Growing number of genetic disorders traced to defective mitochondria

March 08, 1992|By Thomas H. Maugh II | Thomas H. Maugh II,Los Angeles Times

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.

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