A High-Throughput Search for SFXN1 Physical Partners Led to the Identification of ATAD3, HSD10 and TIM50

SIMPLE SUMMARY: Mitochondria are central players in cell fate and cell death. Indeed, mitochondrial dysfunction has been observed in many diseases, including neurodegenerative diseases. The activity of these organelles relies on numerous mitochondrial transporters, among which the sideroflexins have received little attention to date despite their emerging importance in human health. To better understand the cellular functions of these transporters and their associations with diseases, we herein investigated the molecular partners of one human sideroflexin, SFXN1. Several proteins capable of interacting with SFXN1 were identified, including ATAD3 and HSD10, two mitochondrial proteins linked to neuronal disorders. ABSTRACT: Sideroflexins (SFXN, SLC56) are a family of evolutionarily conserved mitochondrial carriers potentially involved in iron homeostasis. One member of the SFXN family is SFXN1, recently identified as a human mitochondrial serine transporter. However, little is known about the SFXN1 interactome, necessitating a high-throughput search to better characterize SFXN1 mitochondrial functions. Via co-immunoprecipitation followed by shotgun mass spectrometry (coIP-MS), we identified 96 putative SFXN1 interactors in the MCF7 human cell line. Our in silico analysis of the SFXN1 interactome highlights biological processes linked to mitochondrial organization, electron transport chains and transmembrane transport. Among the potential physical partners, ATAD3A and 17β-HSD10, two proteins associated with neurological disorders, were confirmed using different human cell lines. Nevertheless, further work will be needed to investigate the significance of these interactions.