Report

Teaser, summary, work performed and final results

Periodic Reporting for period 3 - RevMito (Deciphering and reversing the consequences of mitochondrial DNA damage)

Teaser

More than one in 5000 people may be afflicted by mitochondrial diseases that lead to a variety of debilitating symptoms. Mutations causing mitochondrial disorders are localized to both the mitochondrial and the nuclear genomes, and with the application of next generation...

Summary

More than one in 5000 people may be afflicted by mitochondrial diseases that lead to a variety of debilitating symptoms. Mutations causing mitochondrial disorders are localized to both the mitochondrial and the nuclear genomes, and with the application of next generation sequencing-based approaches, additional genes continue to be linked to mitochondrial dysfunction. While some mutations can more generally affect energy production by, for example, diminishing the synthesis of mitochondria-encoded protein products or hampering mitochondrial DNA replication, other mutations block specific mitochondrial complexes and activities. Beyond heritable mitochondrial disorders, mitochondrial dysfunction can be caused by antiviral drugs and by drugs targeting tumors. There are few to no treatment options for most mitochondrial diseases. Consequently, increased effort toward discovery and rational formulation of new treatments for mitochondria-associated illness is clearly warranted.

The overall objective of this project is to understand the cellular outcomes of mitochondrial disease. Toward this goal, we use mammalian cells and also budding yeast, a model system that has been historically invaluable in understanding mitochondrial assembly and dysfunction. Our specific focus is on the link between events in the cytosol, such as nutrient sensing and protein translation, and the outcome of mitochondrial DNA damage. Furthermore, we take unbiased approaches that are designed to reveal new and unexpected genes that control the response to mitochondrial dysfunction.

Work performed

Several important advances have been made so far within the context of this grant. We have successfully investigated the link between glucose sensation in yeast and the outcome of mtDNA deletion. In this course of this work, we have generated an expanded view of the genes activated or inactivated by removal of the mitochondrial genome. Furthermore, we have developed a novel approach to studying protein insertion at the surface of organelles, and we have applied this workflow to the study of a conserved protein involved in yeast mitochondrial division. We performed pioneering studies demonstrating that hydrophobic stretches obtained from prokaryotic proteins can insert at the mitochondrial outer membrane. Finally, we have proposed a new hypothesis related to mitochondrial evolution, and we continue to make headway in our search for new nuclear genes controlling the outcome of mitochondrial dysfunction.

Final results

We expect further success during the course of this grant action. Specifically, we will soon report upon a gene which allows full benefits to be provided to yeast cells lacking mtDNA after modulation of nutrient sensing pathways. Moreover, we anticipate successful identification of other genes controlling the many outcomes of mitochondrial dysfunction in mammalian cells. We also have focused our attention upon protein folding within mitochondria following damage to these organelles. Our continuing work will allow additional results that are of interest to the wider biomedical science community and that can potentially be exploited toward the treatment of mitochondrial disorders.

Website & more info

More info: http://www.biocenter.helsinki.fi/bi/dunn/lab/DunnLab/.