Mitochondrial Diseases: Current State of Understanding

Marni J. Falk, MD


May 11, 2018

Editorial Collaboration

Medscape &

Good afternoon. My name is Dr Marni Falk. I am a geneticist at the Children's Hospital of Philadelphia (CHOP) and I direct the mitochondrial medicine frontier program. I'm also a board of trustee member and a chair of the scientific and medical advisory board of the United Mitochondrial Disease Foundation. I'm delighted to be talking with you this afternoon about mitochondrial medicine and mitochondrial disease.

Mitochondria Review

It's always good to start at the beginning. Mitochondria are subcellular organelles that arose about 2 billion years ago when one cell invaded another. That historic event enabled multicellular life to evolve because the bacteria could handle oxygen. Those were the original ancestors of our mitochondria.

Mitochondria are commonly known as the powerhouses of the cell. Their major role is to produce energy, which in the chemical form is adenosine triphosphate (ATP). Mitochondria also have many other roles, including being the major places in the cell where free radicals are made and scavenged and where many other aspects of cellular metabolism occur.

Table 1. Mitochondrial Functions

Mitochondria regulate many cellular functions
  1. Energy production

  2. Calcium homeostasis

  3. Apoptosis

  4. Radical species generation

  5. Radical species scavenging

  6. Steroid biosynthesis

  7. Orchestrate metabolism

The way in which our bodies make energy is by breaking down the food energy from fats, sugars, and proteins to its most essential chemical, NADH. [Editor's note: Nicotinamide adenine dinucleotide in its reduced form is abbreviated as NADH.] This charge enters through the electron transport chain, shuttling electrons between the different complexes located within the inner membrane of the mitochondria. As that happens, a charge is sent across the membrane, making the inside of the mitochondria negative and the space between the mitochondria membranes positive.

Figure 1. The production of energy in mitochondria.

This charge separation, or potential difference, is essentially a battery. Complex V uses that battery to phosphorylate ADP to effectively make energy in the chemical form of ATP. This process is very dynamic and is the reason why we need to eat multiple times each day to generate the reducing equivalents, or fuel, to feed the system to make the energy we need to power our bodies.

New Understanding of Mitochondrial Disease

When the mitochondria fail to do this process properly, mitochondrial disease results. This can have varied effects on our bodies—so much so that in the past, a mitochondrial disease was thought of as something that could affect any system by causing any symptom in any organ by any mode of inheritance. It really is that variable. Unfortunately, there is no single test that can determine whether you do or do not have a mitochondrial disease.

It is now clear that mitochondrial disease is actually a very complex set of diseases, with nearly 300 different known genetic causes. These genetic mutations can be located either in the nucleus of the cell or in the DNA of the mitochondria itself. The first mitochondrial DNA disease was identified nearly 30 years ago, leading to an entirely new medical field. Much has been learned in a very short period, and we now know that any organ can be affected.

Many people whose mitochondria fail to produce sufficient energy have neurologic problems. These can include strokes, seizures, and headaches such as migraines. Any part of the nervous system can be affected, including the peripheral and the autonomic nervous systems. Any organ that depends on energy to function—ie, all of them—can be affected. Common systems affected include muscles, kidneys, liver, vision, hearing, the hormonal system, and blood.

Because of the complexity of diagnosing mitochondrial disease and the many etiologies that need to be considered at the genetic level, the international community has banded together and created an online, freely accessible resource through the Mitochondrial Disease Sequence Data Resource Consortium. On it, you will be able to take tutorials about how to use the resource and modules to help better understand the features of mitochondrial disease at the clinical level, as well as the genes and variants that are known to cause disease.

Figure 2. MSeqDR: the Mitochondrial Disease Sequence Data Resource Consortium.

We now understand much about the different ways in which different genes can affect the way that the mitochondria function. Some of the pathways that can become abnormal include the battery itself or the electron transport chain, which is embedded in the inner mitochondrial membrane. There are many ways that the mitochondria can fail in addition to changes directly affecting the electron transport chain.

These include the way that nucleic acids are brought into the mitochondria, called nucleotide import defects, as well as ways in which the mitochondrial DNA makes its own 13 proteins that are essential for the electron transport chain to function. There are many other subtle [changes that we have learned about as a result of] new understanding that mitochondrial disease is not a single disease at the clinical level, nor just one condition at the cellular level. It is very important that we develop therapies that match the ways in which the cellular function is precisely disrupted.

Can Mitochondrial Disease Be Treated?

Are there therapies or cures for mitochondrial disease? Unfortunately, at this time, there are no proven therapies or cures for mitochondrial disease. Why not? As you have just heard, mitochondrial disease is really a constellation of hundreds of different disorders. It therefore makes sense that grouping them all together may not be the most straightforward way to identify a common therapy for specific subsets.

Exercise. It is known that exercise is a definite therapy in mitochondrial disease, as long as the patient can tolerate it based upon their overall health, such as heart and kidney function. Exercise is valuable both aerobically and anaerobically. Exercise can help make more mitochondria and can shift the levels of errors in the mitochondrial DNA that arise in some patients to a lower amount, thereby increasing the function of those mitochondria produced from good mitochondrial DNA.

Nutrition. It is also increasingly recognized that nutrition and vitamins are very important to the functioning of the mitochondrial electron transport chain and all of the enzymes within it. At this time, we don't understand the precise optimal diet for any one patient with mitochondrial disease, but we recognize that it is a key factor in optimizing their health and outcomes.

"Cocktails." Commonly, people are told to take a mitochondrial medicine cocktail. This is an empirically based combination of vitamins, cofactors, and nutrients that are known to replace deficiencies that occur when the mitochondrial energy production system fails and to help its residual function act better.

Table 2. Ingredients That May Be Included in Mitochondrial Medicine "Cocktails"[1,2]

One-size-fits-all empiric "supplement cocktails" theoretically target mitochondrial enzymes and stress with variable clinical use:
  • Agents that increase free coenzyme Q10 pool (carnitine, pantothenate)

  • Enzyme co-factors (vitamin B1 or B2)

  • Metabolite therapies (arginine, folinic acid, creatine)

  • Enzyme activators (dichloroacetate)

  • Antioxidants (vitamins C or E, lipoic acid, coenzyme Q)

Some products that may be used include agents to increase the coenzyme Q pool, which is a part of the electron transport chain that shuttles electrons to help the battery function. Other co-factors for different components or complexes of the electron transport chain can help the body have more resilience when faced with a stressor, which can often be a major cause of decompensation and clinical illness in patients with mitochondrial disease. Activators of other enzyme complexes that help nutrients get to the mitochondria, as well as antioxidants, may also be included in these "cocktails." It is well recognized that most mitochondrial diseases have some level of increased oxidative stress.

The Future of Therapy

Here at CHOP, we are pursuing a precision medicine approach for mitochondrial disease, starting with understanding the cause in each individual patient's body. When the precise genetic cause is identified, or certain subclasses of disease are recognized, models can be created either in the patient's own cells or in invertebrate and vertebrate animal models. These will help to better understand the way in which the biochemistry has caused a problem and [how] the survival of the animal or the functions of the [organs and] organisms are impaired.

From there, therapies such as mitochondrial medicine supplement regimens, nutrients, and exercise can be tested to precisely understand whether they are helpful or harmful in any one type of mitochondrial disease. Additionally, new compounds could be screened to more quickly and effectively identify therapies that are precisely matched to each patient's metabolism and their disease.

Our goal is to take these ideas and concepts learned from animal models and translational research and bring them back to each and every patient, in order to create an outcome that is relevant to their health, growth, and overall well-being. A second goal is to objectively determine whether the therapies that appear to be indicated for a particular patient based upon experience with other patients and [knowledge gleaned] from research are indeed effective. We envision that it is this iterative approach which will ultimately lead to precise therapies for different classes of mitochondrial disease and improve the health, well-being, and survival [of these patients].


Mitochondrial function is essential to generating the fuel in our cells. Errors in the genetic code which impair the ability to make energy [can] affect the functioning of any organ. To use the analogy of a fuel gauge, patients with mitochondrial disease in the fuel gauge model would be all the way to the left—at their best, starting with a low level of energy which falls even lower in response to stressors or activity.

Figure 3. Mitochondrial energy spectrum.

It is important to recognize that many other conditions, even those in which the genetic code for the mitochondria might be normal, can ultimately impair the function of the mitochondria. This includes complex conditions such as cancer, metabolic syndrome, or diabetes, in which mitochondrial energy production can also fail. Researchers are looking at ways to optimize mitochondrial function in these disorders. Additionally, neurodegenerative disorders such as Alzheimer's or Parkinson's disease can involve failure of mitochondrial [function that will] subsequently cause neurologic symptoms. Mitochondria can also, over time, become innocent bystanders [in common, complex diseases] and sustain significant impairment. Active research in mitochondrial medicine will have beneficial effects in these broader groups of patients as well.

It is now recognized that mitochondrial function affects all of us and that there are things we can all do to optimize our mitochondrial health. Our decisions about nutrition and exercise make a big difference in our mitochondrial energy health and our ability to function optimally. It is known that our mitochondrial energy falls as we age. Exercise and nutrition can reverse these outcomes and improve health.

I hope this was helpful to you. There is a lot going on in the field of mitochondrial medicine. Every doctor in every specialty has seen patients whose mitochondria are not functioning optimally, and it's our hope that we will, as a society, better diagnose and care for these patients to improve their health. Thank you.

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