Long term objectives of this project have been to understand mitochondrial genetic system of malarial parasites, to assess mitochondrial physiology, and to assess mitochondrial responses to antimalarial drugs. During the past few years, it has become apparent that malarial parasites -- indeed, all apicomplexans --contain two very unusual cytoplasmic genomes: one, a 6- kb DNA element, discovered in this laboratory, that appears to be the mitochondrial genome, and the other, a 35-kb circular DNA, previously thought to be the mitochondrial DNA, now believed to be a plastid derivative with as yet unknown functions. These genomes represent very unusual genetic systems, and reside in organelles that are proven or potential sites for antimalarial drug actions. It is increasingly apparent that, besides oxidative phosphorylaiton, mitochondria also play critical roles in numerous metabolic steps in most eukaryotes. Interference with these functions is detrimental to the survival of these organisms. The central hypothesis of this project is that mitochondrial function sin malarial parasites are no exception to this. Yet, lack of appropriate tools and reagents has hampered progress in this long-neglected area. Having developed certain new approaches and reagents, this laboratory proposes to apply them to advance athe understanding of mitochondria in malarial parasites. Effects of antimalarial compounds such as hydroxynaphthoquinones and 8-aminoquinolines on mitochondrial electron transport in Plasmodium falciparum and P. yoelii will be examined by monitoring membrane electropotential and respiration. Molecular mechanisms underlying resistance to these drugs will be investigated. Changes in mitochondrial functions accompanying sexual differentiation in P. falciparum will be studied. Unusual features of transcription and translation in parasite mitochondria -- generation of numerous transcripts, likelihood of trans-associated mosaic ribosomes -- will be analyzed to understand the underlying mechanisms which may reveal additional targets for antimalarial drug action.
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