Revival of the Powerhouse: How mitochondrial remodelling controls the energy metabolism of the malaria parasite to enable survival in different hosts (MitoReModel)

The mitochondrion of the malaria agent Plasmodium falciparum is critical for parasite survival and a confirmed drug target. The dynamic organelle undergoes a Plasmodium-specific membrane remodelling process to adapt to changing metabolic conditions in different hosts. This remarkable transformation is thought to be driven by the arrangement of divergent ATP synthase and respiratory chain complexes into supramolecular assemblies, which shape the internal cristae membranes. However, the structures of both oxidative phosphorylation (OXPHOS) protein complexes and the underlying molecular mechanism are unknown. 

Aim 1 will adapt cutting-edge cultivation methods to unlock structural studies of P. falciparum OXPHOS complexes by generating enough sexual-stage mitochondria to perform electron cryo-tomography and visualize the reorganisation of the inner membrane in situ.

Aim 2 will develop a stage-resolved molecular model of the P. falciparum inner membrane and reveal its architecture by determining high-resolution cryo-EM structures of both OXPHOS complexes, investigating their membrane-shaping properties and revealing binding mechanisms of investigational cytochrome-b inhibitors to inform antimalarial drug discovery.

Aim 3 will draw on new structural insights to perform functional characterisation in parasites and understand the role of parasite-specific subunits in mitochondrial remodelling, energy conversion and parasite fitness.

This integrated approach will deliver novel insights into the plasticity and small-molecule modulation of mitochondrial energy metabolism in malaria parasites.

Project details

Basic Science

Jan 2025 — Dec 2029

$1.62M

Finland