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Mitochondrial homeostasis and metabolism are crucial for the survival and propagation of the malaria parasite within the host. Here we have functionally characterized a\n                    <jats:italic>Plasmodium falciparum<\/jats:italic>\n                    HtrA2 (\n                    <jats:italic>Pf<\/jats:italic>\n                    HtrA2) protein, which harbours trypsin-like protease activity that can be inhibited by its specific inhibitor, ucf-101. A transgenic parasite line was generated, using the HA-\n                    <jats:italic>glm<\/jats:italic>\n                    S C-terminal tagging approach, for localization as well as for inducible knock-down of\n                    <jats:italic>Pf<\/jats:italic>\n                    HtrA2. The\n                    <jats:italic>Pf<\/jats:italic>\n                    HtrA2 was localized in the parasite mitochondrion during the asexual life cycle. Genetic ablation of\n                    <jats:italic>Pf<\/jats:italic>\n                    HtrA2 caused significant parasite growth inhibition, decreased replication of mtDNA, increased mitochondrial ROS production, caused mitochondrial fission\/fragmentation, and hindered parasite development. However, the ucf-101 treatment did not affect the parasite growth, suggesting the non-protease\/chaperone role of\n                    <jats:italic>Pf<\/jats:italic>\n                    HtrA2 in the parasite. Under cellular stress conditions, inhibition of\n                    <jats:italic>Pf<\/jats:italic>\n                    HtrA2 by ucf-101 reduced activation of the caspase-like protease as well as parasite cell death, suggesting the involvement of protease activity of\n                    <jats:italic>Pf<\/jats:italic>\n                    HtrA2 in apoptosis-like cell death in the parasite. Under these cellular stress conditions, the\n                    <jats:italic>Pf<\/jats:italic>\n                    HtrA2 gets processed but remains localized in the mitochondrion, suggesting that it acts within the mitochondrion by cleaving intra-mitochondrial substrate(s). This was further supported by trans-expression of\n                    <jats:italic>Pf<\/jats:italic>\n                    HtrA2 protease domain in the parasite cytosol, which was unable to induce any cell death in the parasite. Overall, we show the specific roles of\n                    <jats:italic>Pf<\/jats:italic>\n                    HtrA2 in maintaining mitochondrial homeostasis as well as in regulating stress-induced cell death.\n                  <\/jats:p>","DOI":"10.1371\/journal.ppat.1010932","type":"journal-article","created":{"date-parts":[[2022,10,28]],"date-time":"2022-10-28T13:29:45Z","timestamp":1666963785000},"page":"e1010932","update-policy":"https:\/\/doi.org\/10.1371\/journal.ppat.corrections_policy","source":"Crossref","is-referenced-by-count":8,"title":["Dual role of an essential HtrA2\/Omi protease in the human malaria parasite: Maintenance of mitochondrial homeostasis and induction of apoptosis-like cell death under cellular stress"],"prefix":"10.1371","volume":"18","author":[{"given":"Shweta","family":"Singh","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gaurav","family":"Datta","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shaifali","family":"Jain","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vandana","family":"Thakur","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Priya","family":"Arora","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Azhar","family":"Muneer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohd","family":"Asad","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shakir","family":"Ali","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Asif","family":"Mohmmed","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2022,10,28]]},"reference":[{"key":"ppat.1010932.ref001","author":"WHO","year":"2020","journal-title":"World Malaria Report 2020"},{"key":"ppat.1010932.ref002","author":"Global Health, Division of Parasitic Diseases","year":"2020","journal-title":"CDC\u2014Parasites\u2014Malaria"},{"key":"ppat.1010932.ref003","doi-asserted-by":"crossref","first-page":"156","DOI":"10.1038\/nm.3073","article-title":"Malaria biology and disease pathogenesis: Insights for new treatments","volume":"19","author":"LH Miller","year":"2013","journal-title":"Nat Med"},{"key":"ppat.1010932.ref004","first-page":"1","article-title":"Malaria","volume":"3","author":"MA Phillips","year":"2017","journal-title":"Nat Rev Dis Prim 2017 31"},{"key":"ppat.1010932.ref005","doi-asserted-by":"crossref","first-page":"104","DOI":"10.1016\/j.lfs.2016.06.030","article-title":"Understanding the biology of the Plasmodium falciparum apicoplast; an excellent target for antimalarial drug development","volume":"158","author":"A. Chakraborty","year":"2016","journal-title":"Life Sci"},{"key":"ppat.1010932.ref006","doi-asserted-by":"crossref","first-page":"973","DOI":"10.1042\/BST20170563","article-title":"Targeting the apicoplast in malaria","volume":"47","author":"M Biddau","year":"2019","journal-title":"Biochem Soc Trans"},{"key":"ppat.1010932.ref007","doi-asserted-by":"crossref","first-page":"6","DOI":"10.1038\/cddis.2011.118","article-title":"Disruption of a mitochondrial protease machinery in Plasmodium falciparum is an intrinsic signal for parasite cell death","volume":"2","author":"S Rathore","year":"2011","journal-title":"Cell Death Dis"},{"key":"ppat.1010932.ref008","first-page":"1660","article-title":"The prokaryotic ClpQ protease plays a key role in growth and development of mitochondria in Plasmodium falciparum","volume":"15","author":"S Jain","year":"2013","journal-title":"Cell 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