Overlooked antioxidants remove malfunctioning mitochondria

Breaking new ground 22. jan 2021 2 min Group Leader Giuseppe Filomeni Written by Morten Busch

Mitochondria are cellular power plants that create the energy driving the amazing machinery of the human body. This process produces reactive oxygen species, which are necessary but can also damage the body and result in serious diseases. Researchers have now found a previously overlooked type of antioxidant that can remove mitochondria that are out of control. The hope is that this new knowledge can be used to treat cancer and the rare immune disorder ataxia-telangiectasia.

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The cells’ mitochondria produce small energy-rich molecular blocks that are essential to sustain vital processes of the cell, such as replication and enzymatic catalysis that can be transported around the body as needed. The production of adenosine triphosphate (ATP) molecules usually takes place in a controlled manner but sometimes creates small byproducts called reactive oxygen species. They function as important signalling molecules in the cell but can cause irreparable damage to the cells’ biomolecules, such as DNA, proteins and lipids, and lead to serious diseases such as cancer. To control this balance, the cell is equipped with several control mechanisms. Researchers have now identified a new one.

“The focus had primarily been on finding substances that can neutralize some of the reactive oxygen species. We have now found a mechanism that sustains the removal of mitochondria by autophagy (mitophagy) if the cells produce too many reactive oxygen species. Further, if this mechanism malfunctions, this leads to an imbalance that could contribute to explaining what we observe in cancer. Therefore, if we can learn to control this mechanism, we may also be able to help prevent or cure cancer,” explains Giuseppe Filomeni, Group Leader of the Redox Biology Group at the Danish Cancer Society Research Center in Copenhagen.

Surprising link

For many years, researchers have been interested in mitophagy, the selective process in cells that sustains the removal of mitochondria. This process is activated by various external stimuli and plays an important role in preventing the overproduction of reactive oxygen species, which often results from dysfunctional mitochondria and can lead to serious diseases. How this process is regulated, however, still needs to be fully elucidated.

“A few years ago, we managed to get one step closer, when we found that the metabolism of mitochondria is regulated by placing tiny markers on certain proteins. These nitric oxide (NO) modifications cause the cells to age and eventually die if not maintained under control. We also discovered that an enzyme, S-nitrosoglutathione reductase (GSNOR), by removing these NO modifications, initiates mitophagy, eliminates defective mitochondria and restores the balance in the cell,” says Giuseppe Filomeni.

By eliminating defective mitochondria, GSNOR protects the cell from the damaging effects of the reactive oxygen species arising from mitochondria that have run amok. Although the finding brought the researchers a little closer to understanding how mitophagy is generally regulated, they still did not understand the details of the process, and without this, finding pharmaceutical methods to restore the balance in cancer cells would be difficult. The next piece of the puzzle emerged somewhat by chance.

“We were actually investigating another type of mechanism in which we attempted to influence cells using hydrogen peroxide, when we noticed that it also affects the activity of the GSNOR enzyme. This led us on the trail of a whole new activation mechanism and to a link to a different disease,” explains Giuseppe Filomeni.

Bodybuilder cure

The disease is ataxia-telangiectasia, a rare neurodegenerative disorder that severely impairs the brain and the immune system (mostly specific populations of T cells) and greatly increases the risk of cancer. It develops because of a defect in the ataxia-telangiectasia mutated enzyme (ATM), which by chance the researchers linked to the removal of the defective mitochondria. Thus, they had discovered a new type of antioxidant.

“If we removed GSNOR in animal models, we found the same problems in the immune system as in people with ataxia-telangiectasia: the mice’s T cells could no longer perform mitophagy and remove dysfunctional mitochondria, so we assume that the mice would eventually have a greatly increased risk of cancer,” says Giuseppe Filomeni.

The studies have now enabled the molecular processes to be described in great detail. ATM activates other enzymes, which in turn activate GSNOR, which controls the mitochondrial turnover by removing the NO markers on the proteins. The researchers therefore thought that there might be a very simple way to solve the problem in the mice: using N-acetyl-l-cysteine (NAC), an antioxidant bodybuilders use for detoxification.

“NAC can remove NO groups from these proteins, and tests on mice already showed that it can also eliminate many of the symptoms in the mice with the defective ATM. So, NAC can probably be used to treat ataxia-telangiectasia. Unfortunately, NAC is involved in many cellular processes, so it is not a question of simply being able to cure cancer using NAC. However, the new knowledge provides us with some completely new ways of attacking cancer now that we know these mechanisms,” concludes Giuseppe Filomeni.

ATM plays antioxidant, boosting mitophagy via denitrosylation” has been published in Autophagy. “Redox activation of ATM enhances GSNOR translation to sustain mitophagy and tolerance to oxidative stress” has been published in EMBO Reports. In 2018, the Novo Nordisk Foundation awarded a grant to Giuseppe Filomeni for the project Dissecting the Pathogenic Role of S-nitrosylation in ATM-related Diseases.

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