{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,1,15]],"date-time":"2026-01-15T18:35:41Z","timestamp":1768502141452,"version":"3.49.0"},"posted":{"date-parts":[[2023,1,23]]},"group-title":"Microbiology","reference-count":96,"publisher":"openRxiv","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2023,1,23]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                <jats:p>\n                  The mitochondrial electron transport chain (ETC) of\n                  <jats:italic>Plasmodium<\/jats:italic>\n                  malaria parasites is a major antimalarial drug target, but critical cytochrome functions remain unstudied and enigmatic. Parasites express two distinct cyt\n                  <jats:italic>c<\/jats:italic>\n                  homologs (\n                  <jats:italic>c<\/jats:italic>\n                  and\n                  <jats:italic>c<\/jats:italic>\n                  -2) with unusually sparse sequence identity and uncertain fitness contributions.\n                  <jats:italic>P. falciparum<\/jats:italic>\n                  cyt\n                  <jats:italic>c<\/jats:italic>\n                  -2 is the most divergent eukaryotic cyt\n                  <jats:italic>c<\/jats:italic>\n                  homolog currently known and has sequence features predicted to be incompatible with canonical ETC function. We tagged both cyt\n                  <jats:italic>c<\/jats:italic>\n                  homologs and the related cyt\n                  <jats:italic>c<\/jats:italic>\n                  <jats:sub>1<\/jats:sub>\n                  for inducible knockdown. Translational repression of cyt\n                  <jats:italic>c<\/jats:italic>\n                  and cyt\n                  <jats:italic>c<\/jats:italic>\n                  <jats:sub>1<\/jats:sub>\n                  was lethal to parasites, which died from ETC dysfunction and impaired ubiquinone recycling. In contrast, cyt\n                  <jats:italic>c<\/jats:italic>\n                  -2 knockdown or knock-out had little impact on blood-stage growth, indicating that parasites rely fully on the more conserved cyt\n                  <jats:italic>c<\/jats:italic>\n                  for ETC function. Biochemical and structural studies revealed that both cyt\n                  <jats:italic>c<\/jats:italic>\n                  and\n                  <jats:italic>c<\/jats:italic>\n                  -2 are hemylated by holocytochrome\n                  <jats:italic>c<\/jats:italic>\n                  synthase, but UV-vis absorbance and EPR spectra strongly suggest that cyt\n                  <jats:italic>c<\/jats:italic>\n                  -2 has an unusually open active site in which heme is stably coordinated by only a single axial amino-acid ligand and can bind exogenous small molecules. These studies provide a direct dissection of cytochrome functions in the ETC of malaria parasites and identify a highly divergent\n                  <jats:italic>Plasmodium<\/jats:italic>\n                  cytochrome\n                  <jats:italic>c<\/jats:italic>\n                  with molecular adaptations that defy a conserved role in eukaryotic evolution.\n                <\/jats:p>\n                <jats:sec>\n                  <jats:title>SIGNIFICANCE STATEMENT<\/jats:title>\n                  <jats:p>\n                    Mitochondria are critical organelles in eukaryotic cells that drive oxidative metabolism. The mitochondrion of\n                    <jats:italic>Plasmodium<\/jats:italic>\n                    malaria parasites is a major drug target that has many differences from human cells and remains poorly studied. One key difference from humans is that malaria parasites express two cytochrome\n                    <jats:italic>c<\/jats:italic>\n                    proteins that differ significantly from each other and play untested and uncertain roles in the mitochondrial electron transport chain (ETC). Our study revealed that one cyt\n                    <jats:italic>c<\/jats:italic>\n                    is essential for ETC function and parasite viability while the second, more divergent protein has unusual structural and biochemical properties and is not required for growth of blood-stage parasites. This work elucidates key biochemical properties and evolutionary differences in the mitochondrial ETC of malaria parasites.\n                  <\/jats:p>\n                <\/jats:sec>","DOI":"10.1101\/2023.01.23.525242","type":"posted-content","created":{"date-parts":[[2023,1,23]],"date-time":"2023-01-23T21:40:16Z","timestamp":1674510016000},"source":"Crossref","is-referenced-by-count":0,"title":["Direct Tests of Cytochrome Function in the Electron Transport Chain of Malaria Parasites"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7076-2145","authenticated-orcid":false,"given":"Tanya J.","family":"Espino-Sanchez","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7948-3241","authenticated-orcid":false,"given":"Henry","family":"Wienkers","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rebecca G.","family":"Marvin","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6892-9321","authenticated-orcid":false,"given":"Shai-anne","family":"Nalder","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6751-8304","authenticated-orcid":false,"given":"Aldo E.","family":"Garc\u00eda-Guerrero","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1360-579X","authenticated-orcid":false,"given":"Peter E.","family":"VanNatta","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8289-2222","authenticated-orcid":false,"given":"Yasaman","family":"Jami-Alahmadi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Amanda Mixon","family":"Blackwell","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Frank G.","family":"Whitby","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"James A.","family":"Wohlschlegel","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6357-5579","authenticated-orcid":false,"given":"Matthew T.","family":"Kieber-Emmons","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Christopher P.","family":"Hill","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3464-3042","authenticated-orcid":false,"given":"Paul A.","family":"Sigala","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"54368","reference":[{"key":"2023012503051956000_2023.01.23.525242v1.1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-micro-091313-103537"},{"key":"2023012503051956000_2023.01.23.525242v1.2","doi-asserted-by":"publisher","DOI":"10.1089\/ars.2012.4539"},{"key":"2023012503051956000_2023.01.23.525242v1.3","doi-asserted-by":"publisher","DOI":"10.1111\/febs.15445"},{"key":"2023012503051956000_2023.01.23.525242v1.4","doi-asserted-by":"publisher","DOI":"10.1038\/nm.4381"},{"key":"2023012503051956000_2023.01.23.525242v1.5","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.micro.51.1.97"},{"key":"2023012503051956000_2023.01.23.525242v1.6","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.273.47.31103"},{"key":"2023012503051956000_2023.01.23.525242v1.7","doi-asserted-by":"publisher","DOI":"10.1038\/33612"},{"key":"2023012503051956000_2023.01.23.525242v1.8","doi-asserted-by":"publisher","DOI":"10.1016\/0006-2952(92)90213-3"},{"key":"2023012503051956000_2023.01.23.525242v1.9","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.3005029"},{"key":"2023012503051956000_2023.01.23.525242v1.10","doi-asserted-by":"publisher","DOI":"10.1038\/nature05572"},{"key":"2023012503051956000_2023.01.23.525242v1.11","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1423959112"},{"key":"2023012503051956000_2023.01.23.525242v1.12","doi-asserted-by":"publisher","DOI":"10.1016\/0305-0491(90)90230-Q"},{"key":"2023012503051956000_2023.01.23.525242v1.13","doi-asserted-by":"publisher","DOI":"10.1186\/1741-7007-11-67"},{"key":"2023012503051956000_2023.01.23.525242v1.14","doi-asserted-by":"publisher","DOI":"10.1128\/EC.05049-11"},{"key":"2023012503051956000_2023.01.23.525242v1.15","doi-asserted-by":"crossref","first-page":"e71636","DOI":"10.7554\/eLife.71636","article-title":"Divergent acyl carrier protein decouples mitochondrial Fe-S cluster biogenesis from fatty acid synthesis in malaria parasites","volume":"10","year":"2021","journal-title":"Elife"},{"key":"2023012503051956000_2023.01.23.525242v1.16","doi-asserted-by":"crossref","unstructured":"Y. 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