MOLECULAR ANALYSIS OF MALARIA MITOCHONDRIAL GENE REGULATION

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The human malaria parasite, Plasmodium falciparum, rapidly evolves drug resistance, creating the urgent need for new treatment strategies. A critical barrier to identifying and developing new drug development targets is a knowledge gap regarding most essential processes and regulatory pathways. Ideally, new targets should be highly conserved and be unable or have limited ability to mutate in order to evolve resistance. Parasite mitochondrial function is critically essential across all the life stages and differs substantially from the human organelle; however, most mitochondrial proteins have yet to be identified in malaria parasites. During the intraerythrocytic development cycle (IDC), P. falciparum is supported by a single mitochondrion containing about ~20 copies of the 6 kb genome, characterized by extensive recombination. IDC parasite mitochondria do not make cristae to insert electron transport chain (ETC) enzymes, thus the organelle may have evolved unique transcription or translation repression systems to limit expression of the mitochondrial encoded genes. Results from our integrative approach combining whole genome sequencing and metabolic profiling, suggests a link between mitochondrial gene expression regulation and resistance to ETC inhibitors, potentially due to recombination. Thus, we hypothesize that 1) a feature of the multicopy status is retention of cryptic mitochondrial genome copies encoding mutant alleles, which can be recombined for survival. 2) P. falciparum mitochondria use previously uncharacterized gene expression systems, for repression and activation which are unique to this organelle. The current objectives are to identify the source of recombination between mitochondrial genomes and its contribution to drug resistance as well as to determine the mitochondrial DNA repair pathways and transcriptional machinery of the mitochondria using single-organelle approaches. This proposal will identify and define previously unknown and uncharacterized aspects of parasite biology, with the goal of advancing rational drug design. These studies will refine our knowledge about the basic mechanism of gene regulation in the malaria mitochondria. Investigating the mechanisms underpinning these effects will lead to the identification of highly conserved drug development targets.