Mitochondrial Disease Meeting Highlights New Directions

by Quest Staff on September 1, 2008 - 6:53pm

QUEST Vol. 15, No. 5

The mitochondria, complex bodies inside cells that have their own DNA, are the centers for cellular energy production. When they malfunction, either because of flaws in their own DNA or flaws in DNA in the cell’s nucleus that affect them, the energy deficit can be devastating, particularly for the functioning of the muscles and nervous system.

At a mitochondrial “summit” meeting jointly sponsored by MDA and the Friedreich’s Ataxia Research Alliance, and held in Phoenix May 20-21, some tantalizing new findings to treat mitochondrial myopathies were presented.

Friedreich’s ataxia (FA), although not often classified as a mitochondrial disease, is in fact a disease of the peripheral nervous system and heart for which the underlying cause is a deficiency of a mitochondrial protein.

TAT delivers proteins to mitochondria

Mark Payne, from Indiana University School of Medicine in Indianapolis, described his experiments with the TAT (“transactivator of transcription”) protein, which can carry molecular cargo across biological membranes, including those surrounding each mitochondrion. He said his group is the first to make this strategy work in an animal.

They applied the new technology to the restoration of the frataxin protein into the mitochondria. (Frataxin is deficient in FA.)

Frataxin, like many other mitochondrial proteins, is made from a gene in a cell’s nucleus. The cell “knows” it goes to the mitochondria because of a molecular tag that indicates its destination. “It’s sort of a zip code for the protein,” Payne said.

When frataxin, with its tag, was attached to TAT and injected into the abdomens of mice born without this protein, the compound crossed various membranes, including those around the mitochondria, where it was retained and increased the life span of the mice from an average of 27 days to an average of 39 days.

The strategy has promise for the delivery of many other proteins that have to cross mitochondrial and other membranes.

Blood stem cells provide needed enzyme in MNGIE

Also of note at the meeting was a talk by MDA grantee Michio Hirano, from Columbia University in New York, who described a promising experimental treatment for the mitochondrial disease known as MNGIE (mitochondrial neurogastrointestinal encephalomyopathy), which is due to a defect in an enzyme made from a gene in the cell’s nucleus.

The enzyme, thymidine phosphorylase, normally breaks down thymidine. Without it, thymidine accumulates in the blood, which has an indirect but highly toxic effect on mitochondria.

Hirano and colleagues have been experimenting with blood stem-cell infusions from healthy donors into patients with MNGIE, speculating that the new cells would restore the needed enzyme, which would eliminate the toxic metabolic product.

Hirano described a 30-year-old woman with MNGIE with severe gastrointestinal dysfunction causing weight loss, weakness, peripheral nerve abnormalities, lack of energy and abdominal pain. To supplement her meager food intake, she received 2,400 calories daily by intravenous infusions. Two-and-a-half years after receiving blood stem cells from a donor, he reported, she has shown a remarkable correction of the biochemical abnormalities in her blood, has gained weight, has less abdominal pain, can eat normally, does not require intravenous feeding and can run and jump.

Normally (left), the thymidine phosphorylase enzyme breaks down thymidine, keeping mitochondria healthy. In MNGIE (right), a mutation in the gene for this enzyme keeps it from being produced, allowing toxic levels of thymidine to build up and damage mitochondria.
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