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K-09 caused depolarization of the mitochondrion and the generation of reactive oxygen species, triggering an apoptotic response in<jats:named-content xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" content-type=\"genus-species\" xlink:type=\"simple\">L. donovani<\/jats:named-content>promastigotes. Mitochondrial dysfunction subsequently resulted in the release of cytochrome<jats:italic>c<\/jats:italic>into the cytosol, impairing ATP production. Oxidative stress caused the depletion of reduced glutathione, while pretreatment with antioxidant<jats:italic>N<\/jats:italic>-acetyl cysteine (NAC) was able to abrogate oxidative stress. However, NAC failed to restore the mitochondrial membrane potential or intracellular calcium homeostasis after K-09 treatment, suggesting that the generation of oxidative stress is a downstream event relative to the other events. Caspase-3\/-7-like protease activity and genomic DNA fragmentation were observed. Electron microscopy studies revealed gross morphological alterations typical of apoptosis, including severe mitochondrial damage, pyknosis of the nucleus, structural disruption of the mitochondrion-kinetoplast complex, flagellar pocket alterations, and the displacement of organelles. Moreover, an increased number of lipid droplets was detected after K-09 treatment, which is suggestive of altered lipid metabolism. Our results indicate that K-09 induces mitochondrial dysfunction and oxidative stress-mediated apoptotic cell death in<jats:named-content xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" content-type=\"genus-species\" xlink:type=\"simple\">L. donovani<\/jats:named-content>promastigotes, sharing many features with metazoan apoptosis. These mechanistic insights provide a basis for further investigation toward the development of K-09 as a potential drug candidate for VL.<\/jats:p>","DOI":"10.1128\/aac.02459-14","type":"journal-article","created":{"date-parts":[[2014,7,29]],"date-time":"2014-07-29T06:34:28Z","timestamp":1406615668000},"page":"5916-5928","update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":101,"title":["Induction of Mitochondrial Dysfunction and Oxidative Stress in Leishmania donovani by Orally Active Clerodane Diterpene"],"prefix":"10.1128","volume":"58","author":[{"given":"Manoj","family":"Kathuria","sequence":"first","affiliation":[{"name":"Electron Microscopy Unit, Sophisticated Analytical Equipment Facility, CSIR-Central Drug Research Institute, Lucknow, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arindam","family":"Bhattacharjee","sequence":"additional","affiliation":[{"name":"Electron Microscopy Unit, Sophisticated Analytical Equipment Facility, CSIR-Central Drug Research Institute, Lucknow, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Koneni V.","family":"Sashidhara","sequence":"additional","affiliation":[{"name":"Medicinal &amp; Process Chemistry Division, CSIR-Central Drug Research Institute, Lucknow, India"},{"name":"Academy of Scientific and Innovative Research, New Delhi, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Suriya Pratap","family":"Singh","sequence":"additional","affiliation":[{"name":"Medicinal &amp; Process Chemistry Division, CSIR-Central Drug Research Institute, Lucknow, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kalyan","family":"Mitra","sequence":"additional","affiliation":[{"name":"Electron Microscopy Unit, Sophisticated Analytical Equipment Facility, CSIR-Central Drug Research Institute, Lucknow, India"},{"name":"Academy of Scientific and Innovative Research, New Delhi, India"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"235","reference":[{"key":"e_1_3_2_2_2","volume-title":"Leishmania: after the genome","author":"Myler PJ","year":"2008","unstructured":"MylerPJFaselN (ed). 2008. 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