Mitochondrially Stressed

Written by Dr. Judit M. Pérez Ortiz Edited by Dr. Brenda Toscano Márquez

Scientists describe how SCA2 oxidative stress can affect mitochondrial function, and potentially how to fix it

Mitochondrial Stress

We all have experienced stress. When cramming for an exam last minute, or getting ready for a job interview, our bodies feel stress-related energetic drive and hyperfocus. Small bursts of stress can help us get through specific demands, but too much constant stress takes a toll and makes it difficult for us to function. It turns out that the cells in our bodies experience stress too! While the stress response that we experience in our hectic lives is associated with stress hormones, the stress cells experience is from another source altogether – mitochondria. Scientists at the University of Copenhagen in Denmark identified a novel link between mitochondrial oxidative stress and spinocerebellar ataxia type 2 (SCA2).

Classically, we learn that mitochondria are the powerhouse of the cell responsible for making the bulk of the energy currency that cells need to work and survive, ATP. To do this, mitochondria rely on a cooperative group of protein complexes called the Electron Transport Chain (ETC). Albeit via a more sophisticated procedure than a hot-potato game, the complexes mediate chemical reactions (called redox reactions) by which “hot” electrons are passed from high energy molecules to lower-energy molecules, and so on. The final electron recipient (“acceptor”) is a stable oxygen molecule and their encounter is used to make water. The activity of the ETC helps harness energy that is ultimately used to make ATP in what is called oxidative phosphorylation.

Sometimes not all the electrons make it through; the hot potato “drops”. Electrons leak out and react directly with molecular oxygen (chemical formula O2), turning unstable superoxide (chemical formula O2) which in turn, can create other reactive oxygen species (ROS). The extra electron in superoxide gives it a negative charge and makes it highly reactive and toxic. Just like the small amount of stress primes your body for a challenge to come, low levels of ROS hints the cell that it needs to make some changes to optimize the system. As the superoxide levels go up, cells make more antioxidant enzymes available to keep ROS in check. Antioxidant enzymes convert the highly reactive superoxide to a less reactive hydrogen peroxide (like the one in your bathroom cabinet). This, in turn, can be converted to water and ordinary oxygen molecules. In a word, the antioxidants “detox” the cells from ROS insult.

The cell becomes “stressed out” when there’s too much ROS that can’t be compensated for. This stress caused by oxygen or “oxidative stress” can damage DNA, fats, and proteins that affect the cell and organism as a whole. For example, oxidative stress can contribute to heart disease, diabetes, cancer, and neurodegenerative diseases.

cartoon drawing of human cells that are blue
An artist’s drawing of human cells under a microscope.

How did the investigators draw a link between oxidative stress and SCA2?

First, the scientists obtained skin samples from consenting individuals with and without SCA2. This approach is an option scientist sometimes use when studying neurological conditions, since they cannot obtain brain samples from living patients. It is assumed that at least some of the dysfunctional cell processes occurring in brain cells will be reflected in other cells in the body (there is previous scientific work to support that). The patient skin cell samples, called fibroblasts, were grown in a dish and used to answer specific questions.

The first question was: do the cells show signs of stress? This question was inspired by observations that oxidative stress is also involved in other diseases. Using special fluorescent indicators, they found that the mitochondria of SCA2 fibroblasts shine more brightly, due to increased presence of superoxide and hydrogen peroxide, both indicators of oxidative stress. Are the cells stressed? Yes.

When cells become stressed, they react by trying to mount lines of defense for protection. The investigators found that the SCA2 patient cells were making more of an antioxidant enzyme (called “SOD2”) to try to fight oxidative stress. However, they also found that this wasn’t completely effective. The enzyme “CAT”, responsible for the last step needed to completely neutralize the reactive oxygen, was too low in SCA2 patient cells. This means that although the cells were trying to increase their antioxidant defenses, some of the players were not keeping up with the task to fully clear the insult. Faulty antioxidant defenses? Check.

Another way in which cells try to defend themselves from oxidative stress is by protecting the healthy mitochondria from the damaged ones. Normal mitochondria merge and divide to exchange contents and information (called fusion and fission). Healthy mitochondria look like long threads. However, when mitochondria become damaged, they’re kept from merging with the healthy mitochondria, and instead are sent to the garbage truck for disposal in a process called mitophagy (like getting rid of the “bad apples”). The investigators found that while healthy cells had beautiful healthy-looking threadline mitochondria, the SCA2 patient cells exhibited more of the small, rounded, sickly mitochondria. Abnormal mitochondrial shape? Check.

When mitochondria become unhealthy, the cells try to make more mitochondria and mitochondrial contents in a process called mitochondrial biogenesis. The investigators found that in SCA2 patient cells, the total number of mitochondria didn’t change but noticed changes in specific genes and proteins that help produce increased mitochondrial mass. In other words, the cells were trying to make up for the sickly mitochondria by trying to make more healthy ones. Compensatory mitochondrial biogenesis? Check.

Unfortunately, while it certainly seemed that the SCA2 patient cells were doing everything they could to keep up with the oxidative stress, oxidative damage proved too much. When the investigators looked at mitochondrial activity (the “hot-potato” game), they found that this was affected. In other words, the function of some of the ETC players necessary for passing electrons that eventually makes ATP were disrupted. Mitochondrial dysfunction? Check.

Can we control oxidative stress?

The investigators tried to do this by testing an antioxidant called CoQ10. This molecule helps ETC enzymes handle electrons to make ATP. When they treated SCA2 patient cells with CoQ10, they found that they could partially alleviate some of the stress burden and relief part of the stress response. They saw lower mitochondrial oxidative stress and lower hydrogen peroxide. They also found that some of the changes connected to mitochondria dynamics looked more like normal mitochondria. Importantly, they found that CoQ10 was able to restore the deficits of the electron transport chain in the process necessary to use O2 to make ATP energy molecules.

These results suggested to the investigators that the detrimental changes in the cell of SCA2 patients are at least in part brought on or worsened by oxidative stress. However, they also found that this antioxidant agent was not enough to make every aspect of SCA2 patient cells like healthy patient cells, which means that there are other changes at play that contribute to disease processes in SCA2.

How does this discovery add to what we know about SCA2?

SCA2 is a rare genetic disease that affects the brain and nervous system. SCA2 is the second most common type of spinocerebellar ataxia worldwide, second to SCA3. Children of persons with the disease-related ataxin-2 mutation have a 50% chance of inheriting the mutation and at risk of developing the disease. Clinically, persons with SCA2 develop problems with movement, memory, and thinking that worsen over time. As symptoms get worse, SCA2 patients increasingly rely on their caregivers. SCA2 reduces a person’s life expectancy.

SCA2 is caused by an abnormally repeated sequence of C-A-G (letters of the DNA genetic code) in the ATXN2 gene. The protein that is made from this genetic instruction, is called ataxin-2. It is accepted that the mutant ataxin-2 protein is harmful to neuronal cells in certain vulnerable brain regions. Mutant ataxin-2 protein contributes to cell damage in several ways that eventually leads to neuron death (this is the process of neurodegeneration).

This work gives a novel perspective to our understanding of how SCA2 brain neurons get sick. The authors suggest that damaged mitochondria and oxidative stress could play a role in disease in SCA2.

Therapeutic opportunities in SCA2 and neurodegeneration

There are numerous types of neurodegenerative diseases, including SCAs, and they affect patients a little differently. Biologically, they involve different genetic or DNA abnormalities and show damage and cell death in different parts of the brain. Yet, there is increasing recognition that oxidative stress and mitochondrial dysfunction are part of said damage. Developing therapies that target mitochondria-related abnormalities could provide helpful therapies to help patients.

Important note from the writer:

The molecule CoQ10 in this article was used for research purposes and is not considered a medication. In the USA, CoQ10 is sold as a dietary supplement, has not been approved by the Food and Drug Administration for any medical condition, and its manufacturing is not regulated. Please talk to your doctor before starting or stopping any medication or dietary supplements.

Key Terms

Reactive Oxygen Species (ROS): Reactive molecules that contains oxygen and interact with other molecules in cells. A higher than normal level of these reactive molecules is a source of stress in cells.

Superoxide: it is the anionic form of molecular oxygen, which means molecular oxygen with an extra electron. It is a type or ROS.

Antioxidant: any agent that reduces the levels of reactive oxygen molecules

Enzyme: a protein made by cells to carry out a chemical reaction

Electron Transport Chain (ETC): a series of reactions in which electrons are transferred from high energy electron “donor” enzymes to lower energy electron “acceptor” enzymes, and eventually to molecular oxygen.

Oxidative phosphorylation: The final step by which mitochondria use the activity of the ETC to make ATP energy molecules.

Mitochondrial biogenesis: Process by which mitochondria grow and divide to generate more mitochondria

Redox reactions: type of chemical reaction in which one chemical loses electrons and other gain electrons

Gene: A unit of heredity made up of DNA that fully or partially controls the development of specific traits.

DNA: DNA stands for deoxyribonucleic acid. It is a molecule made up of nucleotides that carries the genetic code in the body’s cells.

Polyglutamine Expansion Disease / CAG-repeat diseases: A family of diseases caused by an expansion of glutamine amino acids in certain proteins, including some spinocerebellar ataxias.

Neuron: a specialized cell type of the nervous system whose role is to transmit electrical signals.

Fibroblasts: Fibroblasts are connective tissue cells. These cells can be taken from patients with diseases (usually by a cheek swab or small skin biopsy) and cultured in the laboratory. This allows researchers to study the disease in a human context, and to see how the cells respond to different therapeutics.

Oxidative stress: A type of disturbance in the normal functioning of a cell caused by an imbalance in the levels of reactive oxygen species. These oxygen species are produced as a normal byproduct of cellular metabolism and are usually cleared by the cell without much trouble. When cells are unable to sufficiently clear reactive oxygen species, these molecules begin to accumulate and cause damage to components that form a cell’s critical structures, such as lipids, proteins, and DNA. As we age, our cells naturally become less efficient at clearing reactive oxygen species and the level of oxidative stress we experience increases.

Protein: A molecule determined by a specific sequence of DNA. These molecules have a specific function in cells, tissues, and organs.

Conflict of Interest Statement

Dr. Judit Pérez Ortiz did not contribute to the experiments, interpretation, or publication of the work by Cornelius et al, but she does work in a research laboratory that focuses on mitochondrial dysfunction in Alzheimer’s disease models. Dr. Brenda Toscano Márquez declares no conflict of interest.

Citation of Article Reviewed

Cornelius, N., et al., “Evidence of oxidative stress and mitochondrial dysfunction in spinocerebellar ataxia type 2 (SCA2) patient fibroblasts: Effect of coenzyme Q10 supplementation on these parameters,” Mitochondrion, vol. 34, pp. 103–114, 2017.https://doi.org/10.1016/j.mito.2017.03.001.