skip navigation
Environmental Factor, October 2015

Whole Issue PDF
This issue's PDF is still being created and should be available 3-5 business days after the first of the month. Please check back in a few days.

Mutations in mitochondrial DNA lead to disease

By Robin Arnette

Doug Wallace

Wallace is the Michael and Charles Barnett Endowed Chair in Pediatric Mitochondrial Medicine and Metabolic Disease, director of the Center for Mitochondrial and Epigenomic Medicine at the Children’s Hospital of Philadelphia Research Institute, and professor of pathology and laboratory medicine at the University of Pennsylvania Perelman School of Medicine. (Photo courtesy of Steve McCaw)

Bill Copeland

"The NIEHS was very fortunate to host Dr. Wallace's visit," Copeland said. "It was refreshing to hear his view of the importance of cellular energy in health and disease processes." (Photo courtesy of Steve McCaw)

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.

Download Media Player:

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."

World migrations in 2013

Wallace and his team reconstructed the migration of women around the globe by examining the mtDNA variation that exists in the human population. According to his studies, women from the Khoisan people of the Kalahari Desert are the original carriers of mtDNAs (L0), with several variants branching off into other African populations. Interestingly, the M and N variants present in Ethiopia were the only 2 mtDNAs that colonized the rest of the world. (Note: MYR, million years; YBP, years before present) (Photo courtesy of Douglas Wallace)

"DeMayo named deputy chief ..." - previous story Previous story Next story next story - "Advisory committee on alternatives ..."
October 2015 Cover Page

Back to top Back to top