Leishmania donovani: dyskinetoplastid cells survive and proliferate in the presence of pyruvate and uridine but do not undergo apoptosis after treatment with camptothecin.
We have shown that treatment with luteolin in leishmanial cells causes loss of mt-DNA and induces apoptosis through mitochondria dependent pathway [Sen, N., Das, B.B., Ganguly, A., Banerjee, B., Sen, T., Majumder, H.K., 2006. Leishmania donovani: intracellular ATP level regulates apoptosis-like death in luteolin induced dyskinetoplastid cells. Experimental Parasitology, in press]. Here, we report that mitochondrial DNA depleted leishmanial cells require exogenous sources of pyruvate and uridine to survive and proliferate. The presence of pyruvate and uridine in a growing media help them to produce sufficient amount of glycolytic ATP to maintain the mitochondrial membrane potential in the absence of their functional ETC. Treatment of wild type cells with CPT causes generation of ROS that leads to apoptosis. But unlike the normal cells ROS was not generated in these mt-DNA depleted cells after treatment with CPT. Taken together we have shown for the first time that dyskinetoplastid cells are auxotrophic for pyruvate and uridine and apoptosis cannot be induced in these cells in the presence of CPT. Therefore, the presence of mitochondrial DNA is absolutely necessary for the cytotoxicity of CPT in kinetoplastid parasites.
Sen
Nilkantha
N
Division of Molecular Parasitology, Indian Institute of Chemical Biology, 4 Raja S.C. Mullick Road, Kolkata 700032, India.
Banerjee
Bijoylaxmi
B
Gupta
Souvik Sen
SS
Das
Benu Brata
BB
Ganguly
Agneyo
A
Majumder
Hemanta K
HK
D000255:Adenosine Triphosphate / Q000032:analysis; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D002166:Camptothecin / Q000494:pharmacology*; D004272:DNA, Mitochondrial / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005978:Glutathione / Q000032:analysis; D007773:Lactates / Q000032:analysis; D007893:Leishmania donovani / Q000166:cytology / Q000187:drug effects* / Q000235:genetics / Q000254:growth & development; D047311:Luteolin / Q000494:pharmacology; D008564:Membrane Potentials; D008928:Mitochondria / Q000378:metabolism; D019289:Pyruvic Acid / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000032:analysis; D059004:Topoisomerase I Inhibitors; D014529:Uridine / Q000378:metabolism*
D004272:DNA, Mitochondrial; D004791:Enzyme Inhibitors; D007773:Lactates; D017382:Reactive Oxygen Species; D059004:Topoisomerase I Inhibitors; D019289:Pyruvic Acid; D000255:Adenosine Triphosphate; D005978:Glutathione; D047311:Luteolin; D014529:Uridine; D002166:Camptothecin