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Deciphering and reversing the consequences of mitochondrial DNA damage

Objective

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.

Field of science

  • /natural sciences/biological sciences/genetics and heredity/mutation
  • /natural sciences/biological sciences/biochemistry/biomolecules/proteins
  • /medical and health sciences/clinical medicine/oncology/cancer
  • /natural sciences/biological sciences/genetics and heredity/genome

Call for proposal

ERC-2014-STG
See other projects for this call

Funding Scheme

ERC-STG - Starting Grant

Host institution

HELSINGIN YLIOPISTO
Address
Yliopistonkatu 3
00014 Helsingin Yliopisto
Finland
Activity type
Higher or Secondary Education Establishments
EU contribution
€ 1 033 640,93

Beneficiaries (2)

HELSINGIN YLIOPISTO
Finland
EU contribution
€ 1 033 640,93
Address
Yliopistonkatu 3
00014 Helsingin Yliopisto
Activity type
Higher or Secondary Education Establishments
KOC UNIVERSITY

Participation ended

Turkey
EU contribution
€ 463 519,07
Address
Rumeli Feneri Yolu Sariyer
34450 Istanbul
Activity type
Higher or Secondary Education Establishments