Mitochondria, the energy-producing organelles in nearly all eukaryotic cells, possess their own small circular genome. The maintenance of this mitochondrial DNA requires a considerable set of nuclear-encoded proteins. As mitochondrial mass and function are strongly influenced by the cell type, both the expression levels of mitochondrial proteins and mitochondrial DNA copy number vary greatly between different tissues and organs. Mitochondrial tissue specificity is also reflected through the replication mechanisms cells use depending on their energy requirement, but also on the oxidative stress level. Here is shown that the utilized replication mechanism correlates with mitochondrial DNA damage in tissues and thus is likely an adaptation for the differences in the oxidative environments of the tissues.
Among the proteins, whose expression level varies between different tissues, are mitochondrial topoisomerases, essential for many aspects of genome maintenance and integrity. Mitochondria contain four topoisomerases, Top1mt, Top3α, Top2α and Top2β. While Top1mt is the only mitochondria-specific topoisomerase and has been investigated to some extent, the mitochondrial function of the topoisomerases Top2 and Top3 have barely been studied. This study shows that the mitochondrial type II topoisomerase Top2b is a regulator of mitochondrial DNA topology and is essential for the relaxation of supercoils. Top3a in contrast is not only involved in resolution of freshly replicated mtDNA molecules, as shown before, but also acts as a replicative topoisomerase in close contact with the replisome, relieving torsional stress behind the replicating fork.
The potential bacterial origin of mitochondria and the homology of many mitochondrial proteins to their bacterial analogues make mitochondria especially vulnerable to antibacterial pharmaceuticals used to treat bacterial infections. Thus, these drugs occasionally have severe side effects caused by mitochondrial dysfunction, but the exact mechanisms are often unclear. Here it is shown that a commonly used antibiotic, ciprofloxacin, interferes with mtDNA replication by inhibiting the function of mitochondrial topoisomerase 2β, explaining the rare but devastating side effects linked to ciprofloxacin therapy.
Proper maintenance of mitochondrial DNA is essential for survival of the cell and the whole organism, and this thesis aims to understand tissue-specific aspects of mtDNA replication and the role topoisomerases play in the maintenance of this tiny but important genome.
The doctoral dissertation of MSc Anu Hangas, entitled Tissue specificity and topoisomerase functions in mitochondrial DNA maintenance will be examined at the Faculty of Science and Forestry on the 11th of December online. The opponent in the public examination will be Professor Rudolf Josef Wiesner, Universität zu Köln, Germany, and the custos will be Researcher, Docent Steffi Goffart, University of Eastern Finland. The public examination will be held in English.
