Abstract
The Apicomplexa phylum encompasses numerous obligate intracellular parasites, some associated 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 and Plasmodium falciparum provided insights into the mechanisms of [Fe-S] biogenesis within this phylum, while the transporter linking mitochondria-generated [Fe-S] with the cytosolic [Fe-S] assembly (CIA) pathway remained elusive. This critical step is catalyzed by a well-conserved ABC transporter, termed ATM1 in yeast, ATM3 in plants and ABCB7 in mammals. Here, we identify and characterize this transporter in two clinically relevant Apicomplexa. We demonstrate that depletion of TgATM1 does not specifically impair mitochondrial metabolism. Instead, proteomic analyses reveal that TgATM1 expression levels inversely correlate with the abundance of proteins that participate in the transfer of [Fe-S] to cytosolic proteins at the outer mitochondrial membrane. Further insights into the role of TgATM1 are gained through functional complementation with the well-characterized yeast homolog. Biochemical characterization of PfATM1 confirms its role as a functional ABC transporter, modulated by oxidized glutathione (GSSG) and [4Fe-4S].
Copyright: © 2024 Shrivastava et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
MeSH terms
-
ATP-Binding Cassette Transporters* / genetics
-
ATP-Binding Cassette Transporters* / metabolism
-
Apicomplexa / genetics
-
Apicomplexa / metabolism
-
Cytosol* / metabolism
-
Humans
-
Iron-Sulfur Proteins / genetics
-
Iron-Sulfur Proteins / metabolism
-
Mitochondria* / metabolism
-
Protozoan Proteins* / genetics
-
Protozoan Proteins* / metabolism
-
Saccharomyces cerevisiae Proteins / genetics
-
Saccharomyces cerevisiae Proteins / metabolism
-
Toxoplasma* / genetics
-
Toxoplasma* / metabolism
Substances
-
ATP-Binding Cassette Transporters
-
Protozoan Proteins
-
Iron-Sulfur Proteins
-
Saccharomyces cerevisiae Proteins
-
ATM1 protein, S cerevisiae
Grants and funding
This work was supported by Council of Scientific and Industrial Research (CSIR, India,
https://www.csir.res.in) project #MLP2031, JC Bose Fellowship (#JCB/2021/000008) from the Science and Engineering Research Board (SERB, India,
https://serb.gov.in), and Department of Biotechnology (DBT, India,
https://dbtindia.gov.in) grant (#BT/PR38444/MED/29/1499/2020) to SH, and grants #TMAG-3_216166 and IZLIZ3_200277 awarded by the Swiss National Science Foundation (
https://www.snf.ch/en) to DS-F. JK is supported through funding by a generous donor advised by CARIGEST SA (
https://carigest.ch/en), acquired by DS-F, and this work was supported by a grant from the Novartis Foundation for Medical Biological Research (#22C164,
http://www.stiftungmedbiol.novartis.com/old-home.html) awarded to JK. DS received Inspire Fellowship from the Department of Science and Technology (DST, India) (IF170777), AC received fellowship from the Council of Scientific & Industrial Research (CSIR) (DEC19C02487) and JPR from the University Grants Commission, India (201610150924). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.