Description:

Rudiyanto Gunawan, Assistant Professor, ETH Zürich

Abstract
As the sites of cellular respiration, mitochondria are the powerhouses of eukaryotic cells. Moreover, these organelles also play an important role in a wide range of regulatory functions, such as iron metabolism, fatty acid oxidation, apoptosis, and the cell cycle. Mitochondria possess their own genome, mitochondrial DNA (mtDNA), encoding proteins that are important for mitochondrial respiration. A single eukaryotic cell can possess 100s-1000s of mtDNA. Mutations in mtDNA, in particular deletions, have been implicated in a wide range of human pathologies, ranging from cancer, diabetes, sacropenia, neurodegenerative disease and the ageing process itself. Because of complementation by wild-type mtDNA, phenotypic expression of mtDNA mutation only happens when the cellular mutation burden exceeds a certain threshold (between 60% and 90%).

In the first part of this talk, I will present findings from a mathematical modeling study in my group related to the (clonal) expansion of mutant mtDNA in cells. In particular, we created a stochastic dynamic model of mitochondrial quality control, involving mitochondrial fusion-fission and turnover processes. We employed global sensitivity analysis and model simulations to determine the likely scenario under which mutant mtDNA could accumulate with age. In the second part of the talk, I will present our study on the role of mtDNA direct repeat (DR) motifs in deletion mutagenesis. Such repeats could cause DNA misalignments during mtDNA replication and repair, leading to the formation of deletion mutations. The frequency of DRs has often been hypothesized to constrain the lifespan of organisms. We revisited this hypothesis by analyzing roughly 600 mammalian and avian mtDNA sequences. In addition, we also developed a first-principle model based on the thermodynamics of DNA-DNA hybridization to determine the relevance of mtDNA misalignments in mtDNA deletion mutagenesis in human and other model organisms.

Bio
Rudiyanto Gunawan is an Assistant Professor of Chemical and Biological Systems Engineering in the Institute for Chemical and Bioengineering at ETH Zurich, Switzerland. His research interests primarily lie at the intersection of systems engineering and biology, more specifically systems modeling and analysis of cellular networks. His research group activities focus on the development of methods for model identification and analysis of gene regulatory networks, signal transduction pathways, and metabolic networks. In the past six years, Prof. Gunawan has also cultivated a deep interest in the area of biogerontology, specifically, the formation and accumulation of mitochondrial DNA mutations. His research work has resulted in more than 50 peer-reviewed journal and conference papers, 3 book chapters and 1 patent. Prof. Gunawan is a co-recipient of two Best Paper awards from the Journal of Process Control and Computers and Chemical Engineering journal.