such as AML, neurodegenerative diseases, and retinal degeneration have been revealed. These findings contribute to understanding the biological processes and mechanisms underlying these diseases, potentially providing new targets for treatment.

References:

1. Dong, Yuxuan, Jin, Fengbo, Wang, Jing, Xia, Leiming, Yang, Mingzhen. . SFXN3 is Associated with Poor Clinical Outcomes and Sensitivity to the Hypomethylating Therapy in Non-M3 Acute Myeloid Leukemia Patients. In Current gene therapy, 23, 410-418. doi:10.2174/1566523223666230724121515. https://pubmed.ncbi.nlm.nih.gov/37491851/

2. 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/

3. Ledahawsky, Leire M, Terzenidou, Maria Eirini, Edwards, Ruairidh, Wishart, Thomas M, Gillingwater, Thomas H. 2022. The mitochondrial protein Sideroflexin 3 (SFXN3) influences neurodegeneration pathways in vivo. In The FEBS journal, 289, 3894-3914. doi:10.1111/febs.16377. https://pubmed.ncbi.nlm.nih.gov/35092170/

4. Jin, Fengbo, He, Limei, Wang, Jing, Zhang, Yu, Yang, Mingzhen. 2024. SFXN3 is a Prognostic Marker and Promotes the Growth of Acute Myeloid Leukemia. In Cell biochemistry and biophysics, 82, 2195-2204. doi:10.1007/s12013-024-01326-5. https://pubmed.ncbi.nlm.nih.gov/38877336/

5. Mi, Danyang, Yanatori, Izumi, Zheng, Hao, Hirayama, Tasuku, Toyokuni, Shinya. 2024. Association of poly(rC)-binding protein-2 with sideroflexin-3 through TOM20 as an iron entry pathway to mitochondria. In Free radical research, 58, 261-275. doi:10.1080/10715762.2024.2340711. https://pubmed.ncbi.nlm.nih.gov/38599240/

6. Rivell, Aileen, Petralia, Ronald S, Wang, Ya-Xian, Mattson, Mark P, Yao, Pamela J. 2019. Sideroflexin 3 is a Mitochondrial Protein Enriched in Neurons. In Neuromolecular medicine, 21, 314-321. doi:10.1007/s12017-019-08553-7. https://pubmed.ncbi.nlm.nih.gov/31177362/

7. Chen, Bo, Aredo, Bogale, Ding, Yi, Beutler, Bruce, Ufret-Vincenty, Rafael L. 2020. Forward genetic analysis using OCT screening identifies Sfxn3 mutations leading to progressive outer retinal degeneration in mice. In Proceedings of the National Academy of Sciences of the United States of America, 117, 12931-12942. doi:10.1073/pnas.1921224117. https://pubmed.ncbi.nlm.nih.gov/32457148/