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Deciphering and reversing the consequences of mitochondrial DNA damage

Descrizione del progetto

Mutazioni del DNA mitocondriale e implicazioni per la salute

I mitocondri contengono il loro genoma, una molecola del DNA compatta, circolare e a doppio filamento che codifica 13 subunità proteiche dei complessi della catena respiratoria. Prove sempre più evidenti indicano un ruolo attivo svolto dalle mutazioni del DNA mitocondriale accumulate nella funzione dell’organello. Il progetto RevMito, finanziato dal Consiglio europeo della ricerca, è interessato a identificare le potenziali implicazioni delle mutazioni del DNA mitocondriale per l’invecchiamento e le malattie. I ricercatori utilizzeranno il lievito Saccharomyces cerevisiae come organismo modello per studiare gli esiti del danno e della perdita di DNA mitocondriale, con particolare attenzione all’omeostasi delle proteine. I risultati potrebbero migliorare la nostra comprensione della disfunzione mitocondriale e, potenzialmente, portare a nuovi trattamenti per le malattie legate a questi organuli.

Obiettivo

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.

Meccanismo di finanziamento

ERC-STG - Starting Grant

Istituzione ospitante

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

Mostra sulla mappa

Regione
Manner-Suomi Helsinki-Uusimaa Helsinki-Uusimaa
Tipo di attività
Higher or Secondary Education Establishments
Collegamenti
Costo totale
€ 1 033 640,93

Beneficiari (2)