Sideroflexin family genes in human diseases: an update

The Sideroflexin (SFXN) family consists of five mitochondrial membrane proteins, SFXN1 through SFXN5. These proteins were initially considered mitochondrial solute carriers, however, SFXN proteins are now recognized as crucial for various cellular functions, including iron uptake, redox balance, amino acid transporters, and metabolic regulation. These SFXN proteins have a highly conserved structure and are integral membrane proteins with multiple transmembrane helices, facilitating their role in transporting small molecules across the mitochondrial inner membrane. Although the precise structure varies slightly between family members, most SFXNs share a characteristic feature of four to six transmembrane domains. They are located primarily within the mitochondrial inner membrane. The genes encoding these proteins are widely conserved across eukaryotes, indicating their fundamental biological roles. SFXN1 is an iron importer, particularly for heme synthesis within the mitochondria. It facilitates the transport of serine and other amino acids that are precursors in metabolic pathways. Defects in SFXN1 function are associated with anemia and mitochondrial dysfunctions because of disrupted heme synthesis. SFXN2 is implicated in the modulation of iron homeostasis and likely contributes to redox balance, although its exact transport function is less defined. Dysregulation in SFXN2 gene expression was linked to iron overload disorders and oxidative stress-related diseases, potentially impacting neurodegenerative conditions. SFXN3 is similar in function to SFXN1 but may have a more prominent role in amino acid metabolism within neurons. Alterations in SFXN3 function are associated with neurological disorders, potentially affecting conditions such as Parkinson’s disease. SFXN4 supports one-carbon metabolism by facilitating serine transport, which is essential for nucleotide synthesis and cellular growth. Mutations in SFXN4 have been implicated in mitochondrial disease. SFXN5 gene is the least characterized of the SFXN family, it likely plays a role in iron homeostasis and amino acid transport based on homology to other family members. SFXN1-SFXN4 genes were associated with the disease progression of multiple human cancers and exerted a strong potential for predicting patient outcomes as either a favorite or unfavorite prognostic factor.