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Core Concept Collection Article Published: September 30, 2020

Mitochondria in Brain Injury: Antioxidants to the Rescue!

Abstract

If you have ever bumped your head, then you may have experienced a traumatic brain injury (TBI). TBI is brain damage caused by an outside force. In the long run, TBI may weaken a person’s ability to think, learn, or remember. In this article, we will learn how the mitochondria, tiny structures inside our cells, are partly responsible for the harmful effects of TBI. Mitochondria produce most of the energy our cells need to function properly. This, however, comes with a cost. Energy production is accompanied by the release of harmful substances, such as reactive oxygen species (ROS). ROS can damage components inside our cells and even lead to cell death. In TBI, damaged mitochondria produce high amounts of ROS. Drugs called antioxidants may protect the brain following TBI. Antioxidants can destroy ROS. However, you should never use these drugs without medical guidance.

What is Traumatic Brain Injury?

Have you ever bumped your head? You most likely have. Your brain is vulnerable to impacts that can occur while you are practicing sports, if you have a bad fall, or if you are in a car accident. These impacts can result in a damage to the brain, which is called traumatic brain injury (TBI). TBIs can have varying levels of severity. Severe TBI causes the most damage to the brain. Mild TBI is the most common form of TBI and typically does not cause permanent symptoms. However, if you receive repeated mild TBIs, symptoms may persist. TBI may affect several brain functions, including a person’s ability to think, concentrate, learn, and remember things. In the long run, repeated mild TBI may also increase the risk of some diseases caused by the death of main cells of the brain called neurons. Tiny structures inside our cells called mitochondria are partly responsible for these harmful long-term effects of TBI [1].

What Are Mitochondria?

Mitochondria are special structures found inside all of body cells. The main function of mitochondria is the production of the energy our cells need to function. A mitochondrion is made of an outer membrane surrounding a space that contains an inner membrane. The inner membrane surrounds an inner cavity, called the matrix. The inner membrane contains the elements responsible for energy production.

Think of the mitochondria as the power generators of our cells. Similar to real generators that release pollutants as they generate power, mitochondria also produce harmful substances as by-products. Among those harmful by-products are reactive oxygen species (ROS). ROS can interact with and damage components of our cells. The cell has several systems to protect itself from excessive ROS. One protective system consists of substances called antioxidants. Antioxidants can control or remove extra amounts of ROS. Under stressful conditions, such as in TBI, damaged mitochondria generate huge amounts of ROS. The protective antioxidant systems become overwhelmed and fail to destroy the excessive ROS. As a result, many cell components may get damaged, which may lead to death of the cell [2] (Figure 1).

Figure 1 - What are mitochondria?
  • Figure 1 - What are mitochondria?
  • Mitochondria are organelles found in almost all of our cells, including neurons. A mitochondrion is made up of an outer membrane, an intermembrane space, an inner membrane, and a space in the middle called the matrix. Mitochondria are responsible for producing the energy our cells need.

What Do Mitochondria Do During Traumatic Brain Injury?

The bump on the head is the mechanical force that leads to TBI. Think of it as the force that sets off the falling of a row of domino tiles. After the bump on the head, a series of events takes place in the brain. In the case of a TBI, the mechanical force first causes damage and injury to neurons and may, later, cause their death. The mechanical force also leads to the abnormal release of molecules, called neurotransmitters, used for communication between brain cells. When released, neurotransmitters knock down another domino tile: they cause the abnormal increase of certain substances inside neurons which, in turn, cause the mitochondria to increase production of ROS. ROS then interact with and damage several components inside neurons. Damage to cellular components leads to the impairment of cellular functions. One result of this damage is inflammation in the brain. Damaged cells are set to die [3]. Death of brain neurons is the main problem in TBI (Figure 2).

Figure 2 - Mitochondria in TBI.
  • Figure 2 - Mitochondria in TBI.
  • In undamaged mitochondria, antioxidants help keep the mitochondria healthy and the cell’s energy levels normal. However, in TBI, ROS are produced in large quantities and antioxidants get overwhelmed. The mitochondria get damaged and energy production decreases.

Antioxidants: to the Rescue!

ROS are one of the main culprits causing neuron dysfunction and death during TBI. If scientists can reduce the levels of ROS in the brain, they may be able to reduce the symptoms of TBI. Antioxidants can act like a sponge that absorbs the harmful amounts of ROS and make them inactive. This ability of antioxidants to reduce the harmful amounts of ROS, in the brain, prevents ROS from damaging the neurons.

So where do we find these antioxidants? Some antioxidants are naturally found in our cells. However, following TBI, antioxidants availability may decrease and our natural antioxidants become overwhelmed. Extra antioxidants can be provided from outside our body (external antioxidants) in the form of a drug or a supplement. In fact, several of these external antioxidants have been used in the treatment of TBI. Scientists have even found ways to guide the antioxidants to the mitochondria. This is important since mitochondria are the major source of ROS. For example, in our lab, we have used a powerful antioxidant called MitoQ for treating TBI. MitoQ is attached to special guide molecules that can take the antioxidant directly to the mitochondria where ROS are made. This increases the efficiency of the MitoQ drug [3, 4].

Can Heroes Become Villains?

Another way to look at antioxidants is to imagine antioxidants as heroes that chase the culprits (ROS) and put them in jail in order to save the cell.

Just like almost everything in life, balance is needed when it comes to taking antioxidants. Consuming too many antioxidants can be dangerous. If taken at high dosages, especially when ROS levels are normal, antioxidants may become toxic to cells. Excessive consumption of antioxidants may increase the production of ROS instead of reducing it. Excessive antioxidants may also increase the occurrence of some diseases, including cancer. Therefore, antioxidants should be taken cautiously and under appropriate guidance from a doctor. We do not want our heroes to turn into villains [5, 6] (Figure 3)!

Figure 3 - Can heroes become villains?
  • Figure 3 - Can heroes become villains?
  • Despite the fact that they can protect neurons from harmful ROS, it has been shown that excessive consumption of antioxidants may cause serious diseases, such as cancer. So, we should never take any antioxidant without a doctor’s permission.

Conclusion

Traumatic brain injuries are very common. Finding a treatment is essential to limit their negative consequences. Mitochondria are the structures responsible for energy production inside our cells. In TBI, mitochondria become damaged and produce dangerous amounts of ROS. This can lead to the damage and even the death of the neurons in the brain. Antioxidants may represent a solution to reduce excessive amounts of ROS and reduce the harm of TBI. Scientists have developed ways to target certain antioxidants to the mitochondria to increase the effectiveness of these drugs. Although antioxidants are available without a prescription, it is always important to seek medical advice before consuming these powerful drugs.

Glossary

Traumatic Brain Injury: Damage caused to the brain by a bump to the head.

Neuron: The main type of cells in the brain. They serve to communicate messages within the brain and between the brain and other body organs.

Mitochondria: Structures found in our cells responsible for producing the energy our cells need.

Reactive Oxygen Species: Substances produced by our cells. ROS, in very high levels, can interact with and damage components inside the cell.

Antioxidant: Molecules that can be man-made or found in nature, such as in fruits. They can protect the cell against the harmful effects of ROS.

Neurotransmitter: A molecule used for communication between neurons.

Inflammation: It is a protective biological response that starts under harmful conditions, such as stress. It is one way your body fights infection, injury, or disease. It involves immune cells, blood vessels, and many molecules inside the cell.

Conflict of Interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


References

[1] Available online at: https://www.cdc.gov/traumaticbraininjury/index.html (accessed July 28, 2020).

[2] Cooper, G. M. 2000. Mitochondria. The Cell: A Molecular Approach. 2nd Edn. Sunderland, MA: Sinauer Associates.

[3] Cheng, G., Kong, R., Zhang, L., and Zhang, J. 2012. Mitochondria in traumatic brain injury and mitochondrial-targeted multipotential therapeutic strategies. Br. J. Pharmacol. 167:699–719. doi: 10.1111/j.1476-5381.2012.02025.x

[4] Oyewole, A. O., and Birch-Machin, M. A. 2015. Mitochondria-targeted antioxidants. FASEB J. 29:4766–71. doi: 10.1096/fj.15-275404

[5] Mendelsohn, A. R., and Larrick, J. W. 2014. Paradoxical effects of antioxidants on cancer. Rejuv. Res. 17:306–11. doi: 10.1089/rej.2014.1577

[6] Rahal, A., Kumar, A., Singh, V., Yadav, B., Tiwari, R., Chakraborty, S., et al. 2014. Oxidative stress, prooxidants, and antioxidants: the interplay. Biomed. Res. Int. 2014:761264. doi: 10.1155/2014/761264