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 donovan
IR@IICB: CSIR-Indian Institute of Chemical Biology, Kolkata
View Archive Info| Field | Value | |
| Title |
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 donovan
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| Creator |
Roy, Amit
Ganguly, Agneyo Bose Dasgupta, Somdeb Das, BB Pal, Churala Jaisankar , P Majumder, Hemanta K |
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| Subject |
Chemistry
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| Description |
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 mito 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.
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| Date |
2008
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| Type |
Article
PeerReviewed |
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| Format |
application/pdf
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| Identifier |
http://www.eprints.iicb.res.in/161/1/Mol_Pharmacol%2D2008%2DRoy%2D1292%2D307[20].pdf
Roy, Amit and Ganguly, Agneyo and Bose Dasgupta, Somdeb and Das, BB and Pal, Churala and Jaisankar , P and Majumder, Hemanta K (2008) 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 donovan. Molecular Pharmacology, 74. pp. 1292-1307. |
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| Relation |
http://dx.doi.org/10.1124/mol.108.050161
http://www.eprints.iicb.res.in/161/ |
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