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Mitochondrial Diseases & Mitochondrial Dysfunction

Written by Puya Yazdi, MD | Reviewed by Ana Aleksic, MSc (Pharmacy) | Last updated:
Evguenia Alechine
Medically reviewed by
Evguenia Alechine, PhD (Biochemistry) | Written by Puya Yazdi, MD | Reviewed by Ana Aleksic, MSc (Pharmacy) | Last updated:

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Mitochondria

Mitochondria turn food into energy for the body. But if they start to malfunction, free radicals can flood the cell, and a number of health problems might arise. Read about the symptoms of mitochondrial dysfunction and the diseases linked to it.

Mitochondrial Dysfunction & Associated Diseases

Recap: Why Mitochondria Are So Important

Properly functioning mitochondria are central to health, as they are the main energy provider of the cell. However, reactive oxidative species produced by mitochondria accumulate over time, and oxidative stress leads to age-related diseases. Due to the vast role of mitochondria in the cell, mitochondrial dysfunction is linked to hundreds of diseases [1, 2, 3].

Additionally, a number of metabolic disorders are associated with genetic mutations in either mitochondrial or nuclear DNA. These mutations may be inherited or occur randomly [2].

Note that while mitochondrial dysfunction has been observed in or linked to these conditions, it is not necessarily the cause (or even a cause). As such, strategies intended to improve mitochondrial function may or may not help manage these diseases. When in doubt, your doctor can help you understand the role of the mitochondria in your health.

Mitochondria produce energy and remove old, damaged cells. But since the mitochondria use oxygen, their dysfunction can lead to a buildup of cellular waste and free radicals.

1) Cancer Research

Cancer cells require mitochondria to power the growth of tumors. Cancer cells tend to have an increased number of mitochondria to provide this energy. The mitochondrial increase is mediated independently by different transcription factors or proteins that initiate the production of specific genes [1].

On the other hand, cancer cells increase the turnover of mitochondria that have accumulated free radicals. Oxidative stress is increased in cancer cells, which damages the surrounding tissue [4].

One of the hallmarks of cancer is the ability of the cell to avoid programmed cell death (apoptosis). Normally, the mitochondria of healthy cells would trigger this process if the cell was replicating too much or too quickly. However, in cancer cells, programmed cell death is avoided by increasing the destruction of mitochondria that have accumulated free radicals. They also turn on antioxidant pathways so that oxidative stress does not trigger cell death [4, 1].

Mitochondria of cancer cells have lower levels of proteins that promote cell death (BAX/BAK) and/or higher levels of proteins that prevent cell death (BCL-2/BCL-XL) [4, 1].

The network of mitochondria in cancer cells is also different. Cancer cells have more fragmented mitochondria (by increasing mitochondrial division and decreasing fusion) [4].

Cancer cells also produce energy differently through a process known as the Warburg effect. Energy production is largely done without oxygen (anaerobically), via glycolysis. This may be caused by turning down mitochondrial function to avoid apoptosis [4, 1].

Aerobic respiration through the Krebs cycle and oxidative phosphorylation still occur in cancer cells but to a lesser degree.

Scientists think that mitochondrial dysfunction may play a role in cancer, but this hasn’t been sufficiently proven.

2) Neurodegenerative Diseases

Mitochondrial dysfunction is a large cause of age-related neurodegenerative diseases like Alzheimer’s, ALS, and Parkinson’s disease. The accumulation of free radicals with age results in DNA and protein damage. Mitochondria accumulate defective proteins that cause loss of energy production and ultimately cell death [3].

The mitochondria have been observed to behave differently (to be dysfunctional) in specific neurodegenerative diseases like Alzheimer’s and Parkinson’s.

Alzheimer’s Disease

  • Amyloid beta proteins build up around the outer mitochondrial membrane.
  • This buildup decreases ATP production, increases oxidative stress, and ultimately causes cell death.
  • Amyloid beta increases mitochondrial protein production.
  • Mitochondrial enzymes have decreased activity, leading to reduced ATP levels.
  • Mitochondria undergo structural changes within the cell. Rather than existing in long tubes (mitochondrial fusion), the mitochondria are fragmented into little pieces within the cell (fission). This adds to the overall dysfunction of brain cells seen in patients with Alzheimer’s disease [3].

Parkinson’s Disease

  • The hallmark of Parkinson’s is the accumulation of alpha-synuclein protein, leading to cell death and loss of neurons.
  • Patients with Parkinson’s accumulate this protein in the mitochondria, leading to increased oxidative stress and reduced energy production.
  • Parkin protein (E3 ubiquitin ligase) and PINK1 protein are responsible for marking damaged mitochondria for destruction. Patients with Parkinson’s disease have low levels of these proteins.
  • Damaged, low functioning mitochondria are not degraded and remain in the cell.
  • Alpha-synuclein continues to accumulate, leading to neurodegeneration [5].
Mitochondrial dysfunction is implicated in the brain changes characteristic of Alzheimer’s and Parkinson’s disease.

3) Diabetes

Improper mitochondrial function has been seen in patients with both type 1 and type 2 diabetes. Aside from having a lack of glucose for respiration, the network and shape of mitochondria in the cells of diabetic patients may be abnormal [6, 1].

In diabetic patients, the mitochondria are broken up into small fragmented networks (increased division, decreased fusion) throughout the cell. This has been observed in both type 1 and type 2 diabetes [6].

Type 2 diabetes is characterized by insulin resistance in cells, reducing the amount of glucose available for respiration. This decreases ATP production and thus the energy available to the cell [6].

It is unknown whether mitochondrial dysfunction is a cause of insulin resistance or a symptom of it. Some researchers have suggested that mitochondrial dysfunction could be a cause of insulin resistance, rather than a symptom [6].

Patients with type 2 diabetes have reduced levels of mitochondrial proteins responsible for energy production [6, 1].

Type 2 diabetes might be marked by poor mitochondrial function, but more research is needed to confirm this.

4) Heart Failure

Heart cells rely heavily on mitochondria to power the pumping of the heart. Mitochondrial dysfunction is implicated in heart failure due to the buildup of oxidative stress [1].

Patients with heart failure exhibit reduced mitochondrial activity. The mitochondria have lower activity at electron transport chains. This is caused by a loss of oxygen supply to the mitochondria [1].

Since oxygen supply is reduced, electrons at the electron transport chain cannot be picked up by oxygen. This leads to the accumulation of electrons, which produce free radicals [1].

5) Chronic Fatigue Syndrome

Chronic Fatigue Syndrome, commonly known as CFS, is a controversial and lifelong disorder characterized by prolonged (over 6 months) symptoms of intense fatigue that can reduce a person’s ability to perform daily functions by over 50%. Patients with CFS suffer from a variety of other symptoms including [7]:

Although it was once thought to be a disease of the mind, increasing evidence points to mitochondrial dysfunction as one of the leading possible causes of this disorder [8].

Multiple clinical trials have been conducted and have produced mixed results. According to some researchers, CFS may be linked to one or more of the following mitochondrial abnormalities [9]:

  • Smaller mitochondrial shape and number
  • Lower L-carnitine, ALCAR, ubiquinone or CoQ10 levels
  • Reduced protein activity in the electron transport chain (oxidative phosphorylation)
  • Reduced ATP production

A number of studies indicated that there were no significant differences in mitochondrial structure or function of healthy and normal patients. Further studies are required to fully understand the cause of this condition, the role of mitochondrial dysfunction and how to effectively treat patients.

A link between mitochondrial dysfunction and chronic fatigue syndrome has been proposed but never confirmed.

6) Genetic Disorders

Genetic mutations in mitochondrial genes can result in mitochondrial dysfunction through 1 or more of 5 distinct mechanisms [2]:

  • Inability to utilize other molecules (substrates) for energy production
  • Improper Krebs cycle
  • Defective energy production through the electron transport chain (oxidative phosphorylation)
  • Defective transport of molecules in and out of the mitochondria
  • Defective proteins in the electron transport chain

These defects can be caused by mutations in mitochondrial and/or nuclear DNA. Additionally, defects can occur when mitochondrial DNA is unable to communicate with nuclear DNA [2].

Some metabolic diseases that are caused by mitochondrial and/or nuclear DNA mutations include [2, 1]:

  • mtDNA depletion syndrome (MDS): MDS refers to a group of disorders, any of which have dysfunctional mitochondrial DNA. This can result in different developmental, muscle, and brain abnormalities. Many known mitochondrial diseases are a result of MDS.
  • Mitochondrial myopathy: a Mitochondrial disease that causes muscle problems such as weakness, exercise intolerance, breathing difficulties, or issues with vision.
  • Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS): A mitochondrial disorder that affects the brain and muscle throughout the body. Stroke-like episodes and the buildup of lactic acid results in dementia, vomiting, extreme pain, and muscle weakness.
  • CoQ10 deficiency: A deficiency in coenzyme Q10, a protein that is part of the electron transport chain.
  • Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE): A rare mitochondrial disease that primarily affects the brain and digestive system. The muscles and nerves of the digestive system do not properly push food through the system.
  • Mitochondrial diabetes: Referred to as maternally inherited diabetes and deafness (MIDD), a subtype of diabetes caused by a single mutation in the mitochondrial DNA (at position 3243). The disease results in loss of hearing and diabetes similar to type 1.
  • POLG mutations: A gene that codes for DNA polymerase subunit gamma, the active (catalytic) part of the mitochondrial protein responsible for DNA synthesis. Mutations in this gene lead to the defective production of mitochondrial proteins and many mitochondrial diseases.
Various mutations in mitochondrial genes can result in mitochondrial dysfunction and an array of metabolic diseases.

The Mitochondrial Bottleneck Effect

Carrying mutations in mitochondrial DNA does not necessarily mean that you will transmit the disease. According to some researchers, the proportion of cells carrying mutated mitochondria may have to be significantly higher than the cells carrying healthy mitochondria in order for the disease to present symptoms [10].

During female egg cell (oocyte) production, each egg cell will carry a random selection of mitochondrial DNA copies. Some of the copies may carry mutations, whereas some may be completely normal. As the egg cell matures and prepares for fertilization, many mitochondria are replicated at random. This may dilute the chance of inheriting mutant mitochondria [10].

This phenomenon means that if the mother carries highly mutant mitochondria, her offspring will not necessarily carry the trait [10].

If enough cells carry mutant mitochondrial DNA – for example, more than 50% of the cells in the body – it is likely that the child will have the associated disorder.

Preventing Inheritance of Dysfunctional Mitochondrial DNA (mtDNA)

New technologies can prevent the transmission of mutated mitochondrial DNA from the mother to the offspring. A new technique, called 3-parent in vitro fertilization, consists of switching nuclear DNA from the mother with the nuclear DNA of a donor female egg that has healthy mitochondrial DNA. Therefore, the donor egg carries the genetic information from the mother but lacks the mutated mitochondrial DNA that she carries as well.

Using in vitro fertilization, the egg is then artificially inseminated using the paternal semen. The fertilized egg is then reintroduced into the mother’s uterus, where it can latch on to the uterus [11].

The offspring will have all of the physical characteristics of their biological parents because the nuclear DNA is unchanged. The only thing that is different is that this child will have proper mitochondrial function, unlike the mother who carries mutated copies of the mitochondrial DNA [11].

Possible Signs & Symptoms of Mitochondrial Dysfunction

Some researchers have identified possible signs that the mitochondria are not functioning as they should. These include:

  • Feeling excessively tired [12]
  • Inability to exercise for long periods of time [13]
  • Shortness of breath, especially during exercise [14, 15]
  • Poor bone growth and health [16]
  • Difficulty controlling movements, balance, and coordination (ataxia) [17]
  • Difficulty walking or talking [18]
  • Muscle weakness and pain [19]
  • Heart muscle disease (cardiomyopathy) [20]
  • Gut and digestive issues [21]
  • Liver and kidney disease [22]
  • Droopy eyelids, vision loss, and other eye problems [23]
  • Diabetes and other hormonal disorders [6, 24]
  • Trouble hearing [25]
  • Migraines, strokes, and seizures [26, 27]
  • Difficulty remembering things [27]
  • Developmental delay [28]
  • Autism [29]
  • Recurrent infections [30, 31]

Note that these symptoms may have many causes other than mitochondrial dysfunction. In fact, they are more likely to be associated with another diagnosable and treatable health problem, which your doctor can identify and address.

If you are currently suffering from symptoms such as these, and they are not currently being addressed, we strongly recommend talking to a doctor to determine the best treatment or management plan for your health.

Takeaway

Mitochondria produce energy (ATP), recycle parts of cells that can be reused, and remove cells that are old and damaged beyond repair.

But since the mitochondria use oxygen, an excess of their byproducts can cause oxidative stress. When mitochondria break down, free radicals and cellular waste can flood cells and cause harm.

Mutations in mitochondrial genes can result in mitochondrial dysfunction and an array of metabolic diseases. Mitochondrial dysfunction is also implicated in neurodegenerative diseases like Alzheimer’s diseases and chronic diseases like diabetes and heart failure.

The symptoms of mitochondrial dysfunction can greatly vary from person to person and may include fatigue, shortness of breath, coordination issues, and neurological problems, among others.

Further Reading

About the Author

Puya Yazdi

Puya Yazdi

MD
Dr. Puya Yazdi is a physician-scientist with 14+ years of experience in clinical medicine, life sciences, biotechnology, and nutraceuticals.
As a physician-scientist with expertise in genomics, biotechnology, and nutraceuticals, he has made it his mission to bring precision medicine to the bedside and help transform healthcare in the 21st century.He received his undergraduate education at the University of California at Irvine, a Medical Doctorate from the University of Southern California, and was a Resident Physician at Stanford University. He then proceeded to serve as a Clinical Fellow of The California Institute of Regenerative Medicine at The University of California at Irvine, where he conducted research of stem cells, epigenetics, and genomics. He was also a Medical Director for Cyvex Nutrition before serving as president of Systomic Health, a biotechnology consulting agency, where he served as an expert on genomics and other high-throughput technologies. His previous clients include Allergan, Caladrius Biosciences, and Omega Protein. He has a history of peer-reviewed publications, intellectual property discoveries (patents, etc.), clinical trial design, and a thorough knowledge of the regulatory landscape in biotechnology.He is leading our entire scientific and medical team in order to ensure accuracy and scientific validity of our content and products.

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