|MITOCHONDRIAL DISEASE IN PERSPECTIVE
SYMPTOMS, DIAGNOSIS AND HOPE FOR THE FUTURE
|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.)
|BEYOND MUSCLE WEAKNESS
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
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
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
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
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.
RADICALS AND ANTIOXIDANTS
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
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
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.
|TOXIC METABOLITE BUILDUP
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
"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
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
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
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
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
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
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