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Columbia University Researcher Discusses Mitochondrial Disorders

By Robin Arnette
February 2009

Di Mauro
According to the United Mitochondrial Disease Foundation Exit NIEHS, where DiMauro is a trustee, every 30 minutes a child is born who will develop a mitochondrial disease by the age of 10. (Photo courtesy of Steve McCaw)

Bill Copeland
NIEHS Laboratory of Molecular Genetics (LMG) Principal Investigator Bill Copeland, Ph.D., fielded questions from the audience. He and Kristine Witt, M.Sc., a toxicologist in the NTP Toxicology Branch, co-hosted the seminar. (Photo courtesy of Steve McCaw)

Sam Wilson, M.D.
Chief of the NIEHS DNA Repair & Nucleic Acid Enzymology Group and former Deputy Director/Acting Director Sam Wilson, M.D., had questions for the speaker. Seated behind Wilson was LMG Chief Jan Drake, Ph.D. (Photo courtesy of Steve McCaw)

Jau-Shyong (John) Hong, Ph.D.
NIEHS Neuropharmacology Group Chief Jau-Shyong (John) Hong, Ph.D., also had a question. Hong was interested in DiMauro's perspective on the causes of Parkinson's disease. (Photo courtesy of Steve McCaw)

On January 13, Salvatore DiMauro, M.D., a leading researcher in the study of mitochondrial disorders, gave a distinguished lecture at NIEHS titled "Mitochondrial Medicine." The talk provided an overview of the progress that has been made in the study of defects in mitochondria, tiny organelles found in every cell of the body. Commonly known as "powerhouses of the cell," mitochondria generate the energy that sustains life and supports growth and defects in these important organelles cause a variety of physiological problems.

Symptoms include neurological problems, developmental delays and learning disabilities. The Mitochondrial Disease Action Committee ( Exit NIEHS reports that many diseases of aging may be attributed to defects in mitochondrial function, such as type 2 diabetes, Parkinson's disease, stroke and Alzheimer's disease. DiMauro ( Exit NIEHS, the Lucy G. Moses Professor of Neurology at Columbia University Medical Center, reiterated the importance of mitochondria in eukaryotic organisms and also traced their curious beginnings.

"One-and-a-half billion years ago, free-living bacteria took up residence in primordial eukaryotic cells, and this arrangement became permanent," DiMauro said. "Mitochondria are the only organelles that don't come from us and as a result have their own DNA."

Although mitochondrial DNA (mtDNA) is a small, double-stranded, circular piece of DNA, the number of bases it contains is similar to that found in eukaryotic nuclear DNA. mtDNA encodes 13 subunits of the electron transport chain, which is responsible for generating energy for the cell in the form of adenosine triphosphate (ATP). Mitochondrial genetics differs from Mendelian genetics in three ways:

  • inheritance - exclusively from the mother
  • heteroplasmy - a single cell containing both mutant and normal mtDNA
  • mitotic segregation - random change in the degree of heteroplasmy, possibly accompanied by a change in clinical phenotype, in subsequent generations of cells

DiMauro explained that mtDNA mutations fit into two categories: single deletions in mtDNA or point mutations in tRNA genes that impair overall mitochondrial protein synthesis. Single deletions of mtDNA can cause Kearns-Sayre Syndrome (KSS), Chronic Progressive External Ophthalmoplegia (CPEO) or Pearson syndrome, while two of the most common point mutations in tRNA genes cause MELAS (mitochondrial myopathy, encephalopathy, lactic acidosis and stroke) and MERRF (myoclonic epilepsy associated with ragged red fibers). Point mutations in protein-coding genes cause specific enzyme defects.

A muscle biopsy from patients with either MELAS or MERRF shows fibers with purple patches, which denote proliferation and accumulation of mitochondria. DiMauro said that mitochondrial proliferation was probably a futile attempt to compensate for the mitochondrial respiratory chain defect. Even though the two disorders overlap, they are different syndromes and clinicians have no difficulty distinguishing between them, but DiMauro and his colleagues are still trying to understand their pathogenesis.

"In MELAS there is a mutation in the tRNA leucine and in MERRF the mutation is in the tRNA lysine," DiMauro said, "so the consequence should be the same - a decrease in ATP production. The fact that they are different syndromes is still unexplainable."

There are several areas, however, in which mitochondrial research has been quite successful. DiMauro's group described the mutations in two genes involved in the biosynthesis of coenzyme Q10 (CoQ10, ubiquinone ) that lead to CoQ10 deficiency. As a result, DiMauro and colleagues can treat these diseases, which usually cause encephalomyopathy. "High doses of CoQ10, taken orally, make these patients better or in some cases cures them," he said.

DiMauro ended his talk with work that may be of great importance to medicine. Recent research suggests that mitochondria actually move around in all cellular tissues. This movement is essential for the balance of energy distribution within the cell. He said, "If you restore mitochondrial motility, you may be able to successfully treat a lot of diseases."

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