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

Introduction

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.

Research Gap

However, the structures of both oxidative phosphorylation (OXPHOS) protein complexes and the underlying molecular mechanism are unknown. Having recently pioneered parasite OXPHOS complex structure determination, I will tackle this longstanding enigma by combining state-of-the-art parasitology, high-resolution and in situ structural techniques, and functional analysis to reconstruct a stage-resolved molecular model of the parasite’s bioenergetic membrane and reveal the mechanism of membrane remodelling.

Aim 1: Structural Studies

In Aim 1, we 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: Molecular Model Development

In Aim 2, we 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. We will investigate their membrane-shaping properties and reveal binding mechanisms of investigational cytochrome-b inhibitors to inform antimalarial drug discovery.

Aim 3: Functional Characterisation

In Aim 3, we 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.

Conclusion

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