{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,2]],"date-time":"2026-10-02T02:44:51Z","timestamp":1790909091718,"version":"4.1.0"},"update-to":[{"DOI":"10.1371\/journal.ppat.1011430","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2023,6,13]],"date-time":"2023-06-13T00:00:00Z","timestamp":1686614400000}}],"reference-count":54,"publisher":"Public Library of Science (PLoS)","issue":"6","license":[{"start":{"date-parts":[[2023,6,1]],"date-time":"2023-06-01T00:00:00Z","timestamp":1685577600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100016290","name":"Infectious and Tropical Diseases Research Center, Health Research Institute, Ahvaz Jundishapur University of Medical Sciences","doi-asserted-by":"publisher","award":["GNT1182369"],"award-info":[{"award-number":["GNT1182369"]}],"id":[{"id":"10.13039\/501100016290","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81971962"],"award-info":[{"award-number":["81971962"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82172303"],"award-info":[{"award-number":["82172303"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Australian Government Research Training Program Scholarship"}],"content-domain":{"domain":["www.plospathogens.org"],"crossmark-restriction":false},"short-container-title":["PLoS Pathog"],"abstract":"<jats:p>\n                    The mitochondrial electron transport chain (ETC) of apicomplexan parasites differs considerably from the ETC of the animals that these parasites infect, and is the target of numerous anti-parasitic drugs. The cytochrome\n                    <jats:italic>c<\/jats:italic>\n                    oxidase complex (Complex IV) of the apicomplexan\n                    <jats:italic>Toxoplasma gondii<\/jats:italic>\n                    ETC is more than twice the mass and contains subunits not found in human Complex IV, including a 13 kDa protein termed\n                    <jats:italic>Tg<\/jats:italic>\n                    ApiCox13.\n                    <jats:italic>Tg<\/jats:italic>\n                    ApiCox13 is homologous to a human iron-sulfur (Fe-S) cluster-containing protein called the mitochondrial inner NEET protein (\n                    <jats:italic>Hs<\/jats:italic>\n                    MiNT) which is not a component of Complex IV in humans. Here, we establish that\n                    <jats:italic>Tg<\/jats:italic>\n                    ApiCox13 is a critical component of Complex IV in\n                    <jats:italic>T<\/jats:italic>\n                    .\n                    <jats:italic>gondii<\/jats:italic>\n                    , required for complex activity and stability. Furthermore, we demonstrate that\n                    <jats:italic>Tg<\/jats:italic>\n                    ApiCox13, like its human homolog, binds two Fe-S clusters. We show that the Fe-S clusters of\n                    <jats:italic>Tg<\/jats:italic>\n                    ApiCox13 are critical for ETC function, having an essential role in mediating Complex IV integrity. Our study provides the first functional characterisation of an Fe-S protein in Complex IV.\n                  <\/jats:p>","DOI":"10.1371\/journal.ppat.1011430","type":"journal-article","created":{"date-parts":[[2023,6,1]],"date-time":"2023-06-01T13:32:25Z","timestamp":1685626345000},"page":"e1011430","update-policy":"https:\/\/doi.org\/10.1371\/journal.ppat.corrections_policy","source":"Crossref","is-referenced-by-count":19,"title":["An essential role for an Fe-S cluster protein in the cytochrome c oxidase complex of Toxoplasma parasites"],"prefix":"10.1371","volume":"19","author":[{"given":"Rachel A.","family":"Leonard","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuan","family":"Tian","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Feng","family":"Tan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giel G.","family":"van Dooren","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8228-8797","authenticated-orcid":true,"given":"Jenni A.","family":"Hayward","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2023,6,1]]},"reference":[{"key":"ppat.1011430.ref001","doi-asserted-by":"crossref","first-page":"111204","DOI":"10.1016\/j.molbiopara.2019.111204","article-title":"Same same, but different: Uncovering unique features of the mitochondrial respiratory chain of apicomplexans","volume":"232","author":"JA Hayward","year":"2019","journal-title":"Mol Biochem Parasitol"},{"key":"ppat.1011430.ref002","article-title":"The assembly, regulation and function of the mitochondrial respiratory chain","author":"I Vercellino","year":"2021","journal-title":"Nat Rev Mol Cell Biol"},{"issue":"7","key":"ppat.1011430.ref003","doi-asserted-by":"crossref","first-page":"1043","DOI":"10.1016\/j.cell.2005.05.025","article-title":"Crystal structure of mitochondrial respiratory membrane protein complex II","volume":"121","author":"F Sun","year":"2005","journal-title":"Cell"},{"issue":"6677","key":"ppat.1011430.ref004","doi-asserted-by":"crossref","first-page":"677","DOI":"10.1038\/33612","article-title":"Electron transfer by domain movement in cytochrome bc1","volume":"392","author":"Z Zhang","year":"1998","journal-title":"Nature"},{"issue":"5373","key":"ppat.1011430.ref005","doi-asserted-by":"crossref","first-page":"64","DOI":"10.1126\/science.281.5373.64","article-title":"Complete structure of the 11-subunit bovine mitochondrial cytochrome bc1 complex","volume":"281","author":"S Iwata","year":"1998","journal-title":"Science"},{"issue":"12","key":"ppat.1011430.ref006","doi-asserted-by":"crossref","first-page":"1385","DOI":"10.1016\/j.ijpara.2009.04.003","article-title":"Toxoplasmosis snapshots: global status of Toxoplasma gondii seroprevalence and implications for pregnancy and congenital toxoplasmosis","volume":"39","author":"G Pappas","year":"2009","journal-title":"Int J Parasitol"},{"issue":"2\u20133","key":"ppat.1011430.ref007","doi-asserted-by":"crossref","first-page":"95","DOI":"10.1016\/j.ijpara.2020.11.001","article-title":"Control of human toxoplasmosis","volume":"51","author":"NC Smith","year":"2021","journal-title":"Int J Parasitol"},{"key":"ppat.1011430.ref008","doi-asserted-by":"crossref","first-page":"e38131","DOI":"10.7554\/eLife.38131","article-title":"Elucidating the mitochondrial proteome of Toxoplasma gondii reveals the presence of a divergent cytochrome c oxidase.","volume":"7","author":"A Seidi","year":"2018","journal-title":"Elife."},{"issue":"1","key":"ppat.1011430.ref009","doi-asserted-by":"crossref","first-page":"123","DOI":"10.1093\/molbev\/mss205","article-title":"Alveolate mitochondrial metabolic evolution: dinoflagellates force reassessment of the role of parasitism as a driver of change in apicomplexans","volume":"30","author":"JC Danne","year":"2013","journal-title":"Mol Biol Evol"},{"issue":"2","key":"ppat.1011430.ref010","doi-asserted-by":"crossref","first-page":"e1009211","DOI":"10.1371\/journal.ppat.1009211","article-title":"Divergent features of the coenzyme Q:cytochrome c oxidoreductase complex in Toxoplasma gondii parasites.","volume":"17","author":"JA Hayward","year":"2021","journal-title":"PLoS Pathog"},{"issue":"3","key":"ppat.1011430.ref011","doi-asserted-by":"crossref","first-page":"e1009301","DOI":"10.1371\/journal.ppat.1009301","article-title":"Complexome profile of Toxoplasma gondii mitochondria identifies divergent subunits of respiratory chain complexes including new subunits of cytochrome bc1 complex.","volume":"17","author":"AE Maclean","year":"2021","journal-title":"PLoS Pathog"},{"issue":"1","key":"ppat.1011430.ref012","doi-asserted-by":"crossref","first-page":"3820","DOI":"10.1038\/s41467-021-23919-x","article-title":"Composition and stage dynamics of mitochondrial complexes in Plasmodium falciparum.","volume":"12","author":"F Evers","year":"2021","journal-title":"Nat Commun."},{"key":"ppat.1011430.ref013","article-title":"Structures of Tetrahymena\u2019s respiratory chain reveal the diversity of eukaryotic core metabolism","author":"L Zhou","year":"2022","journal-title":"Science"},{"issue":"7954","key":"ppat.1011430.ref014","doi-asserted-by":"crossref","first-page":"934","DOI":"10.1038\/s41586-023-05817-y","article-title":"Structural basis of mitochondrial membrane bending by the I-II-III(2)-IV(2) supercomplex.","volume":"615","author":"A M\u00fchleip","year":"2023","journal-title":"Nature"},{"issue":"6","key":"ppat.1011430.ref015","doi-asserted-by":"crossref","first-page":"1294","DOI":"10.1016\/j.bbamcr.2014.10.014","article-title":"Structure-function analysis of NEET proteins uncovers their role as key regulators of iron and ROS homeostasis in health and disease","volume":"1853","author":"S Tamir","year":"2015","journal-title":"Biochim Biophys Acta"},{"issue":"2","key":"ppat.1011430.ref016","doi-asserted-by":"crossref","first-page":"272","DOI":"10.1073\/pnas.1715842115","article-title":"Structure of the human monomeric NEET protein MiNT and its role in regulating iron and reactive oxygen species in cancer cells","volume":"115","author":"CH Lipper","year":"2018","journal-title":"Proc Natl Acad Sci U S A"},{"issue":"10","key":"ppat.1011430.ref017","doi-asserted-by":"crossref","first-page":"1026","DOI":"10.1038\/s41422-018-0071-1","article-title":"Structure of the intact 14-subunit human cytochrome c oxidase","volume":"28","author":"S Zong","year":"2018","journal-title":"Cell Res"},{"issue":"11","key":"ppat.1011430.ref018","doi-asserted-by":"crossref","first-page":"118805","DOI":"10.1016\/j.bbamcr.2020.118805","article-title":"The balancing act of NEET proteins: Iron, ROS, calcium and metabolism","volume":"1867","author":"R Nechushtai","year":"2020","journal-title":"Biochim Biophys Acta Mol Cell Res"},{"issue":"4","key":"ppat.1011430.ref019","doi-asserted-by":"crossref","first-page":"599","DOI":"10.1007\/s00775-018-1538-8","article-title":"The unique fold and lability of the [2Fe-2S] clusters of NEET proteins mediate their key functions in health and disease","volume":"23","author":"O Karmi","year":"2018","journal-title":"J Biol Inorg Chem"},{"issue":"7873","key":"ppat.1011430.ref020","doi-asserted-by":"crossref","first-page":"583","DOI":"10.1038\/s41586-021-03819-2","article-title":"Highly accurate protein structure prediction with AlphaFold","volume":"596","author":"J Jumper","year":"2021","journal-title":"Nature"},{"issue":"D1","key":"ppat.1011430.ref021","doi-asserted-by":"crossref","first-page":"D439","DOI":"10.1093\/nar\/gkab1061","article-title":"AlphaFold Protein Structure Database: massively expanding the structural coverage of protein-sequence space with high-accuracy models","volume":"50","author":"M Varadi","year":"2022","journal-title":"Nucleic Acids Res"},{"issue":"33","key":"ppat.1011430.ref022","doi-asserted-by":"crossref","first-page":"23745","DOI":"10.1074\/jbc.C700107200","article-title":"The outer mitochondrial membrane protein mitoNEET contains a novel redox-active 2Fe-2S cluster","volume":"282","author":"SE Wiley","year":"2007","journal-title":"J Biol Chem"},{"issue":"11","key":"ppat.1011430.ref023","doi-asserted-by":"crossref","first-page":"e1010096","DOI":"10.1371\/journal.ppat.1010096","article-title":"Differential contribution of two organelles of endosymbiotic origin to iron-sulfur cluster synthesis and overall fitness in Toxoplasma","volume":"17","author":"S Pamukcu","year":"2021","journal-title":"PLoS Pathog"},{"issue":"1","key":"ppat.1011430.ref024","doi-asserted-by":"crossref","first-page":"e4288","DOI":"10.21769\/BioProtoc.4288","article-title":"Real-time analysis of mitochondrial electron transport chain function in Toxoplasma gondii parasites using a Seahorse XFe96 extracellular flux analyzer.","volume":"12","author":"JA Hayward","year":"2022","journal-title":"Bio-protocol."},{"issue":"5","key":"ppat.1011430.ref025","doi-asserted-by":"crossref","first-page":"968","DOI":"10.1111\/mmi.14651","article-title":"A key cytosolic iron-sulfur cluster synthesis protein localizes to the mitochondrion of Toxoplasma gondii","volume":"115","author":"YTV Aw","year":"2021","journal-title":"Mol Microbiol"},{"key":"ppat.1011430.ref026","article-title":"A screen of drug-like molecules identifies chemically diverse electron transport chain inhibitors in apicomplexan parasites.","author":"JA Hayward","year":"2022","journal-title":"bioRxiv."},{"issue":"7","key":"ppat.1011430.ref027","doi-asserted-by":"crossref","first-page":"1215","DOI":"10.1074\/mcp.M700076-MCP200","article-title":"High resolution clear native electrophoresis for in-gel functional assays and fluorescence studies of membrane protein complexes","volume":"6","author":"I Wittig","year":"2007","journal-title":"Mol Cell Proteomics"},{"key":"ppat.1011430.ref028","doi-asserted-by":"crossref","first-page":"163","DOI":"10.1016\/j.semcdb.2017.08.055","article-title":"Mitochondrial cytochrome c oxidase biogenesis: Recent developments","volume":"76","author":"A Tim\u00f3n-G\u00f3mez","year":"2018","journal-title":"Semin Cell Dev Biol"},{"issue":"12","key":"ppat.1011430.ref029","doi-asserted-by":"crossref","first-page":"2063","DOI":"10.1002\/pro.2817","article-title":"Use of carbonate extraction in analyzing moderately hydrophobic transmembrane proteins in the mitochondrial inner membrane","volume":"24","author":"H Kim","year":"2015","journal-title":"Protein Sci"},{"issue":"6","key":"ppat.1011430.ref030","doi-asserted-by":"crossref","first-page":"1572","DOI":"10.1107\/S1399004714005458","article-title":"A point mutation in the [2Fe-2S] cluster binding region of the NAF-1 protein (H114C) dramatically hinders the cluster donor properties.","volume":"70","author":"S Tamir","year":"2014","journal-title":"Acta Crystallogr D Biol Crystallogr"},{"key":"ppat.1011430.ref031","doi-asserted-by":"crossref","first-page":"102164","DOI":"10.1016\/j.redox.2021.102164","article-title":"Mitochondrial iron-sulfur clusters: Structure, function, and an emerging role in vascular biology.","volume":"47","author":"AD Read","year":"2021","journal-title":"Redox Biol."},{"issue":"12","key":"ppat.1011430.ref032","doi-asserted-by":"crossref","DOI":"10.1099\/mic.0.001114","article-title":"Orchestrating a heist: uptake and storage of metals by apicomplexan parasites","volume":"167","author":"MA Sloan","year":"2021","journal-title":"Microbiology (Reading)."},{"key":"ppat.1011430.ref033","first-page":"2021","article-title":"The vacuolar iron transporter mediates iron detoxification in Toxoplasma gondii.","author":"D Aghabi","year":"2021","journal-title":"bioRxiv."},{"issue":"11","key":"ppat.1011430.ref034","doi-asserted-by":"crossref","first-page":"1293","DOI":"10.1016\/0020-7519(95)00066-B","article-title":"Interconnection between organellar functions, development and drug resistance in the protozoan parasite, Toxoplasma gondii","volume":"25","author":"S Tomavo","year":"1995","journal-title":"Int J Parasitol"},{"issue":"1","key":"ppat.1011430.ref035","first-page":"3","article-title":"Mitochondrial electron transport chain, ROS generation and uncoupling (Review).","volume":"44","author":"RZ Zhao","year":"2019","journal-title":"Int J Mol Med"},{"issue":"2","key":"ppat.1011430.ref036","doi-asserted-by":"crossref","first-page":"152","DOI":"10.1016\/S1367-5931(99)80027-1","article-title":"Fe-S proteins in sensing and regulatory functions","volume":"3","author":"H Beinert","year":"1999","journal-title":"Curr Opin Chem Biol"},{"issue":"10","key":"ppat.1011430.ref037","doi-asserted-by":"crossref","first-page":"e0139699","DOI":"10.1371\/journal.pone.0139699","article-title":"Cancer-Related NEET Proteins Transfer 2Fe-2S Clusters to Anamorsin, a Protein Required for Cytosolic Iron-Sulfur Cluster Biogenesis.","volume":"10","author":"CH Lipper","year":"2015","journal-title":"PLoS One."},{"issue":"4","key":"ppat.1011430.ref038","doi-asserted-by":"crossref","first-page":"e0175796","DOI":"10.1371\/journal.pone.0175796","article-title":"Interactions between mitoNEET and NAF-1 in cells.","volume":"12","author":"O Karmi","year":"2017","journal-title":"PLoS One"},{"key":"ppat.1011430.ref039","first-page":"119","article-title":"A VDAC1-mediated NEET protein chain transfers [2Fe-2S] clusters between the mitochondria and the cytosol and impacts mitochondrial dynamics","author":"O Karmi","year":"2022","journal-title":"Proc Natl Acad Sci U S A"},{"issue":"8","key":"ppat.1011430.ref040","doi-asserted-by":"crossref","first-page":"1068","DOI":"10.1016\/j.bbabio.2016.02.018","article-title":"The multitude of iron-sulfur clusters in respiratory complex I","volume":"1857","author":"E Gnandt","year":"2016","journal-title":"Biochim Biophys Acta"},{"issue":"9","key":"ppat.1011430.ref041","doi-asserted-by":"crossref","first-page":"1573","DOI":"10.1016\/j.bbabio.2010.04.441","article-title":"Guidelines for tunneling in enzymes","volume":"1797","author":"CC Moser","year":"2010","journal-title":"Biochim Biophys Acta"},{"issue":"10","key":"ppat.1011430.ref042","article-title":"Identification of an Intermediate Form of Ferredoxin That Binds Only Iron Suggests That Conversion to Holo-Ferredoxin Is Independent of the ISC System in Escherichia coli","volume":"87","author":"X Ren","year":"2021","journal-title":"Appl Environ Microbiol"},{"issue":"3","key":"ppat.1011430.ref043","doi-asserted-by":"crossref","first-page":"e01114","DOI":"10.1128\/mBio.01114-14","article-title":"Efficient gene disruption in diverse strains of Toxoplasma gondii using CRISPR\/CAS9.","volume":"5","author":"B Shen","year":"2014","journal-title":"mBio."},{"issue":"4","key":"ppat.1011430.ref044","doi-asserted-by":"crossref","first-page":"e1004074","DOI":"10.1371\/journal.ppat.1004074","article-title":"The apical complex provides a regulated gateway for secretion of invasion factors in Toxoplasma","volume":"10","author":"NJ Katris","year":"2014","journal-title":"PLoS Pathog"},{"issue":"12","key":"ppat.1011430.ref045","doi-asserted-by":"crossref","first-page":"e1002392","DOI":"10.1371\/journal.ppat.1002392","article-title":"A systematic screen to discover and analyze apicoplast proteins identifies a conserved and essential protein import factor","volume":"7","author":"L Sheiner","year":"2011","journal-title":"PLoS Pathog"},{"key":"ppat.1011430.ref046","first-page":"897","volume-title":"Toxoplasma gondii the model apicomplexan\u2014perspectives and methodsThird edition ed","author":"S. Jacot DL","year":"2020"},{"key":"ppat.1011430.ref047","doi-asserted-by":"crossref","first-page":"14455","DOI":"10.1038\/ncomms14455","article-title":"Cationic amino acid transporters play key roles in the survival and transmission of apicomplexan parasites.","volume":"8","author":"E Rajendran","year":"2017","journal-title":"Nat Commun"},{"issue":"12","key":"ppat.1011430.ref048","doi-asserted-by":"crossref","first-page":"e1002416","DOI":"10.1371\/journal.ppat.1002416","article-title":"Autophagy protein Atg3 is essential for maintaining mitochondrial integrity and for normal intracellular development of Toxoplasma gondii tachyzoites","volume":"7","author":"S Besteiro","year":"2011","journal-title":"PLoS Pathog"},{"issue":"36","key":"ppat.1011430.ref049","doi-asserted-by":"crossref","first-page":"13574","DOI":"10.1073\/pnas.0803862105","article-title":"Toxoplasma gondii Tic20 is essential for apicoplast protein import","volume":"105","author":"GG van Dooren","year":"2008","journal-title":"Proc Natl Acad Sci U S A"},{"issue":"2","key":"ppat.1011430.ref050","doi-asserted-by":"crossref","first-page":"235","DOI":"10.1016\/0166-6851(96)02598-4","article-title":"A novel epitope tag system to study protein targeting and organelle biogenesis in Trypanosoma brucei","volume":"77","author":"P Bastin","year":"1996","journal-title":"Mol Biochem Parasitol"},{"issue":"37","key":"ppat.1011430.ref051","doi-asserted-by":"crossref","first-page":"19335","DOI":"10.1074\/jbc.M116.725069","article-title":"The Import of Proteins into the Mitochondrion of Toxoplasma gondii","volume":"291","author":"GG van Dooren","year":"2016","journal-title":"J Biol Chem"},{"issue":"4","key":"ppat.1011430.ref052","doi-asserted-by":"crossref","first-page":"267","DOI":"10.1016\/j.cub.2008.12.048","article-title":"A novel dynamin-related protein has been recruited for apicoplast fission in Toxoplasma gondii","volume":"19","author":"GG van Dooren","year":"2009","journal-title":"Curr Biol"},{"issue":"1","key":"ppat.1011430.ref053","doi-asserted-by":"crossref","first-page":"70","DOI":"10.1002\/pro.3943","article-title":"UCSF ChimeraX: Structure visualization for researchers, educators, and developers","volume":"30","author":"EF Pettersen","year":"2021","journal-title":"Protein Sci"},{"issue":"1","key":"ppat.1011430.ref054","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1016\/j.tree.2019.08.008","article-title":"The New Tree of Eukaryotes","volume":"35","author":"F Burki","year":"2020","journal-title":"Trends Ecol Evol"}],"updated-by":[{"DOI":"10.1371\/journal.ppat.1011430","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2023,6,13]],"date-time":"2023-06-13T00:00:00Z","timestamp":1686614400000}}],"container-title":["PLOS Pathogens"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.ppat.1011430","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,6,13]],"date-time":"2023-06-13T13:35:43Z","timestamp":1686663343000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.ppat.1011430"}},"subtitle":[],"editor":[{"given":"Sean T.","family":"Prigge","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"editor"}]}],"short-title":[],"issued":{"date-parts":[[2023,6,1]]},"references-count":54,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2023,6,1]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.ppat.1011430","relation":{},"ISSN":["1553-7374"],"issn-type":[{"value":"1553-7374","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,6,1]]}}}