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Mitochondria-Dependent Reactive Oxygen Species-Mediated Programmed Cell Death Induced by 3,3'-Diindolylmethane through Inhibition of F0F1-ATP Synthase in Unicellular Protozoan Parasite Leishmania donovani

Molecular Parasitology Laboratory (A.R., A.G., S.B., H.K.M.) and Department of Medicinal Chemistry (C.P., P.J.), Indian Institute of Chemical Biology, Kolkata, India; and Laboratory of Molecular Pharmacology, National Cancer Institute, National Institutes of Health, Bethesda, Maryland (B.B.D.)

Mitochondria are the principal site for the generation of cellular ATP by oxidative phosphorylation. F0F1-ATP synthase, a complex V of the electron transport chain, is an important constituent of mitochondria-dependent signaling pathways involved in apoptosis. In the present study, we have shown for the first time that 3,3'-diindolylmethane (DIM), a DNA topoisomerase I poison, inhibits mitochondrial F0F1-ATP synthase of Leishmania donovani and induces programmed cell death (PCD), which is a novel insight into the mechanism in protozoan parasites. DIM-induced inhibition of F0F1-ATP synthase activity causes depletion of mitochondrial ATP levels and significant stimulation of mitochondrial reactive oxygen species (ROS) production, followed by depolarization of mitochondrial membrane potential (_m). Because _m is the driving force for mitochondrial ATP synthesis, loss of _m results in depletion of cellular ATP level. The loss of _m causes the cellular ROS generation and in turn leads to the oxidative DNA lesions followed by DNA fragmentation. In contrast, loss of _m leads to release of cytochrome c into the cytosol and subsequently activates the caspase-like proteases, which lead to oligonucleosomal DNA cleavage. We have also shown that mitochondrial DNA-depleted cells are insensitive to DIM to induce PCD. Therefore, mitochondria are necessary for cytotoxicity of DIM in kinetoplastid parasites. Taken together, our study indicates for the first time that DIM-induced mitochondrial dysfunction by inhibition of F0F1-ATP synthase activity leads to PCD in Leishmania spp. parasites, which could be exploited to develop newer potential therapeutic targets.

Address correspondence to: Dr. Hemanta K. Majumder, Molecular Parasitology Laboratory, Indian Institute of Chemical Biology, 4, Raja S.C. Mullick Rd., Kolkata-700032, India. E-mail: hkmajumder{at}iicb.res.in

This article has been cited by other articles:

				A. Roy, S. BoseDasgupta, A. Ganguly, P. Jaisankar, and H. K. Majumder Topoisomerase I Gene Mutations at F270 in the Large Subunit and N184 in the Small Subunit Contribute to the Resistance Mechanism of the Unicellular Parasite Leishmania donovani towards 3,3'-Diindolylmethane Antimicrob. Agents Chemother., June 1, 2009; 53(6): 2589 - 2598. [Abstract] [Full Text] [PDF]