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NIEHS Investigators Explore Biochemical Causes of Mitochondrial Disease

By Brian Chorley
August 2009

Rajesh Kasiviswanathan, Ph.D.
The study is Kasiviswanathan's fourth publication as first author. (Photo courtesy of Steve McCaw)

Matthew Longley, Ph.D.
Longley has collaborated with colleagues in the Copeland group and the NIEHS Laboratory of Structural Biology on more than 25 studies published since 1998. (Photo courtesy of Steve McCaw)

Sherine Chan, Ph.D.
Chan is now an assistant professor in the College of Pharmacy at the Medical University of South Carolina. (Photo courtesy of Steve McCaw)

William Copeland, Ph.D.,
Copeland has been a leader in his field since establishing his lab at NIEHS in 1993. In 2007 he received the Mitochondria Research Society's Distinguished Service Award for service as its president in from 2005 to 2007. (Photo courtesy of Steve McCaw)

A recent study published in the July 17 issue of the Journal of Biological Chemistry explored how certain DNA mutations may contribute to genesis and progression of mitochondrial diseases. NIEHS Principal Investigator William Copeland, Ph.D., and Postdoctoral Fellow, Rajesh Kasiviswanathan, Ph.D., led an effort to characterize these DNA mutations which are present in patients of Alper's syndrome, an often fatal disease attributed to mitochondrial dysfunction. Their findings demonstrated that some of these mutations deleteriously impact mitochondrial DNA replication - a function critical for maintenance and activity of this important cellular organelle.

According to the NIEHS Laboratory of Molecular Genetics (LMG) researchers, the study ( Exit NIEHS represents the first structure-function analysis of its kind performed on what is known as the thumb subdomain of the mitochondrial DNA replication enzyme, polymerase gamma (pol γ), and offers insight into the effects of mutations in this region.

Copeland has dedicated his scientific career to uncovering the biochemical and genetic causes of mitochondrial abnormalities (see text box). ( A central player of many projects in Copeland's laboratory is the DNA pol γ enzyme - the sole polymerase available in the mitochondria for replication of its DNA. A mutation within the gene encoding pol γ may lead to a cascade of downstream events, which can result in mitochondrial DNA depletion and, ultimately, mitochondrial-mediated disease. In a recent synopsis of his group's research, Copeland explained, "There are currently more than 150 [single] mutations in the POLG gene that cause a wide spectrum of mitochondrial disease... We have discovered more than 25 percent of these mutations and biochemically characterized the pol γ enzymes that harbor these disease alterations."

In their current study, the researchers focused on 6 pol γ mutations linked to the mitochondrial disease Alper's syndrome. This rare inherited neurological disease typically affects young children who often do not live into their teens due to the cerebral degeneration associated with the disease. Recent work, spearheaded by the Copeland group, has linked pol γ mutations to Alper's syndrome, but only a handful of these mutations have been demonstrated to have direct biochemical effects on the function of the enzyme.

Using purified preparations of polymerases exhibiting these mutations, Copeland's laboratory assessed activity, DNA binding and mutation potential of these enzymes. The results both surprised the group and affirmed their predications. Some of the mutations linked to Alper's syndrome predictably abrogated polymerase activity and function, while other mutations caused only moderate biochemical alterations but were linked to severe disease symptoms. Copeland's explanation for the latter scenario is these mutations work in concert with other mutations which also alter proteins known to contribute to mitochondrial DNA replication leading to the development of Alper's. The exact nature of these interactions were unknown and the authors made it clear that more studies are needed to gain a better understanding of genomic replication in the mitochondria.

While there are no known cures or proven treatment for mitochondrial diseases, studies such as these will further basic understanding of genetic causes for these diseases. This basic understanding will undoubtedly spur therapeutic promise for the future.

In addition to Copeland and Kasiviswanathan, LMG Staff Scientist Matthew Longley, Ph.D., and former NIEHS Postdoctoral Fellow Sherine Chan, Ph.D., were coauthors on the paper.

Citation: Kasiviswanathan R, Longley MJ, Chan SS, Copeland WC ( Exit NIEHS. 2009. Disease mutations in the human mitochondrial DNA polymerase thumb subdomain impart severe defects in mitochondrial DNA replication. J Biol Chem 284(29):19501-19510.

(Brian Chorley, Ph.D., is a postdoctoral fellow in the NIEHS Laboratory of Molecular Genetics Environmental Genomics Group.)

Mitochondrial Disease - Deficits in Energy Production

Mitochondrial disease is defined as a spectrum of ailments resulting from failure of mitochondrial function. Commonly referred to as the "powerhouse of the cell," the mitochondria's primary function is to supply cells with chemical energy. While mitochondrial disease can target practically any organ in the body, cells that require high amounts of energy, such as muscle, brain and nerve cells, are particularly vulnerable. Mitochondrial diseases typically afflict young children before the age of 10. However, adult onset of disease is now being diagnosed more frequently due to better recognition of symptoms and identification of genetic causes.

Mitochondrial diseases are unique because they can display maternal patterns of inheritance. In addition to nuclear-derived proteins whose genes display normal patterns of inheritance, mitochondria are also made up of proteins derived from their own DNA, which encodes 37 genes important for mitochondrial function. The female egg contributes mitochondrial DNA during zygote formation, where the sperm mitochondrial DNA is targeted for destruction. Because of this, any DNA mutation present in the egg's mitochondria will be directly passed to offspring.

Direct mitochondrial diseases affect about 1 in every 2000 births, with about half developing in childhood and the other half presenting in adults. Mitochondrial deficits also have a secondary role in many other diseases, such as Parkinson's Alzheimer's, Huntington's and diabetes. About ten percent of autistic children show biomarkers of mitochondrial disease.

Copeland explored additional aspects of mitochondrial diseases in a review ( Exit NIEHS published in 2008 in the Annual Review of Medicine.

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