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Deciphering and reversing the consequences of mitochondrial DNA damage

Description du projet

Les mutations de l’ADN mitochondrial et leurs implications pour la santé

Les mitochondries contiennent leur propre génome, une molécule d’ADN compacte, circulaire et à double brin qui code 13 sous-unités protéiques des complexes de la chaîne respiratoire. De nouvelles données probantes révèlent que l’accumulation de mutations de l’ADN mitochondrial joue un rôle dans le fonctionnement de l’organite. Financé par le Conseil européen de la recherche, le projet RevMito s’intéresse à l’identification des implications potentielles des mutations de l’ADN mitochondrial sur le vieillissement et les maladies. Les chercheurs utiliseront la levure Saccharomyces cerevisiae comme organisme modèle pour étudier les conséquences des dommages et de la perte d’ADN mitochondrial, en portant une attention plus particulière sur l’homéostasie des protéines. Ces résultats pourraient améliorer notre compréhension du dysfonctionnement des mitochondries et potentiellement mener à de nouveaux traitements des maladies mitochondriales.

Objectif

Mitochondrial DNA (mtDNA) encodes several proteins playing key roles in bioenergetics. Pathological mutations of mtDNA can be inherited or may accumulate following treatment for viral infections or cancer. Furthermore, many organisms, including humans, accumulate significant mtDNA damage during their lifespan, and it is therefore possible that mtDNA mutations can promote the aging process.

There are no effective treatments for most diseases caused by mtDNA mutation. An understanding of the cellular consequences of mtDNA damage is clearly imperative. Toward this goal, we use the budding yeast Saccharomyces cerevisiae as a cellular model of mitochondrial dysfunction. Genetic manipulation and biochemical study of this organism is easily achieved, and many proteins and processes important for mitochondrial biogenesis were first uncovered and best characterized using this experimental system. Importantly, current evidence suggests that processes required for survival of cells lacking a mitochondrial genome are widely conserved between yeast and other organisms, making likely the application of our findings to human health.

We will study the repercussions of mtDNA damage by three different strategies. First, we will investigate the link between a conserved, nutrient-sensitive signalling pathway and the outcome of mtDNA loss, since much recent evidence points to modulation of such pathways as a potential approach to increase the fitness of cells with mtDNA damage. Second, we will explore the possibility that defects in cytosolic proteostasis are precipitated by mtDNA mutation. Third, we will apply the knowledge and concepts gained in S. cerevisiae to both candidate-based and unbiased searches for genes that determine the aftermath of severe mtDNA damage in human cells. Beyond the mechanistic knowledge of mitochondrial dysfunction that will emerge from this project, we expect to identify new avenues toward the treatment of mitochondrial disease.

Régime de financement

ERC-STG - Starting Grant

Institution d’accueil

HELSINGIN YLIOPISTO
Contribution nette de l'UE
€ 1 033 640,93
Adresse
YLIOPISTONKATU 3
00014 Helsingin Yliopisto
Finlande

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Région
Manner-Suomi Helsinki-Uusimaa Helsinki-Uusimaa
Type d’activité
Higher or Secondary Education Establishments
Liens
Coût total
€ 1 033 640,93

Bénéficiaires (2)