{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,2]],"date-time":"2026-10-02T02:44:53Z","timestamp":1790909093289,"version":"4.1.0"},"reference-count":47,"publisher":"Public Library of Science (PLoS)","issue":"8","license":[{"start":{"date-parts":[[2022,8,19]],"date-time":"2022-08-19T00:00:00Z","timestamp":1660867200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"crossref","award":["R01 AI028398"],"award-info":[{"award-number":["R01 AI028398"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"crossref","award":["R01 AI123341"],"award-info":[{"award-number":["R01 AI123341"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Covid Relief Fund of Pennsylvania State University"}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS ONE"],"abstract":"<jats:p>Despite ongoing efforts to control malaria infection, progress in lowering the number of deaths and infections appears to have stalled. The continued high incidence of malaria infection and mortality is in part due to emergence of parasites resistant to frontline antimalarials. This highlights the need for continued identification of novel protein drug targets. Mitochondrial functions in<jats:italic>Plasmodium falciparum<\/jats:italic>, the deadliest species of human malaria parasite, are targets of validated antimalarials including atovaquone and proguanil (Malarone). Thus, there has been great interest in identifying other essential mitochondrial proteins as candidates for novel drug targets. Garnering an increased understanding of the proteomic landscape inside the<jats:italic>P<\/jats:italic>.<jats:italic>falciparum<\/jats:italic>mitochondrion will also allow us to learn about the basic biology housed within this unique organelle. We employed a proximity biotinylation technique and mass spectrometry to identify novel<jats:italic>P<\/jats:italic>.<jats:italic>falciparum<\/jats:italic>proteins putatively targeted to the mitochondrion. We fused the leader sequence of a mitochondrially targeted chaperone, Hsp60, to the promiscuous biotin ligase TurboID. Through these experiments, we generated a list of 122 \u201cputative mitochondrial\u201d proteins. To verify whether these proteins were indeed mitochondrial, we chose five candidate proteins of interest for localization studies using ectopic expression and tagging of each full-length protein. This allowed us to localize four candidate proteins of unknown function to the mitochondrion, three of which have previously been assessed to be essential. We suggest that phenotypic characterization of these and other proteins from this list of 122 could be fruitful in understanding the basic mitochondrial biology of these parasites and aid antimalarial drug discovery efforts.<\/jats:p>","DOI":"10.1371\/journal.pone.0273357","type":"journal-article","created":{"date-parts":[[2022,8,19]],"date-time":"2022-08-19T17:25:23Z","timestamp":1660929923000},"page":"e0273357","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":19,"title":["Mitochondrially targeted proximity biotinylation and proteomic analysis in Plasmodium falciparum"],"prefix":"10.1371","volume":"17","author":[{"given":"Ian M.","family":"Lamb","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6662-6426","authenticated-orcid":true,"given":"Kelly T.","family":"Rios","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anurag","family":"Shukla","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Avantika I.","family":"Ahiya","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joanne","family":"Morrisey","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joshua C.","family":"Mell","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1799-3726","authenticated-orcid":true,"given":"Scott E.","family":"Lindner","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael W.","family":"Mather","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1063-5571","authenticated-orcid":true,"given":"Akhil B.","family":"Vaidya","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2022,8,19]]},"reference":[{"issue":"1","key":"pone.0273357.ref001","doi-asserted-by":"crossref","first-page":"164","DOI":"10.1016\/j.celrep.2015.03.011","article-title":"Genetic investigation of tricarboxylic acid metabolism during the Plasmodium falciparum life cycle","volume":"11","author":"H Ke","year":"2015","journal-title":"Cell Rep"},{"key":"pone.0273357.ref002","doi-asserted-by":"crossref","first-page":"67","DOI":"10.1186\/1741-7007-11-67","article-title":"Mitochondrial metabolism of sexual and asexual blood stages of the malaria parasite Plasmodium falciparum","volume":"11","author":"JI MacRae","year":"2013","journal-title":"BMC Biol"},{"issue":"5","key":"pone.0273357.ref003","doi-asserted-by":"crossref","first-page":"1347","DOI":"10.1124\/mol.108.045120","article-title":"Acridinediones: selective and potent inhibitors of the malaria parasite mitochondrial bc1 complex","volume":"73","author":"GA Biagini","year":"2008","journal-title":"Mol Pharmacol"},{"issue":"12","key":"pone.0273357.ref004","doi-asserted-by":"crossref","first-page":"3649","DOI":"10.1021\/jm8001026","article-title":"Triazolopyrimidine-based dihydroorotate dehydrogenase inhibitors with potent and selective activity against the malaria parasite Plasmodium falciparum","volume":"51","author":"MA Phillips","year":"2008","journal-title":"J Med Chem"},{"issue":"7131","key":"pone.0273357.ref005","doi-asserted-by":"crossref","first-page":"88","DOI":"10.1038\/nature05572","article-title":"Specific role of mitochondrial electron transport in blood-stage Plasmodium falciparum","volume":"446","author":"HJ Painter","year":"2007","journal-title":"Nature"},{"issue":"1","key":"pone.0273357.ref006","doi-asserted-by":"crossref","first-page":"49","DOI":"10.2174\/138945007779315632","article-title":"Mitochondrial drug targets in apicomplexan parasites","volume":"8","author":"MW Mather","year":"2007","journal-title":"Curr Drug Targets"},{"issue":"2","key":"pone.0273357.ref007","doi-asserted-by":"crossref","first-page":"97","DOI":"10.1016\/0166-6851(89)90112-6","article-title":"Sequences similar to genes for two mitochondrial proteins and portions of ribosomal RNA in tandemly arrayed 6-kilobase-pair DNA of a malarial parasite","volume":"35","author":"AB Vaidya","year":"1989","journal-title":"Mol Biochem Parasitol"},{"key":"pone.0273357.ref008","doi-asserted-by":"crossref","first-page":"249","DOI":"10.1146\/annurev.micro.091208.073424","article-title":"Mitochondrial evolution and functions in malaria parasites","volume":"63","author":"AB Vaidya","year":"2009","journal-title":"Annu Rev Microbiol"},{"key":"pone.0273357.ref009","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1146\/annurev.mi.48.100194.000501","article-title":"The extrachromosomal DNAs of apicomplexan parasites","volume":"48","author":"JE Feagin","year":"1994","journal-title":"Annu Rev Microbiol"},{"issue":"1","key":"pone.0273357.ref010","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1016\/0166-6851(93)90088-F","article-title":"Structural features of Plasmodium cytochrome b that may underlie susceptibility to 8-aminoquinolines and hydroxynaphthoquinones","volume":"58","author":"AB Vaidya","year":"1993","journal-title":"Mol Biochem Parasitol"},{"issue":"Pt 1","key":"pone.0273357.ref011","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1017\/S0031182000060297","article-title":"Mitochondria of mammalian Plasmodium spp","volume":"102","author":"M Fry","year":"1991","journal-title":"Parasitology"},{"issue":"1","key":"pone.0273357.ref012","doi-asserted-by":"crossref","first-page":"62","DOI":"10.4269\/ajtmh.1996.54.62","article-title":"Clinical studies of atovaquone, alone or in combination with other antimalarial drugs, for treatment of acute uncomplicated malaria in Thailand","volume":"54","author":"S Looareesuwan","year":"1996","journal-title":"Am J Trop Med Hyg"},{"key":"pone.0273357.ref013","doi-asserted-by":"crossref","DOI":"10.12688\/f1000research.16903.1","article-title":"Recent advances in proximity-based labeling methods for interactome mapping","volume":"8","author":"L. Trinkle-Mulcahy","year":"2019","journal-title":"F1000Res"},{"issue":"9","key":"pone.0273357.ref014","doi-asserted-by":"crossref","first-page":"880","DOI":"10.1038\/nbt.4201","article-title":"Efficient proximity labeling in living cells and organisms with TurboID","volume":"36","author":"TC Branon","year":"2018","journal-title":"Nat Biotechnol"},{"key":"pone.0273357.ref015","doi-asserted-by":"crossref","first-page":"10727","DOI":"10.1038\/ncomms10727","article-title":"Synthetic RNA-protein modules integrated with native translation mechanisms to control gene expression in malaria parasites","volume":"7","author":"SM Ganesan","year":"2016","journal-title":"Nat Commun"},{"issue":"2","key":"pone.0273357.ref016","doi-asserted-by":"crossref","first-page":"155","DOI":"10.1016\/S0166-6851(03)00166-X","article-title":"Targeting GFP to the malarial mitochondrion","volume":"130","author":"S Sato","year":"2003","journal-title":"Mol Biochem Parasitol"},{"issue":"8","key":"pone.0273357.ref017","doi-asserted-by":"crossref","first-page":"615","DOI":"10.1038\/nmeth904","article-title":"Efficient site-specific integration in Plasmodium falciparum chromosomes mediated by mycobacteriophage Bxb1 integrase","volume":"3","author":"LJ Nkrumah","year":"2006","journal-title":"Nat Methods"},{"issue":"1","key":"pone.0273357.ref018","doi-asserted-by":"crossref","first-page":"70","DOI":"10.1038\/nmeth.1541","article-title":"SAINT: probabilistic scoring of affinity purification-mass spectrometry data.","volume":"8","author":"H Choi","year":"2011","journal-title":"Nat Methods"},{"issue":"4","key":"pone.0273357.ref019","first-page":"441","article-title":"MitoProt, a Macintosh application for studying mitochondrial proteins","volume":"11","author":"MG Claros","year":"1995","journal-title":"Comput Appl Biosci"},{"issue":"5","key":"pone.0273357.ref020","doi-asserted-by":"crossref","first-page":"e0061421","DOI":"10.1128\/mSphere.00614-21","article-title":"A Prioritized and Validated Resource of Mitochondrial Proteins in Plasmodium Identifies Unique Biology","volume":"6","author":"SL van Esveld","year":"2021","journal-title":"mSphere"},{"issue":"6388","key":"pone.0273357.ref021","doi-asserted-by":"crossref","DOI":"10.1126\/science.aap7847","article-title":"Uncovering the essential genes of the human malaria parasite Plasmodium falciparum by saturation mutagenesis","volume":"360","author":"M Zhang","year":"2018","journal-title":"Science"},{"issue":"2","key":"pone.0273357.ref022","doi-asserted-by":"crossref","first-page":"260","DOI":"10.1016\/j.cell.2017.06.030","article-title":"Functional Profiling of a Plasmodium Genome Reveals an Abundance of Essential Genes","volume":"170","author":"E Bushell","year":"2017","journal-title":"Cell"},{"issue":"48","key":"pone.0273357.ref023","doi-asserted-by":"crossref","first-page":"41312","DOI":"10.1074\/jbc.M111.290973","article-title":"ATP synthase complex of Plasmodium falciparum: dimeric assembly in mitochondrial membranes and resistance to genetic disruption","volume":"286","author":"PB Nina","year":"2011","journal-title":"J Biol Chem"},{"issue":"D1","key":"pone.0273357.ref024","doi-asserted-by":"crossref","first-page":"D898","DOI":"10.1093\/nar\/gkab929","article-title":"VEuPathDB: the eukaryotic pathogen, vector and host bioinformatics resource center","volume":"50","author":"B Amos","year":"2022","journal-title":"Nucleic Acids Res"},{"issue":"6906","key":"pone.0273357.ref025","doi-asserted-by":"crossref","first-page":"498","DOI":"10.1038\/nature01097","article-title":"Genome sequence of the human malaria parasite Plasmodium falciparum","volume":"419","author":"MJ Gardner","year":"2002","journal-title":"Nature"},{"issue":"2","key":"pone.0273357.ref026","doi-asserted-by":"crossref","first-page":"59","DOI":"10.1016\/j.molbiopara.2003.07.001","article-title":"Properties and prediction of mitochondrial transit peptides from Plasmodium falciparum","volume":"132","author":"A Bender","year":"2003","journal-title":"Mol Biochem Parasitol"},{"key":"pone.0273357.ref027","doi-asserted-by":"crossref","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":"8","key":"pone.0273357.ref028","doi-asserted-by":"crossref","first-page":"e0136401","DOI":"10.1371\/journal.pone.0136401","article-title":"Characterization of Precursor PfHsp60 in Plasmodium falciparum Cytosol during Its Asexual Development in Human Erythrocytes","volume":"10","author":"P Padma Priya","year":"2015","journal-title":"PLoS One"},{"issue":"10","key":"pone.0273357.ref029","doi-asserted-by":"crossref","first-page":"e0205596","DOI":"10.1371\/journal.pone.0205596","article-title":"Identification of Plasmodium falciparum nuclear proteins by mass spectrometry and proposed protein annotation","volume":"13","author":"S Briquet","year":"2018","journal-title":"PLoS One"},{"issue":"4","key":"pone.0273357.ref030","doi-asserted-by":"crossref","first-page":"e1005606","DOI":"10.1371\/journal.ppat.1005606","article-title":"Interrogating the Plasmodium Sporozoite Surface: Identification of Surface-Exposed Proteins and Demonstration of Glycosylation on CSP and TRAP by Mass Spectrometry-Based Proteomics","volume":"12","author":"KE Swearingen","year":"2016","journal-title":"PLoS Pathog"},{"issue":"12","key":"pone.0273357.ref031","doi-asserted-by":"crossref","first-page":"110139","DOI":"10.1016\/j.celrep.2021.110139","article-title":"ATAD3A has a scaffolding role regulating mitochondria inner membrane structure and protein assembly","volume":"37","author":"T Arguello","year":"2021","journal-title":"Cell Rep"},{"issue":"13","key":"pone.0273357.ref032","doi-asserted-by":"crossref","DOI":"10.1242\/jcs.217075","article-title":"ATAD3 controls mitochondrial cristae structure in mouse muscle, influencing mtDNA replication and cholesterol levels","volume":"131","author":"S Peralta","year":"2018","journal-title":"J Cell Sci"},{"issue":"13","key":"pone.0273357.ref033","doi-asserted-by":"crossref","first-page":"6109","DOI":"10.1093\/nar\/gks266","article-title":"Mitochondrial nucleoid interacting proteins support mitochondrial protein synthesis","volume":"40","author":"J He","year":"2012","journal-title":"Nucleic Acids Res"},{"issue":"1\u20132","key":"pone.0273357.ref034","doi-asserted-by":"crossref","first-page":"107","DOI":"10.1016\/j.ymgme.2020.09.002","article-title":"Mitochondrial dysfunction caused by novel ATAD3A mutations","volume":"131","author":"N Dorison","year":"2020","journal-title":"Mol Genet Metab"},{"issue":"4","key":"pone.0273357.ref035","doi-asserted-by":"crossref","first-page":"e452","DOI":"10.1212\/NXG.0000000000000452","article-title":"A splice variant in ATAD3A expands the clinical and genetic spectrum of Harel-Yoon syndrome","volume":"6","author":"I Hanes","year":"2020","journal-title":"Neurol Genet"},{"issue":"21","key":"pone.0273357.ref036","doi-asserted-by":"crossref","DOI":"10.3390\/ijms21217917","article-title":"Emerging Links between Control of Mitochondrial Protein ATAD3A and Cancer","volume":"21","author":"L Lang","year":"2020","journal-title":"Int J Mol Sci"},{"issue":"4","key":"pone.0273357.ref037","doi-asserted-by":"crossref","first-page":"831","DOI":"10.1016\/j.ajhg.2016.08.007","article-title":"Recurrent De Novo and Biallelic Variation of ATAD3A, Encoding a Mitochondrial Membrane Protein, Results in Distinct Neurological Syndromes","volume":"99","author":"T Harel","year":"2016","journal-title":"Am J Hum Genet"},{"issue":"7","key":"pone.0273357.ref038","doi-asserted-by":"crossref","first-page":"e1000418","DOI":"10.1371\/journal.pbio.1000418","article-title":"Highly divergent mitochondrial ATP synthase complexes in Tetrahymena thermophila","volume":"8","author":"P Balabaskaran Nina","year":"2010","journal-title":"PLoS Biol"},{"issue":"21","key":"pone.0273357.ref039","doi-asserted-by":"crossref","first-page":"8128","DOI":"10.1074\/jbc.RA118.002552","article-title":"The mitochondrial ribosomal protein L13 is critical for the structural and functional integrity of the mitochondrion in Plasmodium falciparum","volume":"293","author":"H Ke","year":"2018","journal-title":"J Biol Chem"},{"issue":"20","key":"pone.0273357.ref040","doi-asserted-by":"crossref","first-page":"10931","DOI":"10.1073\/pnas.94.20.10931","article-title":"Transformation with human dihydrofolate reductase renders malaria parasites insensitive to WR99210 but does not affect the intrinsic activity of proguanil","volume":"94","author":"DA Fidock","year":"1997","journal-title":"Proc Natl Acad Sci U S A"},{"issue":"6","key":"pone.0273357.ref041","doi-asserted-by":"crossref","first-page":"801","DOI":"10.1083\/jcb.201112098","article-title":"A promiscuous biotin ligase fusion protein identifies proximal and interacting proteins in mammalian cells","volume":"196","author":"KJ Roux","year":"2012","journal-title":"J Cell Biol"},{"key":"pone.0273357.ref042","first-page":"19.23.1","article-title":"BioID: a screen for protein-protein interactions","volume":"74","author":"KJ Roux","year":"2013","journal-title":"Curr Protoc Protein Sci"},{"issue":"7\u20138","key":"pone.0273357.ref043","doi-asserted-by":"crossref","first-page":"745","DOI":"10.1002\/prca.201400164","article-title":"Trans-Proteomic Pipeline, a standardized data processing pipeline for large-scale reproducible proteomics informatics","volume":"9","author":"EW Deutsch","year":"2015","journal-title":"Proteomics Clin Appl"},{"issue":"5","key":"pone.0273357.ref044","doi-asserted-by":"crossref","first-page":"1127","DOI":"10.1074\/mcp.M112.024505","article-title":"Total and putative surface proteomics of malaria parasite salivary gland sporozoites","volume":"12","author":"SE Lindner","year":"2013","journal-title":"Mol Cell Proteomics"},{"issue":"21","key":"pone.0273357.ref045","doi-asserted-by":"crossref","first-page":"2534","DOI":"10.1093\/bioinformatics\/btn323","article-title":"ProteoWizard: open source software for rapid proteomics tools development","volume":"24","author":"D Kessner","year":"2008","journal-title":"Bioinformatics"},{"issue":"8","key":"pone.0273357.ref046","doi-asserted-by":"crossref","first-page":"730","DOI":"10.1038\/nmeth.2557","article-title":"The CRAPome: a contaminant repository for affinity purification-mass spectrometry data","volume":"10","author":"D Mellacheruvu","year":"2013","journal-title":"Nat Methods"},{"issue":"2","key":"pone.0273357.ref047","doi-asserted-by":"crossref","first-page":"266","DOI":"10.1111\/mmi.13762","article-title":"ALBA4 modulates its stage-specific interactions and specific mRNA fates during Plasmodium yoelii growth and transmission","volume":"106","author":"EE Mu\u00f1oz","year":"2017","journal-title":"Mol Microbiol"}],"container-title":["PLOS ONE"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0273357","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,10,2]],"date-time":"2024-10-02T03:28:34Z","timestamp":1727839714000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0273357"}},"subtitle":[],"editor":[{"given":"Gordon","family":"Langsley","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"editor"}]}],"short-title":[],"issued":{"date-parts":[[2022,8,19]]},"references-count":47,"journal-issue":{"issue":"8","published-online":{"date-parts":[[2022,8,19]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pone.0273357","relation":{},"ISSN":["1932-6203"],"issn-type":[{"value":"1932-6203","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,8,19]]}}}