ATM1, an essential conserved transporter in Apicomplexa, bridges mitochondrial and cytosolic [Fe-S] biogenesis

The Apicomplexa phylum encompasses numerous obligate intracellular parasites with severe implications for human health, including Plasmodium, Cryptosporidium, and Toxoplasma gondii. The iron-sulfur cluster [Fe-S] biogenesis, ISC pathway, localized within the mitochondrion or mitosome of these parasites, is vital for parasite survival and development. Previous work on T. gondii provided insights into the mechanisms of [Fe-S] biogenesis within this phylum, although the transporter linking mitochondria-generated [Fe-S] with cytosolic [Fe-S] assembly (CIA) pathway remained elusive. This critical step is catalysed by a well-conserved ABC transporter in numerous species, termed ATM1 in yeast, ATM3 in plants and ABCB7 in mammals. Here we uncover PfATM1 and TgATM1 and demonstrate its role in transporting [Fe-S] across apicomplexan parasite mitochondrial membranes. While downregulation of TgATM1 does not specifically affect mitochondrial metabolism, it impacts on [Fe-S] protein levels, indicating its role in cellular homeostasis. Depletion of TgATM1 can be complemented through expression of the well-characterized yeast homologue, ScATM1, further validating the function of the apicomplexan transporter. PfATM1's biochemical characterization shows interactions with mitochondrial ISC proteins and the cytosolic CIA protein PfNBP35, confirming it as a functional ABC transporter, modulated by oxidized glutathione (GSSG) and [4Fe-4S].