Last Updated: 15/10/2025
Unveiling the molecular mechanism of mitochondrial remodelling in the blood stages of the malaria parasite Plasmodium falciparum
Objectives
This research aims to uncover the molecular mechanisms behind mitochondrial remodelling in the malaria parasite Plasmodium falciparum during its transition from asexual blood stages to gametocytes. By employing advanced structural biology techniques, the study will investigate the unique architecture of oxidative phosphorylation complexes and their role in cristae formation, which is crucial for the parasite’s development and transmission.
The research team hypothesizes that mitochondrial remodelling during P. falciparum GC development relies on interactions among the parasite-specific complex subunits, enabling stage-specific oligomerization of ATP synthase (ATPS) and assembly of respiratory supercomplexes (SC). These processes are thought to induce membrane bending and cristae formation within the GC mitochondrion, facilitating stage progression and transmission to the mosquito.
To experimentally validate this hypothesis, the investigators will employ state-of-the-art structural biology methods to characterize the dynamic assembly of ATPS and respiratory SC in situ through cryo-tomographic comparisons of ABS and GC stage mitochondria. Specifically, they will quantify alterations in mitochondrial surface area between ABS and GC, while subtomogram averaging will visualize the spatial localization of the complexes within mitochondria.
This experimental design will define the differential arrangement of essential OXPHOS complexes in the inner mitochondrial membrane of ABS and GC and address key questions: why no cristae form in ABS and what spatial, assembly-state, or oligomeric changes occur in GC that drive cristae shaping. A stage-resolved model of cristae biogenesis in P. falciparum will be generated, enabling subsequent functional analysis of complex components by providing novel structural insights.
Furthermore, the generation of subunit knockout or truncation mutants that specifically disrupt OXPHOS oligomer assembly—while keeping monomeric complexes functionally intact—will allow the research team to probe the roles of the secondarily acquired supernumerary subunits in mitochondrial remodelling.
Overall, this study will break new ground by establishing the first direct link between OXPHOS complex structure, mitochondrial remodelling, and parasite viability and proliferation.
Jan 2025
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