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 the relationship between mitochondrial dysfunction and intracellular signaling, protein transit to mitochondria, and proteostasis. Furthermore, we take unbiased approaches that are designed to reveal new and unexpected genes that control the response to mitochondrial dysfunction.
During the course of this grant action, we were indeed able to better understand the links between sugar sensation, protein import to mitochondria, and the outcome of mitochondrial dysfunction. Moreover, we were able to identify an additional protein, a lysine methyltransferase, which seems to impinge upon the outcome of mitochondrial dysfunction. We helped to illuminate how mitochondrial contact sites promote the intracellular distribution of mitochondrial metabolites. Finally, we developed novel approaches toward prediction of which mtDNA variants are likely to cause disease, and our studies of mitochondrial evolution are likely to provide further insight into key aspects of mitochondrial disease.
