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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI028398-11
Application #
2886615
Study Section
Tropical Medicine and Parasitology Study Section (TMP)
Program Officer
Fairfield, Alexandra
Project Start
1989-07-01
Project End
2000-06-30
Budget Start
1999-07-01
Budget End
2000-06-30
Support Year
11
Fiscal Year
1999
Total Cost
Indirect Cost
Name
Mcp Hahnemann University
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
City
Philadelphia
State
PA
Country
United States
Zip Code
19102
Vaidya, Akhil B (2018) Reflections on an inflection: From virology to parasitology guided by POLARIS. PLoS Pathog 14:e1006941
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Ke, Hangjun; Morrisey, Joanne M; Qu, Shiwei et al. (2017) Caged Garcinia Xanthones, a Novel Chemical Scaffold with Potent Antimalarial Activity. Antimicrob Agents Chemother 61:
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Stickles, Allison M; Ting, Li-Min; Morrisey, Joanne M et al. (2015) Inhibition of cytochrome bc1 as a strategy for single-dose, multi-stage antimalarial therapy. Am J Trop Med Hyg 92:1195-201
Ke, Hangjun; Lewis, Ian A; Morrisey, Joanne M et al. (2015) Genetic investigation of tricarboxylic acid metabolism during the Plasmodium falciparum life cycle. Cell Rep 11:164-74

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