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Biology Chemistry

When cells get out of sync

Biochemist and Alexander von Humboldt Professor Christian Frezza is researching how the metabolism of our cells determines health and disease.

If the first violin goes off pitch, the entire orchestra is thrown off balance. Something similar happens in our body when cells suddenly produce energy differently, grow faster, or send out the wrong signals. Biochemist and Alexander von Humboldt Professor Christian Frezza is researching how the metabolism of our cells determines health and disease.

By Anna Euteneuer 

In a recent speech for his »Make America Healthy Again« campaign, US Secretary of Health and Human Services Robert F. Kennedy Jr. said: »I’m looking at kids as I walk through the airports today... and I see these kids that are just overburdened with mitochondrial challenges, inflammation – you can tell from their faces, movements, and lack of social connection.«

»I’d love to spot ›mitochondrial challenges‹ just by looking at people,« writes Christian Frezza in a repost of the speech excerpt on the social media platform Bluesky. After all, he knows only too well how difficult it is to identify mitochondrial dysfunctions as the cause of diseases.

Frezza is a Principal Investigator at the Cluster of Excellence in Aging Research CECAD and has been trying to decipher the cell metabolism in cancer and aging processes for many years. In 2022, the Italian biochemist moved from the University of Cambridge to the University of Cologne as an Alexander von Humboldt Professor. He also studies how metabolic changes, especially in the mitochondria, affect the fate of cells.

What exactly are these mitochondrial challenges? 

As you might recall from your school biology lessons, mitochondria are the ›powerhouses of our cells‹. But today we know that these small, elongated structures, which are surrounded by two membranes, have far more functions than simply producing energy. The smooth outer envelope and the highly folded inner membrane provide the environment for many chemical reactions in our body cells. They serve as the control centres that regulate how cells grow, age, and respond to stress.

If this delicate biochemical rhythm falls out of sync, the consequences can be severe. Mitochondria are particularly important for organs with high energy demands, such as the brain, muscles, and heart. People with mitochondrial diseases may therefore experience symptoms like muscle weakness, movement disorders, cardiac problems, or neurological abnormalities.

Mitochondrial diseases – Malfunctions in mitochondria can cause a multitude of symptoms, making them difficult to diagnose. For example, they can affect the brain, muscles, kidneys, heart, eyes, and ears. In most cases, mitochondrial disorders affect several cells, tissues, or organs.

With a lifetime risk of approximately one in 1,500, mitochondrial diseases are among the most common hereditary diseases. However, because they affect the body in many different ways and present with a wide spectrum of symptoms, they are often misdiagnosed. Around two to three hundred families worldwide are affected by mitochondrial diseases. But they cannot be identified just by looking at someone – not even the US Health and Human Services Secretary could.

»People often don’t even realize that they are affected,« says Frezza. »They might visit a dermatologist because of an itchy rash, and later someone else in the family develops kidney cancer. It often takes several specialists to discover that the true cause lies hidden in the mitochondria.« Many patients never get that far.

In recent years, discussion forums have emerged on the topic, especially on social media. They foster dialogue among those affected and help raise awareness of this rare disease in research and healthcare, enabling patients to receive the correct diagnosis more quickly.

Disharmony in the metabolic concert

For Frezza, cellular metabolism is the key to understanding mitochondrial diseases as well as cancer and aging. In his research, he focuses on the question of how certain metabolic products, so-called oncometabolites, control gene regulation, cell communication, and ultimately the development of diseases. Cancer is caused not only by mutated genes but also by the accumulation of metabolites – metabolic products that act like tiny saboteurs inside the cell, altering its phenotype, i.e. its appearance, and behaviour. 

Frezza and his team were amongst the first to link metabolic dysregulation with cancer. In fumarate hydratase (FH)-deficient renal cell carcinoma, they demonstrated the accumulation of the metabolite fumarate, which causes the development of cancer. 

Fumarate hydratase (FH)-deficient renal cell carcinoma – This type of cancer is a rare, aggressive kidney cancer subtype with high metastasis rates. It is caused by a mutation in the FH enzyme, resulting in loss of function. Fumarate is accumulated and promotes tumour growth. Special therapeutic approaches are necessary as it differs from standard renal cell carcinoma. 

Frezza is particularly interested in this metabolic product. »Our research question is based on early observations that patients who have fumarate hydratase mutations and accumulate fumarate are predisposed to tumours. So, we have been trying to understand how the loss of fumarate hydratase and the accumulation of fumarate can cause cancer in these patients,« explains Frezza. 

The more the team looked into the subject, the more they realized that their findings could really be applied to the disease. »The network at CECAD with a lot of translational research enables us to approach patients to validate our findings from basic research in clinical practice,« says Frezza.

Dancing molecules 

To provide this evidence, the researchers need to understand the exact function of the oncometabolites in cellular functions. This can be demonstrated on various levels. On the one hand, they can observe which new molecules are produced or how much energy a cell generates. They can also measure the activity of specific enzymes or study overall cellular behaviour: Which nutrients are absorbed? Do they grow faster? How do they respond to stress? 

Christian Frezza's research into cellular metabolism not only helps us understand mitochondrial diseases and cancer, but also ageing itself.

Measuring metabolites – a field of research known as metabolomics – is a challenge because the molecules are not as stable as DNA or RNA and are hugely dependent on external factors. That is why it is still possible to analyse the Alpine ice mummy Ötzi’s DNA, but not to gain an insight into his metabolism. 
Metabolites can be measured using a mass spectrometer. Mass spectrometers are super-precise ›molecule scanners‹. The device weighs, identifies, and counts molecules, thus showing what is present in a cell. After a tissue sample has been prepared for analysis in a mass spectrometer, it is separated into tiny particles. The molecules are electrically charged (ionized) so that the device can ›grab‹ them. The charged particles are then passed through an electric or magnetic field. Depending on the mass-to-charge ratio, some particles fly faster or farther than others. 

The device measures where the particles fly and thus calculates how heavy each particle is. A computer then compiles the ›mass spectrum‹, i.e. the molecular profile, showing which molecules are in the sample. A new high-tech mass spectrometer was set up especially for Frezza’s working group at CECAD in order to create optimal research conditions. 

However, not only the equipment is decisive, but also how quickly the samples are obtained and processed to get good results, as his research group demonstrated in a recent study. The path from the sample to the analysis should be as short as possible so that the results are not falsified by other factors. One factor is the lack of oxygen (ischemic stress) in tissue samples. Frezza and his team have investigated whether the oxygen conditions during tissue removal influence the metabolism of tumour samples. »It is important to know whether a sample was taken while it was still ›alive‹, i.e. supplied with oxygen, or afterwards,« says Frezza. »The measurement results vary greatly depending on this.«

The study emphasizes how important it is to optimize the sampling conditions of tumour tissue in order to obtain as authentic an image as possible of the ›natural‹ metabolome, so that the lack of oxygen does not distort the metabolic measurements. In the long term, this can help to create more precise metabolome profiles of tumours. With his interdisciplinary approach, which combines state-of-the-art metabolomics and systems biology methods, Frezza aims to understand fundamental biochemical processes, which in the long run will help open up new avenues for targeted therapies. This is particularly important for certain types of cancer, such as fumarate hydratase (FH)-deficient renal cell carcinoma, as well as mitochondrial diseases, which often remain insufficiently studied precisely because they are rare.
 

The language of metabolism

Many of the things that throw cells out of sync and cause tumours to grow also appear to play a role in natural aging. This means that research findings from studies on rare mitochondrial diseases or cancer may also be relevant for other diseases. Frezza’s aim is to understand the language of cell metabolism so well that diseases can be recognized earlier in future and treated more efficiently. »The metabolism is like an orchestra,« says the researcher. »If just one instrument plays out of tune, it can throw off the whole piece. But if we understand the music, perhaps we can learn to harmonize them again.«

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