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View Proteins belonging to: The Sideroflexin (SFXN) Family (formerly the Mitochondrial Tricarboxylate Carrier (MTC) Family)

2.A.54 The Sideroflexin (SFXN) Family (formerly the Mitochondrial Tricarboxylate Carrier (MTC) Family)

The SFXN family (the (SLC56 family) consists of a limited number of homologues, all from eukaryotes. This sideroblastic-associated protein family was first identified in metazoans and was termed the sideroflexin (Sfxn) family. The metazoan Sfxn family comprises five groups of paralogous proteins, present in mitochondria and whose functions are in many cases uncertain. Using an in silico approach, several sideroflexin sequences from the genomes of different fungal species have been identified. An in-depth phylogenetic analysis of these fungal Sfxn sequences (termed Fsf1p) showed that they form a distinct clade within the metazoan Sfxn family. Hydrophobic cluster analysis and transmembrane topological mapping allowed comparison of conserved regions among Fsf1 and Sfxn proteins. The results indicate that Fsf1 probably belongs to an ancient, mitochondrial group of proteins, necessary to maintain the homeostasis of iron within this organelle (Miotto et al. 2007). Several members of the family have been partially functionally characterized. One is the tricarboxylate carrier from rat liver mitochondria. It is 357 amino acyl residues in length with 5 putative TMSs (Schmidt et al. 2018). It does not exhibit obvious internal repeats or show homology to proteins of the mitochondrial carrier family (TC #2.A.29). Homologues are found in Caenorhabditis elegans, Saccharomyces cerevisiae, Leishmania major and Homo sapiens. They are of 285-293 amino acyl residues with some exceptions, and are reported to possess 3-6 putative TMSs. the five sideroflexin genes in Xenopus show overlapping but nonsimilar expression patterns during Xenopus embryogenesis (Li et al. 2010).

The rat liver mitochondrial tricarboxylate carrier has been reported to transport citrate, cis-aconitate, threo-D-isocitrate, D- and L-tartrate, malate, succinate and phosphoenolpyruvate. Trans-aconitate, α-ketoglutarate and malonate are not substrates. It presumably functions by a proton symport mechanism for the uptake of the variety of anionic substrates listed above (Schmidt et al. 2018). It is possible that it transports a citate-iron complex, explaining its effect on iron metabolism. Sideroflexins are highly conserved multi-spanning transmembrane proteins in the inner mitochondrial membrane in eukaryotes. Tifoun et al. 2021 reviewed sideroflexins, their presumed mitochondrial functions and the evidence linking sideroflexins to iron homeostasis and iron-sulfur cluster biogenesis. Members of this family have been reported to have the SLC56 fold (Ferrada and Superti-Furga 2022).

The generalized transport reaction catalyzed by the SSFXN protein of rat liver mitochondria is therefore probably:

anionic substrate (out) + nH+ (out) → anionic substrate (in) + nH+ (in)

View Proteins belonging to: The Sideroflexin (SFXN) Family (formerly the Mitochondrial Tricarboxylate Carrier (MTC) Family)

References associated with 2.A.54 family:

Acoba, M.G., E.S.S. Alpergin, S. Renuse, L. Fernández-Del-Río, Y.W. Lu, O. Khalimonchuk, C.F. Clarke, A. Pandey, M.J. Wolfgang, and S.M. Claypool. (2021). The mitochondrial carrier SFXN1 is critical for complex III integrity and cellular metabolism. Cell Rep 34: 108869. 33730581

Amorim, I.S., L.C. Graham, R.N. Carter, N.M. Morton, F. Hammachi, T. Kunath, G. Pennetta, S.M. Carpanini, J.C. Manson, D.J. Lamont, T.M. Wishart, and T.H. Gillingwater. (2017). Sideroflexin 3 is an α-synuclein-dependent mitochondrial protein that regulates synaptic morphology. J Cell Sci 130: 325-331. 28049716

Azzi, A., M. Glerum, R. Koller, W. Mertens and S. Spycher (1993). The mitochondrial tricarboxylate carrier. J. Bioenerg. Biomembr. 25: 515-524. 8132491

Ferrada, E. and G. Superti-Furga. (2022). A structure and evolutionary-based classification of solute carriers. iScience 25: 105096. 36164651

Gyimesi, G. and M.A. Hediger. (2020). Sequence Features of Mitochondrial Transporter Protein Families. Biomolecules 10:. 33260588

Hildick-Smith, G.J., J.D. Cooney, C. Garone, L.S. Kremer, T.B. Haack, J.N. Thon, N. Miyata, D.S. Lieber, S.E. Calvo, H.O. Akman, Y.Y. Yien, N.C. Huston, D.S. Branco, D.I. Shah, M.L. Freedman, C.M. Koehler, J.E. Italiano, Jr, A. Merkenschlager, S. Beblo, T.M. Strom, T. Meitinger, P. Freisinger, M.A. Donati, H. Prokisch, V.K. Mootha, S. DiMauro, and B.H. Paw. (2013). Macrocytic anemia and mitochondriopathy resulting from a defect in sideroflexin 4. Am J Hum Genet 93: 906-914. 24119684

Jackson, T.D., D.H. Hock, K.M. Fujihara, C.S. Palmer, A.E. Frazier, Y.C. Low, Y. Kang, C.S. Ang, N.J. Clemons, D.R. Thorburn, D.A. Stroud, and D. Stojanovski. (2021). The TIM22 complex mediates the import of sideroflexins and is required for efficient mitochondrial one-carbon metabolism. Mol. Biol. Cell 32: 475-491. 33476211

Kory, N., G.A. Wyant, G. Prakash, J. Uit de Bos, F. Bottanelli, M.E. Pacold, S.H. Chan, C.A. Lewis, T. Wang, H.R. Keys, Y.E. Guo, and D.M. Sabatini. (2018). SFXN1 is a mitochondrial serine transporter required for one-carbon metabolism. Science 362:. 30442778

Li, X., D. Han, R. Kin Ting Kam, X. Guo, M. Chen, Y. Yang, H. Zhao, and Y. Chen. (2010). Developmental expression of sideroflexin family genes in Xenopus embryos. Dev Dyn 239: 2742-2747. 20737508

Lockhart, P.J., B. Holtom, S. Lincoln, J. Hussey, A. Zimprich, T. Gasser, Z.K. Wszolek, J. Hardy, and M.J. Farrer. (2002). The human sideroflexin 5 (SFXN5) gene: sequence, expression analysis and exclusion as a candidate for PARK3. Gene 285: 229-237. 12039050

Mi, D., I. Yanatori, H. Zheng, Y. Kong, T. Hirayama, and S. Toyokuni. (2024). Association of poly()-binding protein-2 with sideroflexin-3 through TOM20 as an iron entry pathway to mitochondria. Free Radic Res 58: 261-275. 38599240

Miotto, G., S. Tessaro, G.A. Rotta, and D. Bonatto. (2007). In silico analyses of Fsf1 sequences, a new group of fungal proteins orthologous to the metazoan sideroblastic anemia-related sideroflexin family. Fungal Genet Biol 44: 740-753. 17240176

Mon, E.E., F.Y. Wei, R.N.R. Ahmad, T. Yamamoto, T. Moroishi, and K. Tomizawa. (2019). Regulation of mitochondrial iron homeostasis by sideroflexin 2. J. Physiol. Sci 69: 359-373. 30570704

Paul, B.T., L. Tesfay, C.R. Winkler, F.M. Torti, and S.V. Torti. (2019). Sideroflexin 4 affects Fe-S cluster biogenesis, iron metabolism, mitochondrial respiration and heme biosynthetic enzymes. Sci Rep 9: 19634. 31873120

Rivell, A., R.S. Petralia, Y.X. Wang, M.P. Mattson, and P.J. Yao. (2019). Sideroflexin 3 is a Mitochondrial Protein Enriched in Neuron.s. Neuromolecular Med 21: 314-321. 31177362

Schmidt, R.S., J.P. Macêdo, M.E. Steinmann, A.G. Salgado, P. Bütikofer, E. Sigel, D. Rentsch, and P. Mäser. (2018). Transporters of Trypanosoma brucei-phylogeny, physiology, pharmacology. FEBS J. 285: 1012-1023. 29063677

Tifoun, N., J.M. De Las Heras, A. Guillaume, S. Bouleau, B. Mignotte, and N. Le Floch. (2021). Insights into the Roles of the Sideroflexins/SLC56 Family in Iron Homeostasis and Iron-Sulfur Biogenesis. Biomedicines 9:. 33494450

Tifoun, N., M. Bekhouche, J.M. De Las Heras, A. Guillaume, S. Bouleau, I. Guénal, B. Mignotte, and N. Le Floch. (2022). A High-Throughput Search for SFXN1 Physical Partners Led to the Identification of ATAD3, HSD10 and TIM50. Biology (Basel) 11:. 36138777

Zheng, H., C. Ji, X. Zou, M. Wu, Z. Jin, G. Yin, J. Li, C. Feng, H. Cheng, S. Gu, Y. Xie, and Y. Mao. (2003). Molecular cloning and characterization of a novel human putative transmembrane protein homologous to mouse sideroflexin associated with sideroblastic anemia. DNA Seq 14: 369-373. 14756423