Ssm Winter 2007 Biomed Mitochondria

biology + medicine

Mitochondrial Disease

by Julie Boiko

What happens when cellular machinery

malfunctions?

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Photo Credit: http://www.ualr.edu/botany/mitochondrion.jpg

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.

Above: A scanning electron micrograph image of a healthy mitochondrion. Because of their autonomous origins, mitochondria still maintain their own genomes, known as mtDNA, which are inherited maternally. Mitochondrial information, thus, has been used in population genetics and forensics testing. For the past eight years, Associate Professor of Pediatrics and Director of Stanford’s Biochemical Genetics Program

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Gregory Enns, MB, ChB, and his colleagues have studied these exciting organelles and the diseases that result when they malfunction. Working directly with young patients affected by genetic mitochondrial diseases, Enns and his colleagues seek to understand the hallmarks of mitochondrial disorders 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

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

“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

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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Photo Credit: Morgue File - artist xpistwv: TheSneeze.jpg

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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. 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 Many mitochondrial disorders occur during flu-like events as the body catbolizes its own tissues in a useless attempt to create energy.

themselves through a variety of symptoms. “Right now it is often difficult to diagnose, let alone treat, these conditions,” says Enns. “Although there are not many available therapies, 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.” Biomarkers are clinically relevant disease features determined by measuring levels of organic molecules that allow physicians to make accurate diagnoses. At Stanford, Enns has sought to define such features for mitochondrial and other metabolic disorders to measure disease progression. Since 2005, newborns in California have been screened for nearly 40 metabolic and other diseases through simultaneous measurement of various metabolites using tandem mass spectrometry, though mitochondrial disorders 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 screen kids for a lot of different conditions,” comments Enns on spectrometry’s utility in catching diseases before patients become symptomatic. Although such technology has brought a flux of young patients with a variety of metabolic disorders to Stanford recently, Enns remarks that it is “gratifying to see these kids coming in [to the clinic] instead of coming into the emergency room when they’re in a coma.” By defining biomarkers for mitochondrial diseases, Enns hopes that more metabolic diseases will be caught earlier and treated immediately rather than allowed to silently persist

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Mitochondrial disease research has a long way to go, both in its understanding of mitochondrial genetics and in its clinical applications of defining biomarkers. Work published by Enns and other researchers (Molecular Genetics and Metabolism, 2003) indicates that mtDNA mutations may cause diseases long believed to be largely unrelated to impaired mitochondrial function, including diabetes, hypothyroidism, and possibly even cancer. It is thought that dysfunctional mitochondria may produce toxic reactive oxygen and nitrogen species which, in turn, set off a chain reaction leading to such disorders. Enns hopes that his work with pediatric mitochondrial disease patients will serve as a paradigm by which clinical researchers can develop treatments and novel methods for diagnosis. “We’re catching some [patients] before they have a metabolic crisis,” says Enns. He looks forward to the day when knowledge of mitochondrial malfunctions will allow physicians to diagnose and treat patients with mitochondrial diseases even before they begin expressing symptoms. S JULIE BOIKO is a freshman majoring in Biological Sciences, with a minor in Russian Language, Literature, and Culture. In her spare time, she enjoys her immunology research and swimming. To Learn More: For information about mitochondrial disorders, visit the United Mitochondrial Disease Foundation website: www.umdf.org