Imagine having your car towed to the shop for unknown repairs, and watching a trusted local mechanic pop the hood and take a ponderous look inside. Minutes pass as he runs a gauntlet of software and fluid checks, and pokes around the hoses, belts and cords. He finally emerges with a strange-looking broken part in his hand.
“This might be the culprit,” he says. “But honestly, I’ve never seen a part like this before.”
Dave Pagliarini can relate to this feeling. As an associate professor of biochemistry, Pagliarini studies engines of an entirely different stripe—engines called mitochondria, which power biological life. These tiny, grain-shaped organelles reside inside virtually every plant and animal cell type, and perform the critical task of breaking down nutritional elements and converting them into energy for basic cellular function.
The right man for the job: David Pagliarini is leading the charge to foster collaboration and advancement among metabolism researchers across campus. Photo: David Nevala.
Pagliarini says that only two decades ago, science had all but closed the book on mitochondria, assuming all the important pathways and processes had been worked out. But lately, the field of mitochondrial research is being defined more by how little we know about their complex role in maintaining health—and their connection to literally hundreds of diseases when things go haywire.
As one measure of this great unknown, Pagliarini points to “orphan proteins”—more than 300 proteins associated with mitochondria that still have no defined function. In a mechanical sense, they are parts without a defined purpose. A big focus of Pagliarini’s research today is linking these orphan proteins to their rightful homes and understanding how their dysfunction affects disease.
But as a University of California, San Diego graduate student in the early 2000s, Pagliarini didn’t have mitochondria anywhere on his radar. He was studying a group of proteins involved in cell signaling when he made an entirely unexpected discovery: One of those proteins traced directly back to mitochondria. Later, as a postdoctoral researcher at Harvard Medical School, he produced a seminal work on identifying all mitochondrial proteins, published in the journal Cell in 2008, which has been cited more than 1,000 times.
“That set off a whole new direction for me,” Pagliarini says. “To find something that no one expected to be there made me fascinated about what else we didn’t know. And as we began to realize there was a lot we didn’t know, I just saw a lot of opportunity.
“That’s when I became a ‘mitochondriac,’” he says with a laugh.
Mitochondria consume about 95 percent of the oxygen we breathe to make a chemical substance called ATP—or adenosine triphosphate—that is the “chemical energy currency” our bodies use to power cellular processes.
But “cellular powerhouse” is only one important function of mitochondria. For example, mitochondria are recognized as key players in cellular signaling and cellular apoptosis, or programmed cell death. They also appear to play a significant but not fully understood role in certain cancers, Parkinson’s, Alzheimer’s, diabetes and autism. And their composition varies markedly across tissue types—meaning there are many places where things can go awry.
“There are many different ways to break machines like mitochondria,” he says.
The Pagliarini lab focuses on establishing a fundamental understanding of mitochondria, with the recognition that we can’t cure what we don’t understand. There is a dire need to develop therapies for people who suffer from mitochondrial disease, which occur in 1 in 4,000 people and can be fatal or have devastating health consequences.
In Pagliarini’s lab: Postdoctoral associate Natalie Niemi prepares yeast samples for metabolic analysis. Photo: David Nevala.
“There are so many diseases that are rare individually, but collectively affect lots of people,” Pagliarini says. “These are heartbreaking diseases for which we can only offer palliative care. I believe that in the long term, a fundamental understanding of how the mitochondria work will give us an opportunity for real cures.”
Dr. Philip Yeske, the science and alliance officer of the United Mitochondrial Disease Foundation (UMDF), agrees that mitochondrial diseases pose unique medical challenges. There are about 250 mutations on both the nuclear and mitochondrial DNA that can lead to disease. And any given mutation can manifest itself in entirely different symptoms—heart-related problems for one patient and neurological disorders for another.
“The standard of care for patients affected by mitochondrial disease right now is treatment with vitamins and supplements,” Yeske says. “There are no licensed therapies available. And with the vitamin and supplement care, we don’t know enough about them to even say they are effective.”
But thanks to a rapidly growing body of research, prospects are looking more positive. A decade ago, therapeutics would have been a “pipe dream,” Yeske says, but in 2016, four companies are in active clinical trials for mitochondrial disease therapeutics, and many more are in preclinical planning.
“We’re at the beginning of an era of mitochondrial medicine, and that’s really exciting,” Yeske says.
At UW-Madison, Pagliarini’s young career has been on overdrive. Only months after arriving at CALS in 2009, his lab was jump-started by major research support from the federal economic stimulus program, which funded only the top 2 percent of proposals that year. Shortly after, he was named a Searle scholar and helped craft a major grant related to the NIH National Protein Structure Initiative, which further put his work on mitochondrial proteins in the national spotlight.
The past academic year could arguably be Pagliarini’s most exciting yet. In fall 2015, Pagliarini was named director of the Morgridge Institute for Research Metabolism Theme, which aims to establish a vibrant group of researchers focused on the basic underpinnings of metabolism. The Morgridge Institute is poised to make strategic hires and investments under Pagliarini’s direction that will help UW–Madison grow and thrive in this field.
This year, Pagliarini experienced a pinnacle of recognition as the recipient of a Presidential Early Career Award, given to top scientists and engineers in an array of fields. He and 100 national honorees visited the White House in May, touring its opulent historical meeting rooms and chatting with President Barack Obama and special guest Jeff Bezos, the CEO of Amazon.
“It was pretty special,” Pagliarini says. “What really stood out about it was how optimistic and forward-looking it was. You hear so much in science now about problems with funding or rising competition from other countries. This was very much about celebrating what we can do with U.S.-driven scientific research.”
Brad Schwartz, CEO of the Morgridge Institute, started getting indications early that Pagliarini was the right person to lead the campus-wide initiative. While meeting with potential recruits in 2014 from leading research universities, Schwartz was struck by how frequently Pagliarini’s name came up in conversations.
“After a very thorough national search, it only reinforced that Dave had the innovative thinking and creativity we were looking for,” Schwartz says. “He has all the personal characteristics needed to help build stronger community around as many as 500 scientists working on some aspect of metabolism in Madison.”
Continue reading this story in the Fall 2016 issue of Grow magazine.
Banner photo: Close-up of a mitochondrion. Mitochondria provide cells with energy by oxidizing sugar and fat—and perform many functions that are just now being discovered. Photo: Keith Porter/Science Source