Growing number of genetic disorders traced to defective mitochondria


Imagine a metropolitan area with half its power plants shut down. At best, such conditions would produce a "brownout," with large sections of a city working far below optimum efficiency. At worst, traffic lights would blink out, leaving arteries clogged; the computers vital to the city's activities would go off-line; communications would be severely impaired, leaving the entire city rudderless.

Now imagine your body with three-quarters of its energy-producing factories shut down. The brain would be impaired, vision would dim, muscles would twitch spastically, the heart would weaken and the liver would be impaired.

For large numbers of people, that is precisely the situation in which they find themselves. Over the last few years, a growing number of genetic disorders have been linked to specific defects in the small intracellular particles called mitochondria, which are responsible for cellular energy production.

The discoveries have come as a surprise to many researchers who had accepted the conventional wisdom that all genetic defects reside solely in DNA in the nucleus of cells.

Moreover, the recent identification of mitochondrial defects has led to new insight into the nature of many rare diseases and, perhaps more important, opened the door to new avenues of therapy, including gene therapy.

It has also encouraged researchers to take a fresh look at a variety of more common diseases -- Alzheimer's, Parkinson's and Huntington's diseases as well as simple aging -- that may also be caused by mitochondrial defects.

"Within five years, we're going to have a tremendous impact on health because [the mitochondrion] is packed full of disease-relevant problems," said molecular biologist Douglas C. Wallace of Emory University in Atlanta. Mr. Wallace, a pioneer in the field, was the first to discover a mitochondria-linked genetic disorder.

"We're interested in anything that involves the brain, heart, kidney, muscles and eyes," because those organs are the most intensive users of energy in the body, he said. "We feel it is no coincidence that the organ systems most involved in the degenerative process of aging are also the most dependent on oxidative phosphorylation" -- the process by which mitochondria produce energy.

Mitochondria are generally considered to be descendants of primitive, air-breathing bacteria. Perhaps 5 billion years ago, they were engulfed by the progenitors of mammalian and plant cells, becoming a crucial part of those larger, more complex organisms.

Over a period of perhaps half a billion years, most of the mitochondrion's genetic material emigrated to the nucleus of the cell, leaving behind only 35 genes. The DNA -- deoxyribonucleic acid, the blueprint of life -- remaining in the mitochondrion is quite small, containing only 16,569 chemicals, called bases. The nucleus of the human cell, in contrast, contains an estimated 1 billion bases that are the blueprint for at least 100,000 genes.

Mitochondria have one other unique trait discovered by Mr. Wallace. They are transmitted to offspring only in the mother's egg, not in the father's sperm. This means they do not undergo the genetic scrambling that occurs when sperm fertilizes egg, but are passed on intact.

It is this characteristic that has yielded some dramatic findings in evolution and anthropology. It has allowed molecular geneticists, particularly Mr. Wallace and the late Allan Wilson of the University of California at Berkeley, to trace the genetic ancestry of modern humans. Those studies led to development of the highly controversial "African Eve" theory, which posits that all modern humans are descended from a single woman who lived in Africa 200,000 years ago.

Mr. Wallace has also used the technique to trace the ancestry of American Indians, reporting that 95 percent of them are descended from a small band of people who migrated across the Bering Strait 15,000 to 30,000 years ago.

It is, however, the medical role of mitochondria that is having the greatest impact, and Mr. Wallace has been among the most important players in this field. He has been studying them for more than 20 years, beginning with his graduate work at Yale University, and he was the first to link a mitochondrial defect to a disease.

"Once we had shown that mitochondrial DNA could encode genes, the obvious question was whether there were genetic diseases that might be due to mutations" in that DNA, he said. But researchers did not then have any idea of what a disease caused by a mitochondrial mutation should look like.

One way to predict the effects of a genetic defect is to study

people exposed to environmental poisons that affect the target gene. Mr. Wallace knew that many poisons, such as cyanide and rotenone, block the mitochondrial energy process. He studied the literature to see what symptoms develop among people exposed to them.

He found that they developed myoclonic epilepsy, they went blind, their muscles jerked spastically and they developed dementia and ataxia, a lack of muscular coordination. Then he looked for genetic disorders that showed these characteristics and that were maternally inherited. One obvious example was Leber's hereditary optic neuropathy, or LHON.

LHON is a rare disease that is transmitted by the mother but that affects mostly males. It produces a rapid loss of vision accompanied by abnormalities in the rhythm of the heart, typically beginning between ages 20 and 24. Starting in 1977, Mr. Wallace began collecting families with a history of the disease. In 1988, he reported that LHON was caused in most families by the mutation of a single base at position 11,778. It marked the first time a genetic disease was linked to mitochondria.

Meanwhile, other researchers had begun studying mitochondria and they found other disorders. Molecular biologist J. A. Morgan-Hughes and colleagues at the University of London found that a spectrum of other disorders involving theeye were caused by deletion of a large segment of the mitochondrial DNA.

The discovery of the link to mitochondria is making possible therapy for such disorders. Identifying the stage of energy production that is blocked by the defect, may make it possible to bypass the stage by administering a missing or defective chemical.

Some researchers, such as molecular biologist Giuseppe Attardi from the California Institute of Technology, are looking at more permanent forms of therapy. "We are developing new technologies aimed at transferring mitochondria from one cell to another, at replacing completely the mitochondrial DNA of a cell with foreign mitochondrial DNA and at introducing DNA directly into the mitochondria of a living cell."

The greatest potential interest is in the link to more common diseases, such as Parkinson's. A key element in recognizing this link was the discovery by several researchers that the drug MPTP -- which causes Parkinson-like symptoms in animals and humans -- interferes with the energy-production process in mitochondria.

Recently, Mr. Wallace and neurologist Sally Boyson of the University of Colorado have independently found that blood and muscle cells in Parkinson's victims also have an impairment in mitochondrial energy production. They have not identified a specific defect, however. Mr. Wallace believes they will eventually find similar links to Huntington's and Alzheimer's, as well as to the aging process.

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