Mutations in mitochondrial DNA lead to disease
By Robin Arnette
Whether you plug an appliance into a wall outlet, load batteries into an electronic device, or place a solar-powered tool on a windowsill, most of the machines that make life easier in the modern world need energy. The human body is no different in requiring energy for its processes.
One prominent researcher argues that many of the diseases that afflict mankind develop, not as a result of dysfunction in a particular organ, but due to defects in the mitochondria, which are the hundreds of power-producing organelles present in each cell.
Douglas Wallace, Ph.D., specializes in mitochondrial genetics and believes that Alzheimer’s disease, cancer, inflammatory illnesses, neuropsychiatric conditions, and other maladies could result from mutations in genes for mitochondrial energy production. Such genes are present in both nuclear DNA and mitochondrial DNA (mtDNA).
He discussed his theory during a Sept. 15 NIEHS Distinguished Lecture Seminar Series talk titled, "Mitochondrial-Cellular Interactions and Pathophysiology of Disease." Bill Copeland, Ph.D., chief of the NIEHS Genome Integrity and Structural Biology Laboratory and a proponent of studying mitochondria for the origins of disease, hosted the seminar.
When the power plant goes awry
Wallace said that mtDNA is similar to nuclear DNA, in that both are constantly making more copies of themselves, a process known as replication. Because replication can be error-prone, damage or mutations may accumulate in mtDNA, leading to problems when it is time for the cell to divide during mitosis.
"You end up with something called heteroplasmy, which is when you get cells with normal and mutant mtDNAs," Wallace said. When the cell divides, he explained, the mutant and normal mtDNAs are randomly distributed into the daughter cells, so that a person can have cells and tissues with different proportions of mutant and normal DNAs.
As the percentage of mutant mtDNAs increases in a cell, the cell’s energy output decreases. According to Wallace, when it drops below a minimum threshold for a given organ, that organ begins to malfunction. As an example, he mentioned that for mutations in one particular protein synthesis gene, 10 to 30 percent heteroplasmy is associated with diabetes and autism, 50 to 90 percent leads to certain neuromuscular diseases, and 100 percent kills an infant, in Leigh’s syndrome.
Wallace’s group and others have documented hundreds of mtDNA mutations and have said that toxins from the environment can also inhibit mitochondrial function. These chemical compounds can impair mtDNA maintenance, resulting in more damage and further erosion of cellular energy. He and others suggest mitochondrial decline could be the molecular basis of aging.
Energy helped colonize the world
Although there appears to be a direct relationship among mutations in mtDNA, changes in cellular energy levels, and disease, Wallace said not all modifications contribute to illness. After he and his team traveled the world to obtain consent and blood samples from indigenous people, they noted that subtle changes in energetic efficiency allowed humans to adapt to new environments. Because mtDNA is only inherited from the mother, the team was able to compare sequence differences between mtDNAs of different groups and reconstruct the origins and ancient migrations of women.
The research found that the original mtDNAs, labelled L0, have the fewest mutations and belong to the Khoisan people of the Kalahari Desert in Africa. L0 mitochondria are the most efficient, meaning that nearly all of the calories ingested go toward making functional energy, with the body generating very little heat. As people moved north, they accumulated functional mutations that made their mitochondria less efficient. They had to eat more calories for the same amount of metabolism, but they generated more heat, which was advantageous in colder climates.
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Wallace maintains that these variants allowed humans to colonize the world, but they also predisposed people to disease. "In one European lineage, a single A to G nucleotide switch in a particular gene is found in 3 percent of Alzheimer’s disease and 5 percent of Parkinson’s disease, but less than 0.4 percent of the general population," Wallace said. "This substitution happened about 10,000 years ago, but it predisposes some with this lineage to developing late-onset neurological disease."