USA researchers awarded $1 million in grants to study replication of mitochondrial DNA

By Lindsay Lyle
lalyle@health.southalabama.edu

In order to treat mitochondrial diseases, scientists first must understand how mitochondrial DNA (mtDNA) makes copies of itself. With that goal, the U.S. Department of Defense awarded researchers at the University of South Alabama College of Medicine two grants, totaling more than $1.07 million, to study the replication of mitochondrial DNA.

Mikhail Alexeyev, Ph.D., professor of physiology and cell biology at the USA College of Medicine, is principal investigator of the two funded studies. Natalya Kozhukhar, a research technologist, and Viktoriya Pastukh, a research assistant, are working with Alexeyev on the projects.

The mitochondria’s main function is to produce energy for the cell. Mitochondrial diseases are a group of inherited genetic disorders that can cause a wide range of health concerns.

“When we think of inheritance, we first think of chromosomes,” Alexeyev said. Chromosomes are located in the nucleus of each cell and are present in 23 pairs. In each pair, one chromosome is received from the mother and one from the father. “For a long time, it was thought that these 46 chromosomes determine our genetic makeup. That was until mitochondrial DNA was discovered 60 years ago.”

mtDNA molecules are small and circular compared to nuclear chromosomes, which are linear. Unlike nuclear chromosomes, they are present in hundreds to thousands of copies per cell; and different tissues in the body contain different amounts of mtDNA. Moreover, mtDNA is inherited exclusively from the mother.

“In 1987, scientists discovered that mutations in mtDNA can result in incurable, devastating and often lethal diseases, for which we still do not have effective treatments,” Alexeyev said.

The effects of these mutations are most evident in organs and tissues that require a lot of energy, such as the heart, brain and muscles. Symptoms can include fatigue and weakness, problems with movement, cognitive disabilities, vision and hearing loss, diabetes, heart disease, kidney and liver failure.

Scientists measure the extent of their understanding of a particular biological process by their ability to reproduce it. “We have a pretty good handle on nuclear chromosomes and even were able to create a bacterium using a made-from-scratch chromosome,” Alexeyev said. “However, when it comes to mtDNA, our understanding of its replication remains rudimentary. We are not able to replicate mtDNA in a test tube; and even though most enzymes are interchangeable between humans and mice, mouse cells are unable to replicate human mtDNA and vice versa, and we do not know why.”

Alexeyev’s lab has succeeded in generating human/mouse hybrid cells that maintained human mtDNA for more than a year. Although the approaches are different, the aim of both funded studies is similar: to find out why mouse nonhybrid cells do not replicate human mtDNA.

“Our goal is to reconstitute human mitochondrial function in mice. Such ‘humanized’ mice would become an invaluable resource for the development of drugs to treat mitochondrial disease and to study mitochondrial disease in mice,” Alexeyev said. “Currently, such mice are not available, which makes mitochondrial diseases extremely difficult to study.”