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Making of mouse marks move toward ’mitochondrial medicine’

10.02.2004


There sits in most mammalian cells what amounts to a lock-box of DNA tucked away from the bulk of genetic material. While scientists routinely cut and paste snippets of life’s blueprint to learn more about life and to treat disease, crucial DNA within cellular structures known as mitochondria has remained off-limits.



That’s beginning to change, though, thanks in part to work described in the Feb. 10 issue of the Proceedings of the National Academy of Sciences by a team from the University of Rochester Medical Center and the University of Melbourne in Australia. Scientists created a new kind of mouse by replacing the genetic material in the mitochondria of one species with that from another in a gene-swapping exercise necessary if doctors are to understand several currently untreatable human diseases.

"What we call mitochondrial medicine – how specific mitochondrial mutations and deficiencies lead to disease – didn’t even exist 15 years ago. Now the field is in its infancy. The ultimate goal is improved treatment for people with disorders that currently can’t be treated," says Carl A. Pinkert, Ph.D., of the Center for Aging and Developmental Biology at Rochester, who led the Rochester team.


The creation of the new kind of mouse is the result of several years of painstaking research by two groups of scientists working together across the globe. The work marks one of the most successful forays yet into the manipulation of DNA in the mitochondria, cellular structures that play a vital role in creating energy that power cells.

"We used an approach that had a high risk of failure, but one that will now provide exciting new insights into how mitochondrial genes may affect the way common diseases express themselves," says Ian Trounce of the University of Melbourne in Australia, whose team did much of the laboratory work.

Just as last summer’s blackout in the Northeast touched nearly every aspect of life on a societal scale, so too does trouble with the cell’s powerhouse, the mitochondrion, touch upon scores of diseases. In many diseases that become more common as people age – from infertility and diabetes to cancer, Alzheimer’s and Parkinson’s diseases – faltering mitochondria are known to play a role. And the cellular machinery is at the heart of several less common inherited diseases that affect patients more drastically at a younger age. When a cell’s mitochondria fail, the massive power loss not only injures or kills the cell but can even lead to organ failure or death.

For technical reasons, the tiny bit of genetic code carried inside the mitochondria – just 37 genes out of tens of thousands of genes overall in humans – has remained largely off limits to researchers. After all, most cells have anywhere from a few hundred to a few thousand mitochondria, compared to just one nucleus, making the nucleus the easiest and most likely target for manipulation.

"We’ve had the ability to modify genes in the nucleus for more than 20 years," says Pinkert, "but it’s technologically more challenging to change mitochondrial DNA. It’s difficult to isolate and change mitochondria in large numbers without doing major damage to the cell."

Pinkert and Trounce teamed up to tackle the problem. In the research described in the PNAS paper, they started out with 1,136 mouse embryos into which they injected stem cells containing mitochondria from another mouse species. Ultimately, after another generation of breeding, the team ended up with just six "germ-line" offspring containing only the introduced mitochondria – in effect, "transplanted" mitochondria from another species. All six were males; just three lived longer than one day.

"While we’re pleased with the success we did have, we have a lot of work ahead of us to figure out why the numbers are so low," says Pinkert, professor of pathology and laboratory medicine, who was attracted to the university three years ago by a thriving community of researchers focusing on genetic engineering and mitochondrial biology. "It’s important to work this out, if we are to develop models of disease that will allow us to create new strategies and therapies for patients with incurable metabolic diseases affected by mitochondrial function."


Much of the research in Trounce’s laboratory was done by Matthew McKenzie, a former graduate student at the University of Melbourne who is now at University College in London; in Pinkert’s laboratory in Rochester, technical associate Carolyn Cassar contributed to the project. The work was funded by the National Institutes of Health and the Medical Research Council of Australia.

Tom Rickey | EurekAlert!
Further information:
http://www.urmc.rochester.edu/

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