The cells in our bodies perform myriad tasks, from keeping our heart beating to managing the brain’s complex functions. All these activities require energy, most of which comes from the mitochondria.

In the mitochondria, energy from the food we eat and oxygen from the air we breathe is converted into a form of energy that the cell can use.

Additionally, mitochondria have their own DNA, which contains instructions for synthesis of the proteins necessary for energy production. Those proteins are synthesized by ribosomes – small protein factories that put together amino acids in a predetermined order, as though on a conveyor belt.

Rorbach is studying the details of protein synthesis in mitochondria. She is a molecular biologist at Karolinska Institutet (KI) and a Wallenberg Scholar.

“Researchers used to concentrate on the cell’s cytosolic protein synthesis, which takes place outside the mitochondria, but that knowledge does not suffice to understand the complex process occurring inside mitochondria,“ she says.

Links to disease

Understanding mitochondrial protein factories requires new studies and experiments. Mitochondrial DNA produces only 13 proteins, which is quite a small number. But their synthesis requires hundreds of proteins to enter mitochondria from outside at the right points in time.

“This is an exciting and complex field that we’re really starting to understand. One of our aims is to identify the fundamental steps in protein synthesis and their relationship to various cell functions and diseases.”

In recent years it has become clear that mitochondria have a major impact on human health. In particular, there is a link to parts of the body that require plentiful energy, such as the muscles, brain and immune system.

“When these processes don’t work as they should, the result may be metabolic or neurological disorders, as well as impaired anti-pathogen and -cancer responses,“ says Rorbach.

Groundbreaking methods

Thanks to advanced technology, researchers can now study the minute protein factories at molecular level. Using cryogenic electron microscopy (cryo-EM), they can see exactly what ribosomes look like and how they behave during protein synthesis.

“We can see exactly where and how a given protein binds,” says Rorbach.

The researchers are studying different stages of protein synthesis to gain a comprehensive picture of the process from start to finish. They are gradually acquiring more knowledge about which molecules control or fine-tune the process.

While the exact clinical application of a discovery may not always be immediately clear, history has shown that understanding fundamental cell mechanisms is crucial in developing new drugs and therapies. This makes our research especially interesting.

Rorbach and her colleagues are also using other methods, including advanced proteomics and transcriptomics to ascertain which proteins and genes are involved.

Access to the new cryo-EM imaging technology was one of the reasons that Rorbach decided to base her research in Sweden, having previously worked in the United Kingdom.

Since 2018 Karolinska Institutet has been home to Biomedicum, a laboratory for medical research, which is one of Europe’s largest laboratories. Close by, there is also SciLifeLab, a national facility that is collaborating with a number of academic institutions, including KI.

“The environment here, which offers both research and clinical medicine, is of the very highest caliber, which is of course highly stimulating,” she says.

Clinical implications

The fundamental aim of her research is to understand more about the body’s functions. But clinical applications are just around the corner.

By finding out why mistakes sometimes occur when new proteins are synthesized, researchers can gain an insight into how cell damage occurs, enabling them to explain why some people develop severe and rare mitochondrial diseases.

“We are working closely with the unit for mitochondrial diseases at Karolinska University Hospital, and we can link our research findings directly to patients,” says Rorbach.

But the research is not only shedding light on causes; it may also lead to new treatment strategies. One example may be an understanding of why patients with mitochondrial depletion are sensitive to certain drugs.

The research also demonstrates that sensitive mitochondrial systems have other links to human health. One research angle concerns the way certain antibiotics can inhibit mitochondrial protein synthesis, potentially causing side-effects. It is also known that protein synthesis in mitochondria increases in certain types of cancer.

“We are now studying how we can modulate these mechanisms. One thing we need to do is to find strategies for tailoring therapeutics with a minimal impact in order to protect the mitochondria. Alternatively, we can use our knowledge to inhibit particularly harmful cells, such as aggressive tumor cells, in which mitochondrial function could be dampened,“ says Rorbach.

Mitochondrial protein factories could therefore be a key to understanding and treating a number of serious diseases.

Text Nils Johan Tjärnlund
Translation Maxwell Arding
Photo Magnus Bergström