The human malaria parasite, Plasmodium falciparum, is a major cause of morbidity and mortality in much of the world and is rapidly becoming resistant to current treatments, indicating a need for identification of novel targets for intervention. Mitochondrial protein synthesis is a potential target since interruption of organelle protein synthesis impacts the growth and propagation of the parasite. The mitochondrial genome of Plasmodium species encodes twenty small RNAs which appear to be fragments of ribosomal RNAs (rRNAs). Fifteen have homology to highly conserved regions of other rRNAs but some characteristics important for rRNA function are missing or altered. This project will focus on examination of these fragmented rRNAs and the ribosomes which contain them. We will investigate the structure and interactions of the rRNAs, using in vivo and in vitro crosslinking as tools to assess their physical arrangement in ribosomes and to investigate the role of the five unidentified fragments. We will examine the composition of mitochondrial ribosomes to verify that all twenty rRNAs are associated with ribosomes, and will investigate the origins, structure, and interactions of any additional rRNAs which may originate outside the mitochondrial genome. We will also characterize the gene for a ribosomal protein and show that the protein is associated with the mitochondrial ribosome. Despite indications that interference with mitochondrial functions has anti-malarial effects, earlier studies were unable to find direct evidence of mitochondrial protein synthesis. We will use more sensitive methods to investigate this question, using antibodies directed against proteins encoded by the mitochondrial genome to assess production of those proteins during treatment with various inhibitors of organelle and cytoplasmic protein synthesis. The studies here proposed will provide considerable structural and functional information about the unusual rRNAs from the mitochondrial genome and the ribosomes which contain them. The need for a complex assembly process to produce mitochondrial ribosomes from multiple small rRNAs suggests that this may be an apt target for novel anti-malarial drugs. Further, direct demonstration that the rRNAs are part of functional ribosomes, despite their lack of certain expected features, may produce insights into basis ribosome structure/function correlations.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
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Tropical Medicine and Parasitology Study Section (TMP)
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Seattle Biomedical Research Institute
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Li, J; Maga, J A; Cermakian, N et al. (2001) Identification and characterization of a Plasmodium falciparum RNA polymerase gene with similarity to mitochondrial RNA polymerases. Mol Biochem Parasitol 113:261-9
Feagin, J E (2000) Mitochondrial genome diversity in parasites. Int J Parasitol 30:371-90
Rehkopf, D H; Gillespie, D E; Harrell, M I et al. (2000) Transcriptional mapping and RNA processing of the Plasmodium falciparum mitochondrial mRNAs. Mol Biochem Parasitol 105:91-103
Gillespie, D E; Salazar, N A; Rehkopf, D H et al. (1999) The fragmented mitochondrial ribosomal RNAs of Plasmodium falciparum have short A tails. Nucleic Acids Res 27:2416-22