Small structures can explain severe illness
Professor Anna Wredenberg wants to understand in detail how the body works. That is why she delves into the unknown world of mitochondria. For patients with hereditary genetic diseases, this could mean a long-awaited diagnosis.
Text: Cecilia Odlind, first published in Medicinsk Vetenskap nr 4 2024
Mitochondria are small structures found in all our cells. They are often known as the cell’s power stations, burning sugar and fat into water and carbon dioxide. The energy released is stored in a molecule, ATP, which is used in various cell processes.
"In images of a cell, mitochondria are often depicted as small free-floating beans, but in reality, they consist of large networks that constantly change and can redistribute within the cell," says Anna Wredenberg.
Being responsible for the cell’s energy supply is an important task.
“You can become very ill if the mitochondria do not function as they should. There are hundreds of diseases where the mitochondria are affected, and signs of mitochondrial dysfunction can appear at any point in life and cause problems to varying degrees," she says.
Anna Wredenberg first trained as a physiotherapist but soon realised that she wanted to know more about how the body worked. Therefore, she further trained as a doctor and by chance ended up with researcher Nils-Göran Larsson, who researched mitochondria and offered her a position in his research group.
“I went to one of our textbooks to read up on mitochondria. But there were only a few lines about them. That triggered me to want to know more," she explains.
By now Anna Wredenberg has been researching mitochondria for 25 years.
- "In the beginning, it felt like not many of us were interested in this, but today it is a large and growing field of research," she says.
A special feature of mitochondria is that they have their own genome, which is different from that in the cell nucleus. The mitochondrial DNA is inherited only from the mother and codes for thirteen specific mitochondrial proteins. But in total, there are about 1.500 different types of proteins in these organelles (the cell's answer to organs). The aim of Anna Wredenberg's research is to understand the function of these proteins and what happens if there is something wrong with any of them.
“We are trying to identify which disease, and which symptoms are associated with which protein defects. It is basic research and knowledge that is largely lacking but is a prerequisite for us to be able to develop targeted treatment in the future," says Anna Wredenberg.
Complex diseases
Approximately 1 in 5.000 individuals are affected by mitochondrial disease. As a specialist physician, Anna Wredenberg also works at the Centre for Inherited Metabolic Diseases, CMMS at Karolinska University Hospital, CMMS, and participates in the examination of patients with suspected inherited metabolic disease, including mitochondrial diseases, together with several other specialist physicians.
“We all sit in a room and discuss and help each other to reach the correct diagnosis. These are complex diseases and sometimes knowledge is lacking, so you have to think broadly and dynamically," she says.
The patient may have been ill for a long time, and the desire to get a diagnosis can be strong. There are several reasons for this, says Anna Wredenberg.
“A genetic diagnosis provides an explanation for why one is ill, which often brings a sense of relief to the patient and their family. It also means that they can receive more personalised ongoing care and follow-up. And in the best case, there is even a treatment," she says.
At CMMS, advanced mitochondrial investigations are carried out on muscle samples from around 170 individuals per year, and of these, around 25 percent show abnormalities indicative of primary mitochondrial disease. By combining whole genome sequencing with muscle analyses, many of the patients receive a diagnosis. Anna Wredenberg recounts a case where the researchers succeeded. They identified an mutated gene in a severely ill patient who needed intensive care at times. The gene had never before been linked to disease.
“We suspected that this was the explanation for the patient's problems. By contacting our international colleagues, we were able to find two other similar cases, which allowed us to confirm the link," she says.
These patients suffered from several of the typical symptoms that can occur with mitochondrial diseases: muscle weakness, acute liver impairment, and effects on the brain, such as untreatable epilepsy.
- We do not really know why these particular organs are more affected by mitochondrial diseases. Mitochondria are present in all cells. But these are examples of organs whose cells do not renew much during life, unlike, for example, blood. They are also extra energy-demanding organs where mitochondria may be particularly important," says Anna Wredenberg.
In addition to identifying specific hereditary diseases caused by mitochondrial dysfunction, the researchers also try to understand how disrupted mitochondrial function can play a role in a number of other diseases, such as cardiovascular disease, ageing and diabetes. Anna Wredenberg also researches the fundamental role of mitochondria in various biological processes.
“For example, we are investigating how a certain mitochondrial process is involved in the early maturation of the heart," she explains.
Model organism: The fruit fly
In their research, the group uses several different methods and model organisms, one of which is the fruit fly. It has been used in genetic research for over 100 years and is well-suited for studying the mitochondrial system.
“This system is almost identical in mammals and fruit flies. This means that our study results from the fly are largely relevant to humans as well," says Anna Wredenberg.
But explaining how mitochondrial DNA works in more detail - something she finds incredibly exciting - can be challenging.
“Many, not least researchers in medicine, have good knowledge of basic genetics. But mitochondrial genetics works completely differently from that of the cell nucleus," says Anna Wredenberg.
She explains that a cell can contain thousands of copies of mitochondrial DNA and that mutations can occur at any time and only in some of these mitochondrial DNA copies. A particular organ or tissue can then have both mutated and non-mutated genes in its mitochondria.
“It is only when the proportion of mutated gene copies - and thus the proportion of altered proteins - is sufficiently high that one risks developing disease symptoms. This can be difficult to convey," says Anna Wredenberg.
There is still much we do not know about how mitochondria function, much to Anna Wredenberg’s delight.
”It means there is a lot to learn and that we researchers can contribute to increased knowledge. Ultimately, this hopefully means that we can help affected patients better in the future," she says.
About Anna Wredenberg
Title: Professor at the Department of Medical Biochemistry and Biophysics, Karolinska Institutet and Specialist in Clinical Genetics at the Centre for Inherited Metabolic Diseases, Karolinska University Hospital.
Age: 50.
Family: Partner and two sons aged 15 and 17. We also have two Siberian cats. They are brothers and like to disturb us in the middle of the night.
How I relax: By being active, walking in the forest, jogging, group exercise. I used to do Kung Fu but unfortunately, I do not have time for that right now.
Role model: My grandfather died before I was born but was a person who reached out to many. He was a priest, walked ten kilometres every day, and had clear opinions on how to live. I often think of him even though we never met.
Best research skill: I hope that I am analytical and observant combined with a certain creative streak.
Anna Wredenberg on ...
... self-criticism:
It is easy to love your own results. But I think it is very important to always try to remain as objective as possible and critically review your research.
... balance:
Breaks are necessary in life, in order to be creative and brave. I walk to and from work every day, which gives me two hours to just let my thoughts wander.
... knowledge about the body:
The more I understand, the less I worry about my health. There is a lot that can go wrong, but we manage most of it. And some things we do not understand right now, and has to be accepted to some extent we.
... exercise:
Physical activity can improve mitochondrial capacity and muscle endurance, but the training needs to be focused on endurance to achieve this effect.