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While the SUF machinery has been delineated, there is little experimental evidence on the ISC pathway. We confirmed mitochondrial targeting of <jats:italic>Plasmodium falciparum<\/jats:italic> ISC proteins followed by analyses of cysteine desulfurase, scaffold, and [Fe\u2013S]\u2010carrier components. <jats:italic>Pf<\/jats:italic>IscU functioned as the scaffold in complex with the <jats:italic>Pf<\/jats:italic>IscS\u2013<jats:italic>Pf<\/jats:italic>Isd11 cysteine desulfurase and could directly assemble [4Fe\u20134S] without prior [2Fe\u20132S] formation seen in other homologs. Small angle X\u2010ray scattering and spectral studies showed that <jats:italic>Pf<\/jats:italic>IscU, a trimer, bound one [4Fe\u20134S]. In a deviation from reported complexes from other organisms, the <jats:italic>P. falciparum<\/jats:italic> desulfurase\u2010scaffold complex assembled around a <jats:italic>Pf<\/jats:italic>IscS tetramer instead of a dimer, resulting in a symmetric hetero\u2010hexamer [2\u00d7 (2<jats:italic>Pf<\/jats:italic>IscS\u20132<jats:italic>Pf<\/jats:italic>Isd11\u20132<jats:italic>Pf<\/jats:italic>IscU)]. <jats:italic>Pf<\/jats:italic>IscU directly transferred [4Fe\u20134S] to the apo\u2010protein aconitase B thus abrogating the requirement of intermediary proteins for conversion of [2Fe\u20132S] to [4Fe\u20134S] before transfer to [4Fe\u20134S]\u2010recipients. Among the putative cluster\u2010carriers, <jats:italic>Pf<\/jats:italic>IscA2 was more efficient than <jats:italic>Pf<\/jats:italic>NifU\u2010like protein; <jats:italic>Pf<\/jats:italic>IscA1 primarily bound iron, suggesting its potential role as a Fe<jats:sup>2+<\/jats:sup> carrier\/donor. Our results identify the core <jats:italic>P. falciparum<\/jats:italic> ISC machinery and reveal unique features compared with those in bacteria or yeast and human mitochondria.<\/jats:p>","DOI":"10.1111\/mmi.14735","type":"journal-article","created":{"date-parts":[[2021,5,25]],"date-time":"2021-05-25T12:07:11Z","timestamp":1621944431000},"page":"606-623","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["[Fe\u2013S] biogenesis and unusual assembly of the ISC scaffold complex in the <i>Plasmodium falciparum<\/i> mitochondrion"],"prefix":"10.1111","volume":"116","author":[{"family":"Mohammad Sadik","sequence":"first","affiliation":[{"name":"Division of Molecular and Structural Biology CSIR\u2010Central Drug Research Institute Lucknow India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"family":"Mohammad Afsar","sequence":"additional","affiliation":[{"name":"Division of Molecular and Structural Biology 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