Project description
Targeting the powerhouse of the malaria parasite
Scientists are studying the parasite behind malaria to find ways to target its vulnerabilities. Specifically, the Plasmodium parasites contain a unique mitochondrion that is essential for their survival and energy production. This makes it a promising target for new malaria treatments. The ERC-funded MitoReModel project investigates how the parasite’s mitochondrial membranes reorganise to meet changing energy demands during its life cycle. It will map the architecture of the parasite’s energy-producing machinery and examine how its protein complexes shape the organelle. The findings could help pave the way for new strategies to combat malaria, which is a serious and potentially fatal disease.
Objective
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. 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:
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.
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, investigating their membrane-shaping properties and revealing binding mechanisms of investigational cytochrome-b inhibitors to inform antimalarial drug discovery.
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.
This integrated approach will deliver novel insights into the plasticity and small-molecule modulation of mitochondrial energy metabolism in malaria parasites.
Fields of science (EuroSciVoc)
CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques. See: The European Science Vocabulary.
CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques. See: The European Science Vocabulary.
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Project’s keywords as indicated by the project coordinator. Not to be confused with the EuroSciVoc taxonomy (Fields of science)
Project’s keywords as indicated by the project coordinator. Not to be confused with the EuroSciVoc taxonomy (Fields of science)
Programme(s)
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Multi-annual funding programmes that define the EU’s priorities for research and innovation.
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HORIZON.1.1 - European Research Council (ERC)
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Calls for proposals are divided into topics. A topic defines a specific subject or area for which applicants can submit proposals. The description of a topic comprises its specific scope and the expected impact of the funded project.
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Funding scheme (or “Type of Action”) inside a programme with common features. It specifies: the scope of what is funded; the reimbursement rate; specific evaluation criteria to qualify for funding; and the use of simplified forms of costs like lump sums.
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(opens in new window) ERC-2024-STG
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00014 Helsinki
Finland
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