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J. Biol. Chem., Vol. 279, Issue 12, 11798-11813, March 19, 2004

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Apoptotic Death in Leishmania donovani Promastigotes in Response to Respiratory Chain Inhibition

COMPLEX II INHIBITION RESULTS IN INCREASED PENTAMIDINE CYTOTOXICITY^*

Ashish Mehta and Chandrima Shaha

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

The biochemical changes consequent to respiratory chain inhibition and their relationship to cell death in Leishmania spp. remain elusive. Inhibitors of respiratory chain complexes I, II, and III were able to induce apoptotic death of the bloodstream form of Leishmania donovani. Complex I inhibition resulted in mitochondrial hyperpolarization that was preceded by increased superoxide production. Limitation of electron transport by thenoyltrifluoroacetone and antimycin A, inhibitors of complexes II and III, respectively, resulted in dissipation of mitochondrial membrane potential that was sensitive to cyclosporin A, a blocker of mitochondrial permeability transition pore. Further studies conducted with thenoyltrifluoroacetone showed maximal generation of hydrogen peroxide with a moderate elevation of superoxide levels. Complex III inhibition provoked superoxide generation only. Interference with complex II but not complexes I and III increased intracellular Ca²⁺. A tight link between Ca²⁺ and reactive oxygen species was demonstrated by antioxidant-induced diminution of the Ca²⁺ increase. However, chelation of extracellular Ca²⁺ could not abrogate the early increase of reactive oxygen species, providing evidence that Ca²⁺ elevation was downstream to reactive oxygen species generation. Ca²⁺ influx occurred through nonselective cation and L-type channels and Na⁺/Ca²⁺ exchanger-like pathways. Antioxidants such as glutathione and Ca²⁺ channel blockers reduced apoptotic death. This study provides a new possibility that concurrent inhibition of respiratory chain complex II with pentamidine administration increases cytotoxicity of the drug. This increased cytotoxicity was connected to a 4-fold elevation in intracellular Ca²⁺ that was pooled only from intracellular sources. Therefore, inhibition of complexes I, II, and III leads to apoptosis and complex II inhibition in parallel with pentamidine administration-enhanced drug efficacy.

Received for publication, August 22, 2003 , and in revised form, December 10, 2003.

^* This work was supported by grants to the National Institute of Immunology from the Department of Biotechnology and Indian Council of Medical Research, Government of India. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence should be addressed. Tel.: 91-11-2671-7121; Fax: 91-11-2616-2125; E-mail: cshaha{at}nii.res.in.

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