biology

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Mitochondrial
Disease by Julie Boiko

What happens when cellular machinery

malfunctions?

T
wo billion years ago, a hungry protoeukaryote engulfed an aerobic bacterium, but
instead of digesting it, the protoeukaryote formed a symbiotic relationship with
its helpful snack, feeding off the energy the bacterium produced by metabolizing
undigested food particles. With time, natural selection morphed the bacterium into what
has now become an essential organelle called the mitochondrion, the energy-producer
of every eukaryotic cell.
Photo Credit: http://www.ualr.edu/botany/mitochondrion.jpg

Above: A scanning electron micrograph image of a healthy mitochondrion.

Because of their autonomous origins, mitochondria still Gregory Enns, MB, ChB, and his colleagues have studied these
maintain their own genomes, known as mtDNA, which are exciting organelles and the diseases that result when they
inherited maternally. Mitochondrial information, thus, malfunction. Working directly with young patients affected
has been used in population genetics and forensics testing. by genetic mitochondrial diseases, Enns and his colleagues
For the past eight years, Associate Professor of Pediatrics seek to understand the hallmarks of mitochondrial disorders
and Director of Stanford’s Biochemical Genetics Program and develop novel methods of diagnosis and treatment.

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Photo Credit: ©sxc.hu/Billy W
Individuals with mitochondrial disease can be affected by retinitis pigmentosa, a disorder affecting eyesight. An example of
how a normal image (left) might appear to someone suffering from retinitis pigmentosa (right).
Mitochondrial Disorders
Enns and his colleagues treat young patients with genetic
metabolic disorders caused by mutations both in mtDNA
and in nuclear DNA. Enns deals with diseases such as Leigh
syndrome and neurogenic muscle weakness, ataxia, retinitis
pigmentosa (NARP), which manifest themselves primarily
“Right now it is often difficult to diagnose, let alone treat,
these conditions. We want to figure out if any treatments
we’re using actually work. To do that we need to have
biomarkers of the disease itself.”
in neural and muscle tissue, although other tissues can be
affected by the mitochondria’s inability to produce sufficient
ATP for everyday activities. The severity of mitochondrial
diseases is thought to be closely tied to the mitochondrial
mutant load (the percentage of mitochondria with significant
mutations) present in germ layers during embryonic
development and to the resulting propagation of affected
mitochondria to specific cell lines.
Many mitochondrial and metabolic disorders worsen
during times of intercurrent illness (e.g., “flu-like” illnesses),
layout design: Sze Suen
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resulting in catabolism of healthy tissue—that is, the
breakdown of organic molecules necessary to the body
—which can result in a vicious downward spiral in which
mitochondria race to produce energy to no avail and only
destroy themselves in the process. Enns likens this problem
to “stepping on the gas pedal with a flooded engine.” This
mitochondrial breakdown often results in the failure of
multiple organ systems. Enns’ goal is to develop better ways
to diagnose mitochondrial diseases and to monitor their
progression.
Finding Biomarkers
Because mutant mitochondria are often present in multiple
tissue types, Enns points out that diagnosis of mitochondrial
diseases can be challenging, as these disorders present
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Enns hopes that his work

will serve as a paradigm by
which clinical researchers
can develop treatments
and novel methods for
diagnosis.
Photo Credit: Morgue File - artist xpistwv: TheSneeze.jpg

until it is too late for medical intervention. Additionally,

further identification of biomarkers will allow physicians to
monitor the progression of mitochondrial disorders more
easily and make appropriate treatment decisions.

Promising Research
Mitochondrial disease research has a long way to go,
Many mitochondrial disorders occur during flu-like events as the body both in its understanding of mitochondrial genetics and
catbolizes its own tissues in a useless attempt to create energy. in its clinical applications of defining biomarkers. Work
published by Enns and other researchers (Molecular
themselves through a variety of symptoms. “Right now it is Genetics and Metabolism, 2003) indicates that mtDNA
often difficult to diagnose, let alone treat, these conditions,” mutations may cause diseases long believed to be largely
says Enns. “Although there are not many available therapies, unrelated to impaired mitochondrial function, including
we want to figure out if any treatments we’re using actually diabetes, hypothyroidism, and possibly even cancer. It is
work. To do that we need to have biomarkers of the disease thought that dysfunctional mitochondria may produce toxic
itself.” reactive oxygen and nitrogen species which, in turn, set
Biomarkers are clinically relevant disease features off a chain reaction leading to such disorders. Enns hopes
determined by measuring levels of organic molecules that that his work with pediatric mitochondrial disease patients
allow physicians to make accurate diagnoses. At Stanford, will serve as a paradigm by which clinical researchers can
Enns has sought to define such features for mitochondrial and develop treatments and novel methods for diagnosis. “We’re
other metabolic disorders to measure disease progression. catching some [patients] before they have a metabolic crisis,”
Since 2005, newborns in California have been screened says Enns. He looks forward to the day when knowledge of
for nearly 40 metabolic and other diseases through mitochondrial malfunctions will allow physicians to diagnose
simultaneous measurement of various metabolites using and treat patients with mitochondrial diseases even before
tandem mass spectrometry, though mitochondrial disorders they begin expressing symptoms. S
are currently not part of this expanded newborn screen. “It’s
[this] technology that allows us to look at a lot of different
metabolites at the same time...and makes it possible for us to JULIE BOIKO is a freshman majoring in Biological Sciences, with a
screen kids for a lot of different conditions,” comments Enns minor in Russian Language, Literature, and Culture. In her spare
on spectrometry’s utility in catching diseases before patients time, she enjoys her immunology research and swimming.
become symptomatic. Although such technology has brought
a flux of young patients with a variety of metabolic disorders To Learn More:
to Stanford recently, Enns remarks that it is “gratifying to
see these kids coming in [to the clinic] instead of coming into For information about mitochondrial disorders, visit the
the emergency room when they’re in a coma.” United Mitochondrial Disease Foundation website:
By defining biomarkers for mitochondrial diseases, Enns www.umdf.org
hopes that more metabolic diseases will be caught earlier and
treated immediately rather than allowed to silently persist

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