Mitochondria and Ageing

Mitochondrial dysfunction is a central and conserved feature of the ageing process. Mitochondria are the powerhouses of eukaryotes, producing much of the cellular energy. A human cell houses 100s-1000s of mitochondrial DNA (mtDNA), which encode proteins that are necessary for energy production. Accumulations of mutant mtDNA molecules could lead to the loss of mitochondrial function, a hallmark of many age-related diseases. Mitochondrial quality control (QC) processes exist for the purpose of maintaining mitochondrial function and genomic integrity. While the machinery of this QC has been shown to deteriorate with ageing, it is however difficult to identify targets for intervention against mutant mtDNA accumulation without a comprehensive understanding of the intricate interplay among the QC components. Such an understanding however would require an enormous experimental undertaking.

In collaboration with the groups of Professors external pageBarry Halliwell (National University of Singapore, NUS) and external pageJan Gruber (NUS-Yale), we have been applying systems biological modeling and analysis to gain a better understanding on the formation and accumulation of mtDNA mutant molecules. More specifically, we have created mathematical models of mitochondrial QC with increasing complexity and realism, to identify the critical processes that are involved in mutant mtDNA accumulation. In addition, we have also compiled and analyzed large compendia of mtDNA breakpoints from different organisms to determine the causal factors in the formation of mtDNA deletion mutations. Using model simulations and analysis, we have been able to generate testable hypotheses and actionable insights.