The Importance of Maintaining Mitochondrial DNA

In a recent WCMR Science Seminar, we heard from James Chapman about his research that focuses on how physical changes to mitochondrial DNA can affect the ability of our mitochondria to function and the impact of this for human health. Read on to find out more.

Each human cell contains thousands of separate copies of mitochondrial DNA. We use high-resolution microscopy to visualise mitochondrial DNA within cells. In the microscope image shown below, a cell can be seen with the mitochondria stained in purple and the many copies of mitochondrial DNA in green. The number of mitochondrial DNA molecules in the cell is sustained by copying (replicating) the DNA. We have identified a protein called Topoisomerase 3α that is responsible for separating mitochondrial DNA once it has been replicated, an important process for maintaining healthy cells and mitochondria. When Topoisomerase 3α does not work efficiently due to a mutation, the mitochondrial DNA cannot be separated when it is replicated. This is called catenation and eventually results in multiple copies of the mitochondrial DNA being physically tangled up. This presents a significant challenge for the cell as it is difficult to use this DNA to maintain and produce the proteins responsible for energy production. As a consequence, mutations in Topoisomerase 3α are linked to mitochondrial disease.

We are interested in other cellular proteins that work alongside Topoisomerase 3α to prevent mitochondrial DNA from becoming catenated. This enables us to understand the molecular basis of disease in some patients. In my presentation, I covered some of the work where we have identified a crucial protein that is necessary to prevent mtDNA from becoming catenated. When studying this protein in human cells, we have found that its loss causes a number of problems with our mitochondria. Firstly, the amount of mitochondrial DNA is severely reduced, and what remains is catenated. Secondly, we have found that the interior structure of mitochondria, which is essential for efficient energy production, is disrupted. This also results in a reduced number of the important energy producing proteins that are found here. These are often features observed in patients with mitochondrial disease.

Following the identification of this protein, I discussed some of the future experiments we have planned that will hopefully allow us to fully dissect its relationship with Topoisomerase 3α and how it is important in maintaining mitochondrial DNA. Longer term, we hope that this knowledge will further our understanding of the molecular basis of mitochondrial DNA related disease and together with our clinical colleagues, help to inform treatment options for patients.