by Sharon Hesterlee

Each of our cells contains, on average, 500 to 2,000 little "factories" called mitochondria that are responsible for supplying our energy needs. When the mitochondria aren't working properly, the effects are particularly apparent in parts of the body with high energy requirements, such as the nervous system, skeletal muscles and heart.

This is the second article in a two-part series on mitochondrial diseases affecting these organs. Part 1 (vol. 6, no. 4) covered mitochondrial anatomy, the basics of mitochondrial disease inheritance and common types of mitochondrial disorders affecting muscle.

Part 2 takes a closer look at diagnosis, symptoms and their management. In addition, MDA researcher and mitochondria expert Eric Schon of Columbia University gives an inside view of projects in the research pipeline that hold promise for mitochondrial disease treatments.

Mitochondrial disorders differ from other genetic disorders affecting the muscles in a number of ways. Most significantly, although mitochondrial disease can present as a "pure myopathy," meaning that only the skeletal or heart muscles are affected, it more often causes problems in many different organ systems, including the nervous, visual, renal (kidneys), digestive and circulatory systems.

The mitochondria are essential for turning the food we eat into energy in the form of the molecule ATP. Although there are many working parts in each mitochondrion, the mitochondrial encephalomyopathies (those disorders affecting brain and muscle and the type covered in MDA's program) are most often caused by defects in the proteins that make up the respiratory chain. The respiratory chain inside the mitochondrion is an assembly line of protein complexes that combines electrons with oxygen to generate potential energy in the form of ATP. (This respiratory chain has nothing to do with breathing.)

Despite the fact that mitochondrial diseases can be so variable and affect so many organ systems, a few symptoms are common to many of these disorders. These include muscle weakness, muscle cramps, extreme fatigue, gastrointestinal problems (constipation, acid reflux), droopy eyelids (ptosis), eye muscle paralysis (external ophthalmoplegia), retinal degeneration (retinitis pigmentosa) with visual loss, seizures, ataxia (loss of balance and coordination) and learning delays. See illustration below:

Commonly Affected Systems in Mitochondrial Disorders
The main problems associated with mitochondrial disease -- low energy, free radical production and lactic acidosis -- can result in a variety of symptoms in many different organs of the body. This diagram depicts common symptoms of mitochondrial disease, of which most people have a specific subset. Many of these symptoms are very treatable.
Another category of symptoms called "soft signs" may be noticeable in people who have none of the more overt symptoms of mitochondrial disease. Soft signs include deafness, mild exercise intolerance, diabetes, short stature and migrainous headaches.

Sometimes when a person is found to have a mitochondrial disease on the basis of more severe symptoms, the soft signs of the disease may be recognized in hindsight in other family members.

All of these problems start when something goes wrong in the mitochondria. Some are a direct result of interruptions in the energy supply, while others may be due to the secondary buildup of toxic byproducts, and still others to combinations of these two problems.

When key components of the respiratory chain in the mitochondria are missing or defective, the result is kind of like the aftermath of a train derailment. First, because a component of the assembly line isn't working, electrons aren't delivered. ATP isn't made efficiently and the cells lack the energy to perform their normal functions.

Second, all of the steps behind the point where the problem starts become backed up -- often leading to abnormal chemistry that produces toxic charged molecules. These byproducts include free radicals and excess metabolites, such as lactic acid, that can be harmful in large quantities.

These observations lead to three prime suspects as causes of the symptoms of mitochondrial disease: energy deficit, free radical generation and the buildup of toxic metabolites. Researchers are looking for ways to address these underlying causes. In the meantime, it's good to keep in mind that, although mitochondrial diseases are rare, many of their specific symptoms, such as heart failure and seizures, are relatively common in the general population. Thus, good medical treatments exist to help manage these symptoms.

Tissues that need large amounts of energy, such as the brain, heart, skeletal muscles, eye muscles and the renal tubules of the kidney, probably malfunction, in part, because they run out of fuel. The result is muscle weakness, cardiomyopathy, renal problems, droopy eyelids, cognitive problems and general fatigue.

Although there's no way to combat this type of energy loss directly, eating a healthy, well-balanced diet is important. Sometimes special diets are necessary or beneficial in the management of specific mitochondrial and metabolic diseases. Always consult your doctor on this point, as dietary changes can be dangerous in some of these disorders.

Also, a preliminary report indicates that the dietary supplement creatine may produce modest increases in muscle strength in people with a variety of neuromuscular disorders, including mitochondrial diseases.

Creatine is a small molecule similar to an amino acid that's converted to a compound called phosphocreatine in the body and used as a source of energy. Phosphocreatine actually contains even more energy than ATP and is normally used by our muscle cells for supplying the first burst of energy at the start of strenuous physical activity.

But keep in mind that the experimental results with creatine are very preliminary, and the long-term effects of creatine supplementation in people with any kind of neuromuscular disorder aren't yet known.

Also, although dietary supplements are available over the counter without a prescription, that doesn't mean they're always harmless. You should consult your physician before taking any dietary supplement.

Free radicals are highly reactive charged molecules that can damage DNA and cell membranes by oxidizing them (the same chemical process that causes iron to rust). Normally, the mitochondrial respiratory chain generates a low level of free radicals during the process of making ATP. When there's a malfunction in the respiratory chain, the scale may be tipped toward higher free radical production.

These free radicals, in turn, may cause further damage to the mtDNA (the unique DNA that's found only inside the mitochondria), creating a vicious cycle of damage and free radical production. It's unclear exactly how large a role the generation of free radicals plays in causing or worsening the symptoms of mitochondrial disease, but to play it safe, many doctors recommend antioxidants to their patients.

Antioxidants, usually in the form of vitamins or cofactors, help neutralize free radicals. These same antioxidants and vitamins may also help the struggling enzymes of the respiratory chain run more smoothly. Unfortunately, studies of their effects in people with mitochondrial diseases have produced mixed results, usually because some of the trial participants respond to the supplements and others don't.

"It probably won't hurt, but it probably won't do much good," says one researcher of taking antioxidants. "It's a bit like emptying the ocean with a teaspoon."

Some examples of antioxidants are vitamin E, coenzyme Q10, idebenone (related to coQ10, but penetrates the nervous system more easily), lipoic acid, vitamin C, vitamin K and riboflavin (B2). Many doctors prescribe a "cocktail" of these supplements tailored to the individual patient.

When the mitochondrial respiratory chain is blocked, metabolites that are normally processed by its enzymes may build up in the cells and cause problems.

For example, pyruvate is a chemical derived from glucose that's normally shipped into the mitochondria and then processed further so that its potential energy can be harvested by the respiratory chain.

However, when the respiratory chain is blocked, pyruvate accumulates outside the mitochondria, and when too much pyruvate has accumulated, the cells start to convert it to lactic acid.

"Many patients with mitochondrial disease have lactic acidosis -- lactate in the blood," neuroscientist Eric Schon of Columbia University in New York says. "And there's decent evidence that the lactate isn't just a sign of faulty mitochondria, but that the lactate itself is bad -- especially in the brain, but probably also in the muscle. If this is true, then holding that lactate down would help the patient."

With this in mind, two groups, one at the University of Florida led by Peter Stacpoole and one at the University of California-San Diego led by Richard Haas, are conducting clinical trials with a drug called dichloroacetate (DCA) to try to lower lactate levels in children with Leigh syndrome, Pearson syndrome, MELAS or MERFF (all mitochondrial myopathies).

A third group of researchers led by Darryl DeVivo of Columbia University is also planning to start a DCA trial next spring, but it will limit the enrollment to people with MELAS who have the A3243G mutation. DeVivo says lactate levels in the brain are higher in MELAS than in other mitochondrial diseases, and he hopes that, by narrowing the participation criteria, the study will produce more meaningful results on the effects of DCA.

In addition to lactic acid, other metabolites that normally feed into the respiratory chain can build up in the cells of people with mitochondrial diseases.

In an attempt to rid the body of certain of these extra metabolites, carnitine supplementation is sometimes tried. Carnitine is a natural compound made in the body that functions as a "molecular escort" for other molecules.

One of the duties of carnitine is to move long-chain fatty acids into the mitochondria. Another of its important roles is to bind to extra metabolites and escort them out of the cells and into the kidneys for excretion in the urine.

In this way, carnitine helps the body rid itself of certain extra metabolites.

Carnitine supplementation is often prescribed in mitochondrial disorders, but, as with antioxidants, the evidence that it's helpful is controversial. Carnitine can be bought over the counter at health food stores or can be taken in the prescription form Carnitor (the maker of Carnitor, Sigma Tau, guarantees the purity of its product). Again, consult your doctor before taking any kind of drug or supplement.

Although it may not be possible to treat all of the primary causes of mitochondrial diseases, a recent study in the journal Neurology suggests that people with diseases such as MELAS, MERFF and progressive external ophthalmoplegia (PEO) are actually in greater danger from the treatable complications such as heart failure or stroke than from the mitochondrial disease itself. The authors advise that people living with a mitochondrial disease could benefit by more actively monitoring these conditions and seeking prompt medical attention when necessary.

Fortunately, good treatments do exist for many of the associated complications of mitochondrial disease. For instance, seizures can be managed with antiepileptic medications such as carbamazepine. However, the common antiepileptic valproic acid should be avoided because it depletes the body of carnitine.

Heart failure or arrhythmias can be managed with medications or pacemakers.

Also, people at risk for stroke can reduce that risk with medication, and diabetes can often be managed through careful diet and medication. Specialists treating these symptoms should always be informed about your mitochondrial disorder.

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