CBE/ENGR 225 Faculty Seminar: Rudiyanto Gunawan, Professor, Institute of Chemical and Bioengineering, ETH Zurich, Switzerland, Swiss Institute of Bioinformatics, Lausanne, Switzerland

Tuesday, November 8, 2016 @ 4PM, Elings Hall, Room #1601

Tuesday, November 8, 2016

Elings Hall, Room #1601

4 - 5pm

*Light refreshments will be provided*

Rudiyanto Gunawan, Ph.D.
Professor, Institute for Chemical and Bioengineering, ETH Zurich, Switzerland
Swiss Institute of Bioinformatics, Lausanne, Switzerland

Host: Adele Doyle, Ph.D.

Mitochondrial DNA Mutations in Ageing

Abstract: Mitochondria are the powerhouses of eukaryotic cells, generating much of the cell’s ATP through respiration. Mitochondrial dysfunctions have been implicated in a wide range of human pathologies, ranging from cancer, diabetes, sacropenia, neurodegenerative disease and the ageing process. Mitochondrial organelles possess their own genome, mitochondrial DNA (mtDNA), which encode key proteins of oxidative phosphorylation complexes. A single eukaryotic cell harbors 100s-1000s copies of mtDNA, providing a buffer for the phenotypic expression of deleterious mtDNA mutations. However, an accumulation of mutant mtDNA molecules in a cell beyond a certain burden threshold (between 60% and 90%) would cause mitochondrial respiratory defects and dysfunction.

In the first part of this seminar, I will present findings from a modeling study in understanding the accumulation of mutant mtDNA molecules. Here, we developed stochastic models of mitochondrial quality control, including mitochondrial turnover and fusion-fission, to simulate the dynamics of wild-type and mutant mtDNA in individual cells. Through model simulations and sensitivity analysis, we found mitochondrial autophagy, a process that degrades mitochondrial organelles, to be an interesting intervention target against age-related mitochondrial dysfunction. We validated this hypothesis on nematode worms (Caenorhabditis elegans) using lithium to upregulate autophagy.

In addition to mutant accumulation, my group has also been studying the formation of mtDNA mutations, particularly deletions. In the literature, mtDNA deletions have been commonly associated with DNA misalignments during replication or repair, possibly involving direct repeat (DR) motifs. Direct repeats are sequences of nucleotides that appear in multiple positions in the genome. Because of DR involvement in deletion mutagenesis, the number of DRs in mtDNA sequences has long been hypothesized to constrain the lifespan of organisms. In the second part of the seminar, I will present some recent findings from our analysis of 600 mammalian and avian mtDNA sequences, regarding evolutionary selection on DRs and mtDNA deletions. Finally, if time permits, I will describe the use of mtDNA misalignment thermodynamics to elucidate the dominant source(s) of mtDNA deletion mutations in human ageing and mitochondrial diseases.