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Deciphering and reversing the consequences of mitochondrial DNA damage

Descripción del proyecto

Mutaciones del ADN mitocondrial e implicaciones para la salud

Las mitocondrias tienen su propio genoma, una molécula de ADN compacta, circular y de doble cadena que codifica trece subunidades proteicas de los complejos de la cadena respiratoria. Cada vez hay más pruebas de que la acumulación de mutaciones en el ADN mitocondrial influye en la función del orgánulo. El objetivo del proyecto RevMito, financiado por el Consejo Europeo de Investigación, es identificar las posibles implicaciones de las mutaciones del ADN mitocondrial en el envejecimiento y la enfermedad. Los investigadores emplearán la levadura «Saccharomyces cerevisiae» como organismo modelo para investigar los resultados del daño y la pérdida de ADN mitocondrial, prestando especial atención a la homeostasis de las proteínas. Sus hallazgos podrían mejorar nuestra comprensión de la disfunción mitocondrial y conducir potencialmente a nuevos tratamientos para las mitocondriopatías.

Objetivo

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.

Régimen de financiación

ERC-STG - Starting Grant

Institución de acogida

HELSINGIN YLIOPISTO
Aportación neta de la UEn
€ 1 033 640,93
Dirección
YLIOPISTONKATU 3
00014 Helsingin Yliopisto
Finlandia

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Región
Manner-Suomi Helsinki-Uusimaa Helsinki-Uusimaa
Tipo de actividad
Higher or Secondary Education Establishments
Enlaces
Coste total
€ 1 033 640,93

Beneficiarios (2)