Protein production problems and quality control conundrums in the wondrous world of mitochondria

As we age, the cells in our body accumulate errors that occur when they produce proteins. This is also the driving factor behind diseases like Parkinson’s disease and Alzheimer’s disease. To prevent this from happening, cells have built-in quality control systems that monitor proteins as they are produced. However, the effectiveness of these systems seem to decline with age. If we could improve or maintain the function of the cell’s own quality control systems, we might be able to prevent or delay the onset of age-related diseases – a crucial aspect of future-proofing societies where a demographic shift towards an older population is taking place.

Andreas Kohler, Assistant Professor at the Department of Medical Biochemistry and Biophysics, is hard at work uncovering the mechanisms and characteristics of these quality control systems, especially concerning the mitochondria – famously known as “the powerhouse of the cell”. And yes, mitochondria are responsible for producing ATP, the molecule that gives us energy, but they also have other important duties in the cell.

Mitochondria are essential to maintain the cell's life and death

“They are essential to keep up the physiology of the cell, but also to maintain its life and death”, Kohler explains. “If a cell is damaged, the mitochondria in that cell will initiate programmed cell death, apoptosis, to prevent it from harming the rest of the organism.”

A second set of DNA

If faulty proteins are used to carry out the cell's normal functions, the cell could be damaged. This is something that occurs naturally as we age, but if it happens to a very high extent, neurodegenerative diseases like Alzheimer's or Parkinson’s can develop. Neurons are very energy-demanding and produce new proteins constantly; therefore, they are also vulnerable to the accumulation of these defects or when the processes don’t work as they should. Thus, it is crucial for the cell to monitor the quality of proteins and to take care of faulty proteins immediately.

“We have systems that can try to repair the proteins, and we have systems that can destroy them, so they can cause no harm,” Kohler explains.

Mitochondria were originally bacteria that developed a symbiotic relationship with early single-celled organisms. As such, they contain their own DNA that is different from the DNA in the cell nucleus. This means they can produce a unique set of proteins that are crucial for cell respiration, the process that allows mitochondria to convert energy from the oxygen in the air we breathe and nutrients from the food we eat.

“The systems for maintaining the quality of this unique set of proteins are themselves produced in the cell and first need to be imported into mitochondria. But it is largely unknown how these specialised quality control mechanisms actually operate inside the mitochondria. This is something that is quite… yeah, understudied, I would say. And it is something we accepted the challenge to do.”

Uncovering an understudied system

The challenge lies in the complexity of mitochondria and the combination of looking at mitochondrial protein quality control systems and how ageing affects these processes. You need special equipment and highly specialized know-how, Kohler explains. Here, recent grants from Vetenskapsrådet and the Swedish Foundation’s Starting Grant by Kempestiftelserna come in handy to expand the lab in both terms of personnel and equipment. Andreas Kohler has also been selected as a Wallenberg Academy Fellow, a program for supporting promising young researchers in Sweden with long-term funding.

“We’re a small and young lab so I still do a lot of the experiments myself, and I really enjoy that. But teaching and supervising people is really fantastic. I’m very fortunate with my team because they’re very talented people, and when you see the spark in their eyes when they learn something new, that’s a really cool process,” Kohler says.

The most beautiful and exciting thing in doing research is discovering something new

“The most beautiful and exciting thing in doing research is discovering something new. And since the system we’re looking at is under-explored, we already have some great new data and new insights. It’s so exciting that on one hand our work is challenging, as these processes are not easy to study, and on the other hand, when we do find something, it’s something completely new and never described before.”

Partnership across borders

Andreas Kohler came to Umeå from Austria in 2023. And there’s an interesting story behind this: Andreas and his wife, Verena, applied for the same position as assistant professor, and both ended up getting interviewed for the job.

“And apparently we were quite convincing that we’re good scientists, because we then got an e-mail from the Dean of the Faculty of Medicine saying they would hire both of us,” Kohler says with a laugh.

Today, Verena Kohler works at the Department of Molecular Biology. They work together a lot, since she is interested in how protein quality control works during ageing in other parts of the cell. Having a partner who is also a scientist is fantastic, Kohler says, since they can support each other in many ways.

“She understands, for example, the frustration when experiments fail, as well as the excitement of a new discovery. Having someone who truly shares those experiences is extremely helpful.”

A fast track to understanding cellular ageing

Verena and Andreas Kohler have set up a unique method for genome-wide screens called Flexible Ageing Screening Technology (FAST). They have large collections of yeast strains, so-called libraries. In one library, each cell is missing a different gene; in another, a gene is turned up; and in a third, proteins are marked so they can be followed under the microscope. With about 6,000 strains in each library, this allows for exploration of the role of every gene in a systematic way. With special robotic systems, Andreas and Verena Kohler can perform fully automated, genome-wide screens, for example, to study what happens to a specific process in a cell when a specific gene is missing and how ageing affects these processes. Yeast is a great model organism when studying the effects of ageing, Kohler explains – the lifespan of a yeast cell is about 9 days.

“We can screen the whole ageing process in approximately one week. It takes us one week, for a specific research question, to analyze every single gene in a cell to see if it plays a role in that mechanism or not. And then we can compare if it plays a role only in young cells, only in old cells, or in both.”

Humans have lots of different types of cells – muscle cells, neurons, skin cells and so on. Yeast, on the other hand, doesn’t have a brain, muscles or skin. So why are scientists using it as a model to understand how our own cells work?

Yeast cells are actually very similar to our cells

“Yeast cells and yeast mitochondria are actually very similar to our cells,” Kohler says. “However, they are much simpler. In humans, we often have multiple genes that perform essentially the same job, whereas in yeast cells there is often just a single gene. For example, when we’re looking at systems that maintain protein quality, the basic machinery is very similar between yeast and humans. But in humans, it is often more elaborate. A process that is controlled by a single gene in yeast may involve two or more closely related genes in human cells. This doesn’t change what the process does, but it allows human cells to fine‑tune it for different situations, such as the needs of different tissues.”

Since the protein quality control systems play such an important role in ageing, they could potentially constitute new targets for drugs.

“After we discovered and characterised a system for protein quality control, the logical next step is to see if we can find or develop a drug that can modify this system, to stimulate it during ageing to avoid diseases like Parkinson’s and Alzheimer’s,” Kohler says.

Closing the gap between health and lifespan

But the implications could be much bigger than new drugs; yeast cells are used in a lot of biotechnological processes, and if we find ways to improve the quality control systems of the cells as they age, we could for example save a lot of energy. And since the mechanisms they study are highly conserved, i.e., work the same way in a lot of different organisms, this could be important in for example plant physiology or other areas.

In theory, Kohler says, you could potentially make these processes perfect – every protein created in the cell would be flawless and stay flawless even during ageing. But he rejects the notion of immortality or eternal youth for a more grounded goal.

It’s not about extending lifespans – it’s about extending health spans

“It’s not about extending lifespans – it’s about extending health spans. We have a situation where our lifespans are increasing, but our health is not keeping up, so there’s an increasing gap between health and lifespan. Closing that gap is where I think our research has great potential.”