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Mitochondrial serine (and possibly cystine and alanine) carrier, Sideroflexin-1 (SFXN1; SLC56A1), of 322 aas and probably 5 TMSs (Kory et al. 2018). This system is believed to be required for one-carbon metabolism because serine is converted into glycine and formate in the mitochondrion. SFXN1, an integral inner mitochondrial membrane (IMM) protein with an uneven number of transmembrane domains, is a TIM22 complex substrate. An SFXN1 deficiency leads to mitochondrial respiratory chain impairments, the most detrimental being to complex III (CIII) biogenesis, activity, and assembly, compromising coenzyme Q levels (Acoba et al. 2021). The CIII dysfunction is independent of one-carbon metabolism, the known primary role for SFXN1 as a mitochondrial serine transporter. Instead, SFXN1 supports CIII function by participating in heme and alpha-ketoglutarate metabolism. Thus, SFXN1-based amino acid transport impacts mitochondrial and cellular metabolic efficiency in multiple ways. The TIM22 complex mediates the import of sideroflexins which transport L- and D-serine and other amino acids, and it is therefore required for efficient mitochondrial one-carbon metabolism (Jackson et al. 2021). SFXN1 interacts with ATAD3 and HSD10, both associated with neurological disorders (Tifoun et al. 2022).

Metazoa, Chordata
SFXN1 of Homo sapiens

Hypothetical 36.7 KDa protein AH6.2
Metazoa, Nematoda
AH6.2 of Caenorhabditis elegans

Sideroflexin-4 (Breast cancer resistance marker 1) or SFXN4 (SLC56A4) of 337 aas and 6 TMSs in a  2 +2 + 2 TMS arrangement. It has been found mutated in mice with siderocytic anemia (Zheng et al. 2003).

Metazoa, Chordata
Sideroflexin-4 of Homo sapiens

Probable mitochondrial transport protein FSF1 (Fungal sideroflexin-1)
Fungi, Ascomycota
FSF1 of Saccharomyces cerevisiae

Sideroflexin-5 (SFXN5; SLC56A5) of 342 aas and 5 TMSs in a 1 + 2 + 2 TMS arrangement. The identification and characterization of the human sideroflexin 5 gene, and its high expression in the brain have been reported (Lockhart et al. 2002). It does not appear to be a Parkinson disease protein but may be a citrate transporter. It is 99% identical to the human ortholog.

Metazoa, Chordata
Sfxn5 of Mus musculus

Sideroflexin-3, Sfxn3 or SLC56A3, of 321 aas and 4 TMSs in a 2 + 2 TMS arrangement. It is an α-synuclein-dependent mitochondrial protein that regulates synaptic morphology (Amorim et al. 2017). It is highly expressed in mature neurons of the mouse, with expression developing as development occurs from birth to adulthood.  Within neurons, Sfxn3 localizes to mitochondria in all major neuronal compartments (Rivell et al. 2019). The human ortholog is 94% identical to the mouse protein.

Metazoa, Chordata
Sfxn3 of Mus musculus

Tricarboxylic acid (TCA) transporter of 327 aas and 6 TMSs. Found to be essential for bloodstream-form Trypanosoma brucei through a genome-wide RNAi screen (Schmidt et al. 2018).

TCA carrier of Trypanosoma brucei

Sideroflexin 2, SFXN2, TMEM241 or SLC56A2, of 322 aas and 5 or 6 TMSs in a 1 or 2 + 2 + 2 TMS arrangement.  SFXN2 is involved in mitochondrial iron metabolism and is localized to the mitochondrial inner membrane (Mon et al. 2019). SFXN2-knockout (KO) cells have an increased mitochondrial iron content and decreases in the heme content and heme-dependent enzyme activities. By contrast, the activities of iron-sulfur cluster-dependent enzymes were unchanged. Abnormal iron metabolism impaired mitochondrial respiration in SFXN2-KO cells and accelerated iron-mediated death (Mon et al. 2019). It may exert its effects by alterning heme biosynthesis.

Metazoa, Chordata
SFXN2 of Homo sapiens

Sideroflexin4, SFXN4, of 479 aas and possibly 7 TMSs in a 1 + 2 + 2 + 2 TMS arrangement, is important for mitochondrial function.  Macrocytic anemia and mitochondriopathy result from a defect in SFXN4in humans (Hildick-Smith et al. 2013).


Metazoa, Chordata
SFXN4 of Sturnus vulgaris

Sideroflexin-4 isoform X4 of 327 aas and 7 probable TMSs in a 1 + 2 + 2 + 2 TMS arrangement. Sideroflexin 4 affects Fe-S cluster biogenesis, iron metabolism, mitochondrial respiration and heme biosynthetic enzymes (Paul et al. 2019; Gyimesi and Hediger 2020).

Metazoa, Chordata
SFXN4 of Pogona vitticeps

Uncharacterized protein of 331 aas and 6 putative TMSs in a 2 + 2 + 2 TMS arrangement.

UP of Peronospora effusa

Putative tricarboxylate/iron carrier of 332 aas and 5 or 6 TMSs in a 1 or 2 + 2 + 2 TMS arrangment.

Fungi, Mucoromycota
UP of Glomus cerebriforme

Sideroflexin 5 of 310 aas and 5 TMSs in a 1 + 2 + 2 TMS arrangement.

SFXN5 of Chrysochromulina tobinii