Project description
Exploring mitochondria’s role in protecting cells from ferroptosis
Ferroptosis is a form of cell death linked to iron-dependent oxidative stress, often seen in conditions like neurodegenerative disorders. Mitochondria, the energy centres of cells, play a surprising role in preventing ferroptosis despite their reputation as triggers of cell death. They do this by producing and transporting Coenzyme Q (CoQ), a molecule that protects cells and supports key metabolic processes. However, how mitochondria decide to export or retain CoQ and whether they have other ways to stop ferroptosis remain unclear. With this in mind, the ERC-funded Mito-FerroQuest project will study mitochondrial communication and defence strategies. The aim is to uncover new ways to treat diseases linked to ferroptosis such as Leigh syndrome.
Objective
Mitochondria serve as the epicenter of cellular metabolism. Their dynamic communication with other compartments within the cell ensures proper cellular function. My recent work reveals how mitochondria communicate with the plasma membrane (PM) to transport a redox-active lipid Coenzyme Q (Ubiquinone or CoQ). This communication is crucial for inhibiting a form of iron-mediated cell death called ferroptosis. Notably, CoQ is exclusively synthesized within the mitochondria and plays a pivotal role in maintaining the mitochondrial respiratory chain, as well as other metabolic pathways, such as pyrimidine synthesis, fatty acid oxidation and proline metabolism. My work highlights that cellular defense is primarily orchestrated from the mitochondria and surprisingly dependent on a molecule—CoQ—that is indispensable for mitochondrial function. This work shows that mitochondria—known as cell death inducers—protect cells from ferroptosis and opens several key questions that I will address in Mito-FerroQuest, including:
i) Which proteins and metabolic pathways within the mitochondria dictate whether CoQ should be exported or retained within the mitochondria?
ii) Do mitochondria have other ways to defend against ferroptosis, or is CoQ export their only defense?
iii) Does mitochondrial communication extend beyond the PM and involve interactions with other organelles, such as the endoplasmic reticulum (ER), in protecting cells against ferroptosis?
Answers to these questions will enhance our understanding of mitochondrial strategies in ferroptosis, potentially paving the way for new therapies in conditions where ferroptosis is implicated, like neurodegenerative disorders. Mito-FerroQuest sets the stage for my overarching goal of exploring ferroptosis in diseases with compromised mitochondrial function, such as Leigh syndrome, with the aim to assess its potential as a therapeutic target.
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Project’s keywords as indicated by the project coordinator. Not to be confused with the EuroSciVoc taxonomy (Fields of science)
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HORIZON.1.1 - European Research Council (ERC)
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(opens in new window) ERC-2024-STG
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85764 Neuherberg
Germany
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