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Originally published In Press as doi:10.1074/jbc.M201961200 on April 30, 2002

J. Biol. Chem., Vol. 277, Issue 27, 24717-24727, July 5, 2002
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Increase in Cytosolic Ca2+ Levels through the Activation of Non-selective Cation Channels Induced by Oxidative Stress Causes Mitochondrial Depolarization Leading to Apoptosis-like Death in Leishmania donovani Promastigotes*

Sikha Bettina Mukherjee, Manika Das, Ganapasam Sudhandiran, and Chandrima ShahaDagger

From the National Institute of Immunology, Aruna Asaf Ali Marg, New Delhi 110067, India

Reactive oxygen species are important regulators of protozoal infection. Promastigotes of Leishmania donovani, the causative agent of Kala-azar, undergo an apoptosis-like death upon exposure to H2O2. The present study shows that upon activation of death response by H2O2, a dose- and time-dependent loss of mitochondrial membrane potential occurs. This loss is accompanied by a depletion of cellular glutathione, but cardiolipin content or thiol oxidation status remains unchanged. ATP levels are reduced within the first 60 min of exposure as a result of mitochondrial membrane potential loss. A tight link exists between changes in cytosolic Ca2+ homeostasis and collapse of the mitochondrial membrane potential, but the dissipation of the potential is independent of elevation of cytosolic Na+ and mitochondrial Ca2+. Partial inhibition of cytosolic Ca2+ increase achieved by chelating extracellular or intracellular Ca2+ by the use of appropriate agents resulted in significant rescue of the fall of the mitochondrial membrane potential and apoptosis-like death. It is further demonstrated that the increase in cytosolic Ca2+ is an additive result of release of Ca2+ from intracellular stores as well as by influx of extracellular Ca2+ through flufenamic acid-sensitive non-selective cation channels; contribution of the latter was larger. Mitochondrial changes do not involve opening of the mitochondrial transition pore as cyclosporin A is unable to prevent mitochondrial membrane potential loss. An antioxidant like N-acetylcysteine is able to inhibit the fall of the mitochondrial membrane potential and prevent apoptosis-like death. Together, these findings show the importance of non-selective cation channels in regulating the response of L. donovani promastigotes to oxidative stress that triggers downstream signaling cascades leading to apoptosis-like death.

* This work was supported by the Indian Council of Medical Research, Department of Biotechnology, Government of India, and a fellowship from the Council of Scientific and Industrial Research (to S. B. M.).The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Dagger To whom correspondence should be addressed: National Institute of Immunology, Aruna Asaf Ali Marg, New Delhi 110067, India. Fax: 11-616-2125, E-mail: cshaha@nii.res.in.

Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.
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