Mid-Atlantic Consortium Newsletter Summer 2013

Falk Scrutinizes Mitochondrial Diseases in the Lab and the Clinic

TargetClinical geneticist and pediatrician Marni Falk, M.D., has dedicated her career to studying the genetics of human mitochondrial diseases, a group of rare conditions affecting one in every 4,000 people in the United States.

Falk’s research laboratory at Children’s Hospital of Philadelphia, supported by the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) and the National Institute of Neurological Disorders and Stroke, focuses on the metabolic consequences of mitochondrial disease in human tissues, and is developing diagnostic approaches to identify specific genetic causes in affected individuals. So far, in conjunction with collaborators at Loyola University and Massachusetts Eye and Ear Infirmary, they have sequenced and analyzed all genes in seven families with previously rare, undiagnosed mitochondrial diseases. They iden¬tified a definite or highly probable genetic cause for each. In addition, Falk and colleagues identified a novel genetic cause for congenital blindness that was due to deficiency of an enzyme involved in basic cellular metabolism, NMNAT1. This work was published in September 2012, in Nature Genetics.

Falk’s team has contributed widely toward better understanding of mitochondrial disorders, which result from genetic muta¬tions affecting the work of mitochondria, structures within cells that generate energy needed to fuel biological activity. There are hundreds of mitochondrial diseases causing symptoms that vary considerably in their types and severity. While symptoms can be quite mild, more severely affected children or adults can develop deafness, diabetes, impaired vision, growth retardation, weakness, heart problems, or epilepsy.

Mitochondria contain their own DNA, with 37 genes distinct from genes found in the nuclear chromosomes. Only 13 mitochondrial DNA genes code for proteins within these tiny energy machines, with the remaining more than 1000 mitochondrial proteins encoded in nuclear DNA.

“Our ultimate goal is to translate scientific knowledge into targeted therapies—effective ways to intervene,” Falk says, “but first we need to understand the underlying disease mechanisms.”

Among their contributions, Falk and her colleagues proved the microscopic worm C. elegans, an animal that has been remarkably well-suited for studies of many basic biological mechanisms, can be used to understand the effects of human mitochondrial disease. With this model, they identified an evolutionary signature of primary mitochondrial respiratory chain dysfunction, reported in 2008 in the journal Molecular Genetics and Metabolism.

Falk and her long-standing collaborators at the University of Washington in Seattle are now discovering how parts of complex I, the largest component of the energy-generating mitochondrial respiratory chain, affect the way worms, and human mito-chondrial disease patients, react to anesthesia. Falk is also using this model to hunt for and evaluate drugs to improve symptoms of mitochondrial diseases, work funded by NICHD.

Recently, Falk’s group, collaborating with geneticist David Gasser, Ph.D., at the University of Pennsylvania Perelman School of Medicine, used a mouse model of mitochondrial disease to show that probucol, a drug formerly used to treat high cholesterol, may have benefits for hard-to-treat mitochondrial respiratory chain defects. Mice unable to produce coenzyme Q, a powerful antioxidant that helps convert food to energy, develop fatal kidney failure. But mice fed probucol either did not develop kidney disease or actually had their kidney disease reversed. The drug also raised tissue levels of coenzyme Q, and corrected basic cell signaling abnormalities that contribute to disease symptoms. This work was published May 2011, in EMBO Molecular Medicine.

“Probucol showed remarkable benefits in the mice, especially when compared to directly feeding the mice the missing metabolite — coenzyme Q10,” Falk says. “If this approach can be safely translated to humans, we may have a more effective treatment for mitochondrial disease than anything currently being used.”


Mitochondria produce 90% of the energy needed to sustain life by combining oxygen from the air we breathe with calories from food.

Source: United Mitochondrial Disease Foundation


For more information about the diagnostic clinic or active research studies, contact mccormicke@email.chop.edu. For more information about mitochondrial disease, see the United Mitochondrial Disease Foundation’s Web site.

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