Nebraska biochemist investigates cells’ ‘power supply’ for disease clues

For University of Nebraska–Lincoln biochemist Oleh Khalimonchuk, what began as a simple research question about a single protein has morphed into an expansive quest to identify the complex causes of numerous degenerative diseases. His research could help lead to new therapies for degenerative diseases, including Lou Gehrig’s, Parkinson’s and Alzheimer’s, some cancers and other progressive illnesses.

For his earlier success, and the wide-ranging implications of that research, Khalimonchuk earned a $1.8 million National Institutes of Health Maximizing Investigators’ Research Award, a five-year grant that allows talented researchers to explore promising new directions.

Khalimonchuk, Susan J. Rosowski associate professor of biochemistry, investigates mitochondria, cells’ power supply centers. To function properly, mitochondria rely on an extensive quality-control system, a complex network of proteins and other molecules working together to maintain and repair the mitochondria.

When something goes haywire in this intricately choreographed system — proteins aren’t assembled correctly or aren’t broken down when they should be, for example — the system clogs up, triggering a chain of events leading to mitochondrial death. The accumulation of dysfunctional mitochondria leads to degenerative diseases, particularly in neurons that direct the nervous system.

“Unlike classical mitochondrial diseases linked to a particular mutation in a particular protein” — which include a long list of primarily inherited disorders — “this is the failure of a process as a whole,” Khalimonchuk said. “If you look at just one player, you might not get at the whole picture.”

His team’s goal expanded from researching the function of one mitochondrial protein, OMA1, implicated in amyotrophic lateral sclerosis, or ALS, to investigating mechanisms underlying the mitochondria’s quality-control system. The team is studying the individual roles of a variety of key proteins, how they function together to protect the mitochondria and how they interact with other parts of the cells to contribute to cell stability.

The comprehensive approach requires research techniques drawn from cellular physiology, molecular biology and mechanistic biochemistry.

“It’s a combination of three pretty diverse areas. We’re bringing them together and trying to see a holistic picture of what’s going on,” said Khalimonchuk, a member of the Nebraska Redox Biology Center and the Nebraska Center for Integrated Biomolecular Communication.

He’s collaborating with researchers at the University of California, Los Angeles; Stockholm University; and the University of Nebraska Medical Center.

As Khalimonchuk’s research expands, so does his understanding of the link between the cumulative problems of a mitochondrial quality-control system gone awry and a wide range of diseases. Now, he routinely receives calls from researchers investigating a variety of diseases, including cancer and heart disease.

“I’ve never seen myself as a cancer researcher, but we just published a paper showing that OMA1 is really important to some breast cancer progression and invasiveness,” Khalimonchuk said. “There’s more and more appreciation of mitochondria being in the middle of a lot of things that are highly physiologically important. Fewer people are referring to mitochondria as just the powerhouse of the cell. It’s so much more.”