Last Updated: 01/05/2025
Nonconventional mitochondrial ribosomes of malaria parasites
Objectives
The overall goal of this project is to investigate the structure and function of the mitochondrial ribosome (mitoribosome) in Plasmodium falciparum malaria parasites.
This project proposes two specific aims:
- Characterize the structural composition of the parasite mitoribosome. This will involve isolating the mitoribosome followed by mass spectrometry to identify associated protein subunits. High-throughput small RNA sequencing will be used to characterize its rRNA content.
- Assess the functionality and essentiality of the mitoribosome. This aim will use genetic knockout and knockdown approaches targeting three evolutionarily conserved ribosomal protein subunits to determine their roles in parasite survival and mitochondrial translation.
Ribosomes are large macromolecular complexes (~2 MDa) composed of RNAs and proteins that are essential for translating genetic information into functional proteins. In P. falciparum, three distinct translation systems operate within the nucleus, apicoplast, and mitochondrion. Among these, the mitochondrial translation machinery remains the least understood and is structurally and phylogenetically divergent from both the cytosolic and human mitochondrial ribosomes, making it a promising target for antimalarial drug development.
This research aims to elucidate the components and biological functions of the parasite mitoribosome, thereby advancing understanding of this ancient protein synthesis apparatus. The study will also contribute to broader insights into ribosomal RNA (rRNA) function and the general mechanisms of protein translation. Importantly, it may provide a foundation for the development of novel antimalarial therapeutics targeting mitochondrial protein synthesis.
The mitochondrion is a critical organelle throughout the parasite’s lifecycle. It supports essential biosynthetic processes, including pyrimidine synthesis and iron-sulfur cluster biogenesis, and plays a central role in energy production through oxidative phosphorylation during the insect stages. The mitochondrial electron transport chain (mtETC), particularly the cytochrome bc1 complex, is already validated as a drug target. Yet, the structural and functional properties of the mitoribosome that translates key mtETC components—cytochrome b and two subunits of cytochrome c oxidase—remain largely unknown.
P. falciparum mitochondrial DNA (mtDNA) is highly reduced, encoding only three mtETC proteins and approximately 30 fragmented rRNA gene segments. The fragmented nature of the rRNA and the absence of mitochondrial tRNA genes once cast doubt on whether mitochondrial protein translation occurred at all in the parasite.
This study will address a critical knowledge gap in mitochondrial biology and parasite translational machinery, while opening new avenues for therapeutic intervention through the identification of parasite-specific vulnerabilities in mitochondrial protein synthesis.
Aug 2017 — Jul 2019
$270,000
