Knowledge of DNA damage in the cell’s power plant could pave the way for new medicines

The power plants of cells, the mitochondria, produce the energy that cells need to function. It is also central to other important processes in the cell. Damage to mitochondrial DNA can cause diseases for which there is currently no cure. Paulina Wanrog studies mitochondrial signals to the cell in the event of DNA damage. The goal is the best methods of diagnosis and treatment.

Wallenberg Academy Fellow 2021

institution:
Umeå University

Research area:
Damage to mitochondrial DNA and how it signals and affects the rest of the cell.

In our cells there are small organelles, mitochondria, whose main role is to produce energy. If mitochondria do not function properly, diseases can occur. One in every 5,000 children in the world is born with mitochondrial diseases, for which there is currently no cure. This is what Paulina Wanrui, who researches the mitochondrial genetic cluster at Umeå University, tells us.
It says that the bulk of our genetic mass is found in the nucleus of cells. Also around the cell are mitochondria, which carry their own smaller DNA (see fact box), inherited from the mother.

Mitochondrial DNA is a kind of “underdog” in research, a part of the genetic mass that is sometimes forgotten. The focus is usually on the largest genetic cluster in the cell nucleus. But the mitochondrial genome is involved in many important processes in the cell in addition to energy production, including inflammation. It is more central than we previously thought and we are now beginning to understand this better.

A large percentage of mitochondrial diseases are caused by mutations. It’s either in the mitochondrial DNA or in the genes in the cell nucleus that code for the proteins needed to copy or repair the mitochondrial DNA, Paulina Wanrog explains.

– In these cases, when there is a problem with the mitochondrial DNA, the cell does not produce enough energy. Then an energy deficiency is created. This, in turn, can cause a variety of symptoms in all organs, such as muscle weakness and brain damage, which also makes these diseases difficult to diagnose. I hope my research will lead to us being able to develop better diagnostics and treatments for mitochondrial diseases.

Mitochondrial signal

Some mitochondrial diseases are not caused by a lack of energy but by stress signals from the mitochondria. As a fellow of the Wallenberg Academy, Paulina Wanrooij wants to study the messages sent from the mitochondria of the cell.

– We believe that if we can turn off certain signals, it may be possible to develop treatments that can benefit patients. Because in some cases, the signals can be a kind of overreaction of the body. But it’s a fairly new area of ​​research, the signals are complex, and there’s a lot of knowledge that’s lacking today.

The search is experimental. Many parts of the project revolved around studying human cells that had been grown in a special way in the laboratory. In these cells, researchers can damage the mitochondrial DNA and then study the signals that the mitochondria send.

– It took time for everything to work properly because we want to damage the mitochondrial DNA and not the DNA of the cell nucleus, and only study the signals from the mitochondria. But we now have the tools in place. When it comes to mitochondrial DNA damage, the field of research lags behind in molecular understanding. So we want to contribute this knowledge.

It also works with yeast cells, whose genome is easier to manipulate.

– When we find an interesting signaling process in yeast, we look to see if the same process is triggered when mitochondrial DNA is damaged in human cells. We also study the purified proteins in a controlled environment, to understand how different molecular factors contribute to damage.

Mitochondrial dysfunction and instability in mitochondrial DNA can also be associated with various forms of cancer. Paulina Wanrog will also study this under the fellowship.

Like a marathon

Paulina Wanrui is from Finland, where she studied biotechnology at the University of Tampere.

– I was interested in both medical and technical topics, so the Biotechnology program was perfect for me. Interest in mitochondrial DNA began very early, when already in my first year I had the opportunity to work part-time in a research group that studied mitochondria. I continued with him throughout my studies and did my thesis there. So I was completely sold on mitochondria from the start.

“Mitochondrial DNA is a kind of ‘underdog’ in research, a part of the genetic mass that is sometimes forgotten. But it’s more important than we once thought and that makes it so much fun to study.”

I first moved to Sweden in 2006 for my Ph.D., splitting time between Karolinska Institutet and the University of Gothenburg. Subsequently, she served two years as a postdoctoral fellow in the United States at Washington University in St. Louis. After that, she moved back to Sweden but this time to Umeå, where she founded her own research group.

So far, we have worked to understand how mitochondrial signaling affects cell growth. And now we think we’ve found clues to the kind of signals that stop or slow cell growth when mitochondria aren’t working properly.

It takes time to build a research environment and get publishable results. Paulina Wanrog laughs when asked if she is being patient.

– No, not really, but I’m a runner and I view research more like a marathon. You have to run at a steady pace and at the same time keep calm so that you can continue for a longer period of time. And when I run a lot I get clarity on many issues and can see the bigger picture.

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