Molecular mechanisms for maturation of the Rieske Fe-S protein in malaria parasites

Malaria is a mosquito-borne disease caused by the eukaryotic Plasmodium falciparum parasites. Clinical symptoms become apparent during the blood stage of the lifecycle and may result in cardiovascular complications, respiratory distress, and death. Plasmodium parasites have evolved unique metabolic adaptations compared to other eukaryotes. In human and yeast mitochondria, the acyl carrier protein (mACP) interacts with a protein chaperone called MZM1, which stabilizes the Rieske Fe-S protein before assembly and insertion into the electron transport chain (ETC) Complex III. However, Plasmodium parasites lack an MZM1 homolog but require Rieske for parasite viability, suggesting that an alternative mechanism exists for Rieske maturation independent of MZM1. Preliminary immunoprecipitation experiments have revealed that parasite mACP binds directly to Rieske despite the absence of MZM1. Additionally, it has been observed that parasite Rieske has an extended N-terminus containing two LYR-like motifs that are not present in human or yeast Rieske. It is hypothesized that the Rieske N-terminus directly binds to mACP via LYR-like motifs and provides an essential function that facilitates Rieske maturation beyond conferring mitochondrial targeting. The mitochondrial ETC has been considered a promising drug target, primarily because of its divergent features when compared to mammalian cells. While most research has focused on cytochrome b, the ETC continues to hold potential as a therapeutic target. Therefore, unraveling novel and divergent features is expected to provide insights into pathogen evolution and unveil potential new therapeutic targets to mitigate cardiovascular pathologies caused by malaria.

Basic Science

Jan 2024 — Dec 2025

$67,388

United States