Abstract EN:

Sideroflexins (SFXN) form a new family of mitochondrial proteins. Their functions are currently unknown. These proteins are evolutionary conserved and found from yeast to humans. Five SFXN exist in vertebrates. SFXN1, the first member of the family, was described in flexed-tail mouse that harbors a mutation in the SFXN1 gene. Other members of the sideroflexin family have been described later. Nevertheless since the discovery of SFXN1 few data on the putative functions of the sideroflexins exist. When the key word “sideroflexin” is typed in Pubmed database only thirteen articles are found. Interestingly most recent articles suggest the involvement of sideroflexins in neurodegenerative disorders and mitochondriopathies. We are thus interested in understanding the normal and pathologic functions of sideroflexins at the mitochondrial level. Sideroflexins present five putative transmembrane domains in their structure. These proteins are localized at the inner mitochondrial membrane. A putative function of transporter has been proposed for SFXNs. Fleming and colleagues suggest that SFXN1 was involved in the iron metabolism since flexed-tail mouse displays sideroblastic anemia that is characterized by iron deposition at the mitochondria in erythrocytes. This has not been experimentally proved and another mutation (affecting Madh5 gene) has been later associated with flexed-tail phenotype. SFXN have also been proposed as tricarboxylate transporters. However, their predicted structure is different from that of the other members belonging to the superfamily of anion transporters. Thus the functions of sideroflexins remain largely unknown. Mitochondria occupy a central place in the energetics metabolism and are also involved in various pathologies such as neurodegenerative disorders, cancers and mitochondriopathies. In neurodegenerative diseases such as Parkinson disease (PD), Alzheimer disease (AD) or Huntington disease (HD), defects in mitochondrial dynamics and mitochondrial respiration are observed. Moreover mutant proteins involved in these pathologies accumulate at the mitochondria. Recently involvement of SFXN1 and SFXN3 in AD and PD respectively has been proposed. Furthermore mutations in SFXN4 are thought to be causative of a mitochondriopathy. Defects in mitochondrial respiration are observed consecutive to a loss of function of SFXN4. In the study of Amorim et al, defects in mitochondrial respiration are not seen with synaptomes originating from sfxn3 KO mice. Nevertheless this could be explained by functional redundancy since all members of the sideroflexins are found in brain. Mutant proteins involved in neurodegenerative disorders tend to form aggregates inducing a stress of the endoplasmic reticulum (ER). Interestingly it has been recently shown that SFXN1 interacts with SCIRR69. SCIRR69 is a protein found at the ER and induced upon ER stress. Thus, considering that few data exist concerning SFXNs and that these proteins are associated with diseases where mitochondria are largely involved, we expect to give answers to some questions: What are the basal activities of SFXNs at the mitochondria? Are they important for mitochondrial respiration or do they regulate mitochondrial dynamics? Are they involved in response to diverse stress that converge to mitochondria (genotoxic or ER stress for example)?