{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,6]],"date-time":"2026-07-06T15:48:01Z","timestamp":1783352881709,"version":"3.54.6"},"update-to":[{"DOI":"10.1371\/journal.ppat.1011566","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2023,9,13]],"date-time":"2023-09-13T00:00:00Z","timestamp":1694563200000}}],"reference-count":89,"publisher":"Public Library of Science (PLoS)","issue":"8","license":[{"start":{"date-parts":[[2023,8,31]],"date-time":"2023-08-31T00:00:00Z","timestamp":1693440000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100006492","name":"Division of Intramural Research, National Institute of Allergy and Infectious Diseases","doi-asserted-by":"publisher","award":["R01 AI138714"],"award-info":[{"award-number":["R01 AI138714"]}],"id":[{"id":"10.13039\/100006492","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.plospathogens.org"],"crossmark-restriction":false},"short-container-title":["PLoS Pathog"],"abstract":"<jats:p>As an obligate intracellular parasite, <jats:italic>Toxoplasma gondii<\/jats:italic> must import essential nutrients from the host cell into the parasitophorous vacuole. We previously reported that the parasite scavenges cholesterol from host endocytic organelles for incorporation into membranes and storage as cholesteryl esters in lipid droplets. In this study, we have investigated whether <jats:italic>Toxoplasma<\/jats:italic> utilizes cholesterol as a precursor for the synthesis of metabolites, such as steroids. In mammalian cells, steroidogenesis occurs in mitochondria and involves membrane-bound type I cytochrome P450 oxidases that are activated through interaction with heme-binding proteins containing a cytochrome b5 domain, such as members of the membrane-associated progesterone receptor (MAPR) family. Our LC-MS targeted lipidomics detect selective classes of hormone steroids in <jats:italic>Toxoplasma<\/jats:italic>, with a predominance for anti-inflammatory hydroxypregnenolone species, deoxycorticosterone and dehydroepiandrosterone. The genome of <jats:italic>Toxoplasma<\/jats:italic> contains homologs encoding a single type I CYP450 enzyme (we named TgCYP450mt) and a single MAPR (we named TgMAPR). We showed that TgMAPR is a hemoprotein with conserved residues in a heme-binding cytochrome b5 domain. Both TgCYP450 and TgMAPR localize to the mitochondrion and show interactions in <jats:italic>in situ<\/jats:italic> proximity ligation assays. Genetic ablation of <jats:italic>cyp450mt<\/jats:italic> is not tolerated by <jats:italic>Toxoplasma<\/jats:italic>; we therefore engineered a conditional knockout strain and showed that i\u0394TgCYP450mt parasites exhibit growth impairment in cultured cells. Parasite strains deficient for <jats:italic>mapr<\/jats:italic> could be generated; however, \u0394TgMAPR parasites suffer from poor global fitness, loss of plasma membrane integrity, aberrant mitochondrial cristae, and an abnormally long S-phase in their cell cycle. Compared to wild-type parasites, i\u0394TgCYP450mt and \u0394TgMAPR lost virulence in mice and metabolomics studies reveal that both mutants have reduced levels of steroids. These observations point to a steroidogenic pathway operational in the mitochondrion of a protozoan that involves an evolutionary conserved TgCYP450mt enzyme and its binding partner TgMAPR.<\/jats:p>","DOI":"10.1371\/journal.ppat.1011566","type":"journal-article","created":{"date-parts":[[2023,8,31]],"date-time":"2023-08-31T17:41:50Z","timestamp":1693503710000},"page":"e1011566","update-policy":"https:\/\/doi.org\/10.1371\/journal.ppat.corrections_policy","source":"Crossref","is-referenced-by-count":6,"title":["Function and regulation of a steroidogenic CYP450 enzyme in the mitochondrion of Toxoplasma gondii"],"prefix":"10.1371","volume":"19","author":[{"given":"Beejan","family":"Asady","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vera","family":"Sampels","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julia 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