The mitochondrion is at the crossroad of critical metabolic pathways, thus being a crucial player in cell fate in response to stress or infection. The mitochondrion is also an essential organelle for iron metabolism, being the place of heme and iron-sulfur clusters (Fe-S), two co-factors required for mitochondrial respiration. Iron intracellular levels are thus tightly controlled to prevent the accumulation of free ferrous iron that, when in excess, generates oxidative stress and may induce ferroptosis, an iron-dependent regulated cell death (RCD). Ferrous iron will react with ROS and generate, by Fenton reaction, lipids peroxidation. Oxidized lipids accumulation into cellular membranes can be lethal and drives ferroptosis. Ferroptosis, a physiological cell death contributing to tissue homeostasis aging and diseases as neurodegenerative, organ injury. Furthermore a number of tumor suppressors exert part of their tumor-suppression function through the induction of ferroptosis. Sideroflexins (SFXNs) are mitochondrial transporters localized in the inner mitochondrial membrane whose functions are progressively being specified. SFXNs are conserved in eukaryote forming a family of five mitochondrial proteins in mammals. The main function reported to date for Sideroflexin 1 (SFXN1) is to transport serine but SFXN1 may also be involved in iron metabolism. The serine transporter function appears to be conserved between mammalian and yeast. Our project is to study if SFXN1 can regulate cell viability, mitochondrial functions and structure, as well as its role in iron homeostasis and if SFXN1 can modulate cell sensitivity to ferroptosis inducers. References : Kory N, Wyant GA, Prakash G, Uit de Bos J, Bottanelli F, Pacold ME, Chan SH, Lewis CA, Wang T, Keys HR, Guo YE, Sabatini DM. SFXN1 is a mitochondrial serine transporter required for one-carbon metabolism. Science. 2018 Nov 16;362(6416):eaat9528. doi: 10.1126/science.aat9528. PMID: 30442778; PMCID: PMC6300058. Acoba MG, Alpergin ESS, Renuse S, Fernández-Del-Río L, Lu YW, Khalimonchuk O, Clarke CF, Pandey A, Wolfgang MJ, Claypool SM. The mitochondrial carrier SFXN1 is critical for complex III integrity and cellular metabolism. Cell Rep. 2021 Mar 16;34(11):108869. doi: 10.1016/j.celrep.2021.108869. PMID: 33730581; PMCID: PMC8048093. Tifoun N, De Las Heras JM, Guillaume A, Bouleau S, Mignotte B, Le Floch N. Insights into the Roles of the Sideroflexins/SLC56 Family in Iron Homeostasis and Iron-Sulfur Biogenesis. Biomedicines. 2021 Jan 21;9(2):103. doi: 10.3390/biomedicines9020103. PMID: 33494450; PMCID: PMC7911444. Stockwell BR. Ferroptosis turns 10: Emerging mechanisms, physiological functions, and therapeutic applications. Cell. 2022 Jul 7;185(14):2401-2421. doi: 10.1016/j.cell.2022.06.003. PMID: 35803244; PMCID: PMC9273022.