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.
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)