Insights into the Roles of the Sideroflexins/SLC56 Family in Iron Homeostasis and Iron-Sulfur Biogenesis

Abstract

Sideroflexins (SLC56 family) are highly conserved multi-spanning transmembrane proteins inserted in the inner mitochondrial membrane in eukaryotes. Few data are available on their molecular function, but since their first description, they were thought to be metabolite transporters probably required for iron utilization inside the mitochondrion. Such as numerous mitochondrial transporters, sideroflexins remain poorly characterized. The prototypic member SFXN1 has been recently identified as the previously unknown mitochondrial transporter of serine. Nevertheless, pending questions on the molecular function of sideroflexins remain unsolved, especially their link with iron metabolism. Here, we review the current knowledge on sideroflexins, their presumed mitochondrial functions and the sparse—but growing—evidence linking sideroflexins to iron homeostasis and iron-sulfur cluster biogenesis. Since an imbalance in iron homeostasis can be detrimental at the cellular and organismal levels, we also investigate the relationship between sideroflexins, iron and physiological disorders. Investigating Sideroflexins’ functions constitutes an emerging research field of great interest and will certainly lead to the main discoveries of mitochondrial physio-pathology.

Development and Validation of a Robust Ferroptosis-Related Gene Panel for Breast Cancer Disease-Specific Survival

“…Nonetheless, SLC1A4 may promote ferroptosis and may function as a marker of ferroptosis, according to the FerrDb website data. Moreover, SFXN5 may be involved in cellular iron ion homeostasis ( Tifoun et al, 2021 ). These two genes need further study to confirm their relationship with ferroptosis.…”

The Role of Iron in Cancer Progression

“…confirmed a new regulatory mechanism of IRP2, which senses the absence of ISC synthesis, and ISC defects could enhance the binding of IRP2 to target mRNA ignoring the changes in IRP1, IRP2, and FBXL5 protein levels. ISC are made up of iron and sulfur ions to form [1Fe-0S], [2Fe-2S], [3Fe-4S] and [4Fe-4S] clusters ( 6 , 119 ). Suppressing ISC synthesis can activate IRP2 and promote ferroptosis sensitivity ( 120 ); in line with this finding, insufficient ISC maintenance has been shown to robustly activate the iron-starvation response and trigger ferroptosis ( 121 ).…”

“…This element plays a vital role in various cellular processes, such as cellular respiration (e.g., cytochrome c oxidase, ferredoxin, cytochrome, and Rieske protein), energy metabolism (e.g., aconitase, citrate synthase, succinate dehydrogenase, and isocitrate dehydrogenase), DNA replication, DNA synthesis and nucleic acid repair (e.g., the catalytic subunit of replicative DNA polymerases, DNA helicase and ribonucleotide reductase), and iron-dependent signaling (3,4). Iron is also used in the synthesis of heme and iron-sulfur clusters (ISC), which are incorporated into proteins that carry out the citric acid cycle, oxidative phosphorylation, and many other essential functions (5,6). However, although Abbreviations: DCYTB, duodenal cytochrome B; DMT1, divalent metal transporter 1; HO-1, heme oxygenase-1; FPN1, ferroportin; HEPH, hephaestin; TF, transferrin; TFR1, transferrin receptor; STEAP3, six-transmembrane prostate epithelial antigen 3; LIP, labile iron pool; IRPs, iron-responsive element binding proteins; IRE, iron responsive element; mRNA, messenger RNA; BMP6, bone morphogenetic protein; ROS, reactive oxygen species; DFO, Desferoxamine; IREB2, Iron responsive element binding protein 2 gene; ISC, iron-sulfur cluster; GSSG, glutathione disulphide; GSH, glutathione; L-OHs, lipid alcohols; L-OOHs, lipid hydroperoxides; PUFA, polyunsaturated fatty acids; GPX4, glutathione peroxidase 4; NCOA4, nuclear receptor coactivator 4; FTH1, ferritin heavy chain 1; FTL, ferritin light chain.…”

“…This element plays a vital role in various cellular processes, such as cellular respiration (e.g., cytochrome c oxidase, ferredoxin, cytochrome, and Rieske protein), energy metabolism (e.g., aconitase, citrate synthase, succinate dehydrogenase, and isocitrate dehydrogenase), DNA replication, DNA synthesis and nucleic acid repair (e.g., the catalytic subunit of replicative DNA polymerases, DNA helicase and ribonucleotide reductase), and iron-dependent signaling ( 3 , 4 ). Iron is also used in the synthesis of heme and iron–sulfur clusters (ISC), which are incorporated into proteins that carry out the citric acid cycle, oxidative phosphorylation, and many other essential functions ( 5 , 6 ). However, although iron is essential for the normal physiological function of the human body, it may also be toxic in that it generates a large number of free radicals in the presence of hydrogen peroxide ( 7 ).…”

Prime Real Estate: Metals, Cofactors and MICOS

“…Other notable mitochondrial transporters involved with metals are sideroflexins (Slc56). One of the five sideroflexin proteins, sideroflexin-1, has been shown to have a role in serine transport in mitochondria, and both sideroflexin-1 and sideroflexin-3 have been linked to iron homeostasis and Fe-S cluster biogenesis ( Tifoun et al, 2021 ). Sideroflexins are 5 transmembrane domain proteins that contain a conserved mitochondrial tricarboxylate/iron carrier domain (PFAM: 03820).…”