MYOPATHY: AN ENERGY CRISIS IN THE CELLS
|by Sharon Hesterlee
This is the first of a two-part Quest
series about mitochondrial myopathy. This article covers the
basic biology of mitochondria and explains inheritance
patterns and determinants of severity in mitochondrial
diseases. Part 2 will discuss diagnosis and treatment,
including a look at new information about mitochondrial
diseases in the research pipeline.
We all know what it's like to drive or ride in a car that
isn't performing at its peak; we know from experience that
trouble-shooting the problem can be a difficult, costly
In some ways, the cells in our bodies are like little
mechanical devices that occasionally break down. They have a
lot of parts, some moving and some not, each with a specific
role to perform in the cell. An endless variety of things
can go wrong in the cell, affecting the entire body's
ability to perform.
We can compare a cell with muscular dystrophy to a car with
cracks in the frame. The cracks become slightly wider
whenever the car is driven. In the same vein, a cell with
mitochondrial disease might be compared to a car that's only
running on three cylinders. No matter how much gas you put
into the car, without a fully operating engine it's not
going to go over 25 miles per hour.
In each of our cells, the mitochondria (singular:
mitochondrion) make up the equivalent of a car's engine.
These tiny biological machines combine the food we eat with
oxygen to produce energy to keep our bodies going. The
energy produced by the mitochondria is stored in the form of
a chemical called adenosine triphosphate, or ATP.
In addition to making energy, mitochondria are also deeply
involved in a variety of other activities, such as making
steroid hormones and manufacturing the building blocks of
DNA. Each cell in our body contains, on average, between 500
and 2,000 of these hard-working machines. When the
mitochondria aren't functioning properly, an "energy
crisis" can develop in tissues such as muscle, brain
and heart, which normally are heavy energy consumers.
Just as engine problems can slow or stop a car, problems
with mitochondria can bring the body to a halt.
William Duff of Orchard Run, W.Va., who was once an avid
hiker, suspected he might have a problem when he started
getting tired on the trail and having to take frequent
breaks. Then the muscles in his legs began to contract
spontaneously all of the time. A mitochondrial disease
called MELAS was diagnosed two years ago.
Duff suggests that having MELAS is like experiencing old
age at 37.
"Any kind of exertion brings on fatigue. Sometimes
I get up in the morning and I just have no energy at all,"
he says. "It's hard to explain. Just simple daily
functions are very tiring."
The Downs Family
Duff's spontaneous muscle contractions
have spread throughout his extremities, trunk and face. Now
he's also having trouble with drooping eyelids, memory
deficits, stomach reflux, and difficulty absorbing
For Lori and Jeff Downs of North Reading, Mass., their
daughter Alycia's mitochondrial disease has meant an uphill
battle to cope with her severe gastrointestinal problems.
"Alycia was a normal-term baby and her birth was
fairly normal," says Lori Downs. "The first
problem that we had was with her feeding -- it was just a
struggle. It would take her an hour to take that half an
ounce and she would sweat and struggle, and she wasn't
The Downses eventually worked out a feeding solution for
Alycia by boosting her calorie intake and making the nipple
easier to use. Now almost 4 years old, Alycia still
struggles with gaining weight, and has some muscle weakness,
drooping eyelids, difficulty maintaining her balance and
focused cognitive deficits.
The experiences of Duff and the Downs family illustrate
just a few of the different manifestations of mitochondrial
disease. In the same way that a car can show many different
signs of engine problems, mitochondrial diseases -- of which
hundreds of varieties have been identified -- can cause a
complex variety of symptoms.
These include muscle weakness, muscle cramps, seizures,
food reflux, learning disabilities, deafness, short stature,
paralysis of eye muscles, diabetes, cardiac problems and
strokelike episodes, to name a few. The symptoms can range
in severity from life-threatening to almost unnoticeable,
sometimes taking both extremes in members of the same
Because some people have specific subsets of these
symptoms, clinical researchers have grouped those that occur
together into "syndromes," producing a bewildering
array of descriptive acronyms such as MELAS (mitochondrial
encephalomyopathy with lactic acidosis and strokelike
episodes) or MERFF (myoclonus epilepsy with ragged red
You may also hear the terms "mitochondrial myopathy"
(indicating muscle involvement) or "mitochondrial
encephalomyopathy" (indicating brain and muscle
involvement). MDA covers diseases in both of these
categories, which include many different syndromes (see
mitochondrial encephalomyopathies chart, below).
The mitochondrial encephalomyopathies and myopathies are
typically caused by defects in a part of the mitochondrion
known as the respiratory chain or the electron transport
chain. To see exactly how these diseases occur, see "What
Mitochondria Do and What Can Go Wrong."
DISEASES AFFECTING MUSCLE
used in describing mitochondrial disorders can be
confusing. A single syndrome (combination of symptoms)
may have many different causes, while more than one
syndrome may have the same cause.
In most cases, the
underlying causes of these syndromes are deficiencies
in the respiratory chain of the mitochondria (see "What
Mitochondria Do"). You may be given a diagnosis
named for the cause, such as COX deficiency or complex
I and IV deficiency. The following have names based on
the symptoms of the disease, but are caused by
respiratory chain deficiencies.
KSS: Kearns-Sayre syndrome
Onset: Before age 20
Disease characteristics: May cause blindness,
eye muscle paralysis, severe heart problems,
coordination problems, mental retardation and coma.
Leigh's syndrome: Subacute
Onset: Infancy; progression can be fast or
Disease characteristics: May cause brain
abnormalities, vomiting, seizures, feeding
difficulties, heart problems, epilepsy, speech
difficulties and muscle weakness.
encephalomyopathy, lactic acidosis and strokelike
episodes. This is the most common type of
Onset: Before age 20
Disease characteristics: May cause exercise
intolerance, seizures, dementia, muscle weakness,
Myoclonus epilepsy with ragged-red fibers
Onset: Usually before adolescence; variable
Disease characteristics: May cause epilepsy,
coordination loss, dementia and muscle weakness.
Maternally inherited Leigh's syndrome
Disease characteristics: Same as Leigh's
Onset: Before age 20
Disease characteristics: May cause eye muscle
paralysis, muscle weakness, digestive tract disorders,
loss of coordination and brain abnormalities.
Neuropathy, ataxia and retinitis pigmentosa
Onset: Infancy or childhood
Disease characteristics: May cause vision
problems, lack of coordination and mental retardation.
This syndrome may represent a less severe form of
PEO: Progressive external
Onset: Usually in adolescence or early
adulthood; slow progression.
Disease characteristics: May cause paralysis
of eye muscles, drooping eyelids, muscle weakness and
Disease characteristics: Severe anemia and
pancreas malfunction; children who survive the disease
may develop KSS as adolescents.
MITOCHONDRIA DO, AND WHAT CAN GO WRONG
When the breakdown products of the
food that we eat enter the mitochondria for processing,
they're passed along a well-orchestrated assembly line made
up of hundreds of proteins, each with a specific role to
play in the energy production process. Raw materials enter
the beginning of the assembly line, and ATP energy molecules
come out the other side.
The major steps in the energy extraction process are (see
the following illustration):
- import and export of materials, such as fat and sugar
derivatives, to and from the mitochondria
- the breakdown of fatty acids through beta-oxidation
and the removal of electrons in the citric acid cycle
- the passage of electrons through the major complexes
of the respiratory chain, or electron transport chain,
- the manufacture of ATP by ATP synthase.
any one of these steps is blocked, usually because a genetic
defect has prevented the manufacture of a protein required
for that step, mitochondrial disease can occur. The body
can't function properly because the cell's ability to make
energy is reduced or stopped, and metabolic intermediates
and toxic by-products begin to build up.
The energy shortage in the tissues is the major cause of
muscle weakness, fatigue and problems in the heart, kidneys,
eyes and endocrine system. The buildup of toxic
intermediates can be responsible for liver problems, muscle
cramps, brain dysfunction or even greater mitochondrial
damage. Many times these two types of problems reinforce one
another, each making the other worse. (The specific problems
and symptoms that occur in mitochondrial disorders, and
their management, will be discussed in greater detail in
Part 2 of this series.)
Salvatore DiMauro, a neurologist at Columbia University in
New York, says that, although there are many different types
of defects that cause mitochondrial disorders, the term
mitochondrial encephalomyopathy has come to refer only to
disorders of the respiratory chain (numbers 3 and 4 in the
illustration). (The respiratory chain is part of the cell
and has nothing to do with a person's breathing.)
The respiratory chain consists of four large protein
complexes: I, II, III and IV (cytochrome c oxidase, or COX),
ATP synthase, and two small molecules that ferry around
electrons, coenzyme Q10 and cytochrome c. The respiratory
chain is the final step in the energy-making process in the
mitochondrion where most of the ATP is generated; as DiMauro
puts it, it's "the business end of mitochondrial
metabolism." Mitochondrial encephalomyopathies that can
be caused by deficiencies in one or more of the specific
respiratory chain complexes include MELAS, MERFF, Leigh's
syndrome, KSS, Pearson, PEO, NARP, MILS and MNGIE.
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