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 parasites 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.
- medical and health sciences health sciences infectious diseases malaria
- medical and health sciences health sciences parasitology
- natural sciences biological sciences biochemistry biomolecules proteins
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Keywords
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)
Multi-annual funding programmes that define the EU’s priorities for research and innovation.
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)
MAIN PROGRAMME
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Topic(s)
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.
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.
Funding Scheme
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.
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.
HORIZON-ERC - HORIZON ERC Grants
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Call for proposal
Procedure for inviting applicants to submit project proposals, with the aim of receiving EU funding.
Procedure for inviting applicants to submit project proposals, with the aim of receiving EU funding.
(opens in new window) ERC-2024-STG
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Net EU financial contribution. The sum of money that the participant receives, deducted by the EU contribution to its linked third party. It considers the distribution of the EU financial contribution between direct beneficiaries of the project and other types of participants, like third-party participants.
00014 HELSINGIN YLIOPISTO
Finland
The total costs incurred by this organisation to participate in the project, including direct and indirect costs. This amount is a subset of the overall project budget.