COSAM » News » Articles » 2018 » April » The Transporter: COSAM professor researching mitochondrial copper storage reveals biochemical 'breakthrough'

# The Transporter: COSAM professor researching mitochondrial copper storage reveals biochemical 'breakthrough'

Published: 04/06/2018

By: Jeremy Henderson

Video by: Phillip Coxwell

Come lunchtime, you probably won’t find Dr. Paul Cobine at the Chick-fil-A inside the Auburn University Student Center.

Maybe it’s the long lines. Maybe it’s his Australian palate.

“I mean, I’ll eat it,” he says. “But I don’t love it.”

That doesn’t stop him from using the restaurant’s popularity as an analogy—he’s big on analogies—for his biochemical experiments into just how your body metabolizes copper, the same stuff that’s in batteries and the bracelet he wore as a kid in Brisbane that turned his wrist green, and that’s helping to produce the energy you’re using to read this right now.

“If I went and sat outside the student center and I watched students walk out, I would say Chick-fil-A is the only restaurant that we have that serves chicken, and that’s like a genetic experiment because I’m just observing what happens,” says Cobine, an associate professor of biological sciences in Auburn University’s College of Sciences and Mathematics. “If I give a student some money and I say ‘can you go in and buy me Chick-fil-A,’ they’ll go in and buy Chick-fil-A and bring it back to me, and that's a biochemical experiment that confirms that Chick-fil-A is there.

“But if I ask a student to just buy me something with chicken, maybe they get it somewhere else. Maybe they buy me a chicken salad from Au Bon Pain, or they go to the Mediterranean Cafe and buy me something with chicken in it. So we just have to make sure we ask the right biochemical questions.”

One of the most fundamental biochemical questions about copper’s role in human health, one that Cobine has been asking since coming to Auburn in 2008, is how the copper your body needs manages to cross the finicky inner membrane of a cell’s mitochondria.

Last fall, Cobine finally found the answer.

“Mitochondria have two membranes, an outer membrane and an inner membrane, and the inner membrane has to be sealed so you can generate energy,” Cobine says. “If you let things cross the inner membrane, that basically kills the cell.”

“That means that if you want to get across the inner membrane of the mitochondria, you need a transporter.”

Cobine says that by treating the mitochondria of yeast cells (which behave almost identically to human cells) like the student center Chick-fil-A, he finally identified at least one of those unknown copper transporters. It’s a protein called SLC25A3, and, frankly, it owes him a debt of gratitude because it’s only been getting half the credit it deserves.

Scientists have known that SLC25A3 smuggles phosphates into the mitochondria, but its newly discovered cargo is an equally important ingredient in the recipe for cytochrome c oxidase, an enzyme that allows your cells to share energy.

Also, without copper, breathing is kind of pointless.

“You cannot use oxygen if you don't have copper,” Cobine says. “So (if) you lose copper, you remodel the metabolism (of a cell), and that has effects on all sorts of different diseases.”

We’re not just talking general fatigue or wiry hair.

Dr. Paul Cobine has a $1 million grant from the National Institutes of Health to continue copper transport research in his Auburn University lab with the assistance of undergraduate and graduate students. His long-term goal is to discover life-saving, targeted drug treatments to change the body’s response to excessive or deficient amounts of copper. “We expect that understanding this pathway at its base will have impact on heart health, it will have impact on diabetes, it will have impact on Alzheimer's disease, it will have impact on Parkinson's disease,” Cobine says, “because all of these diseases are related to mitochondrial function in recruiting copper, and building the copper enzymes that we need in cells is related to having good mitochondrial function.” Cobine’s findings, which were published in the Feb. 9 issue of the Journal of Biological Chemistry, may even have implications for treating some forms of Amyotrophic Lateral Sclerosis (ALS), also known as Lou Gehrig's disease. “But we really don't understand everything that copper does,” Cobine says, speaking both generally and of his revolving team of graduate and undergraduate research assistants. “We've focused on a few targets and we understand what those targets do… and for 10 years we've looked for individual components (of copper homeostasis), and in this case we found a transporter that moves copper at one of the critical steps at the end of the (copper intake) process, but we still don't understand all of the process.” He breaks out another mitochondria analogy, this time involving a place he describes as “higher on my list than Chick-fil-A.” “When you fly over a city, you know there is a Starbucks there, but you don't know where it is when you're flying over the top. You have to keep getting closer and closer,” he says. “But if I'm standing on the street corner, now I can see the Starbucks and walk in there and get a coffee. So for us, we’re trying to get on the street corner, and that takes discovery. So we have discovery-based projects and then we have some other aspects that are really working out how the espresso machine works, not just how to get to Starbucks.” He laughs. “I’m not sponsored by Starbucks.” He is, however, sponsored by the National Institute of Health (NIH). After 10 years of searching, Paul Cobine, associate professor of biological sciences in Auburn University’s College of Sciences and Mathematics, discovered how the copper your body needs for survival manages to cross the mitochondrial membrane, a discovery that could have treatment implications for heart disease, diabetes, Alzheimer's disease, Parkinson's disease, and even some forms of Amyotrophic Lateral Sclerosis (ALS), also known as Lou Gehrig's disease. Last summer, the NIH approved Cobine’s proposal for a four-year,$1 million R01 grant meant specifically to finance continued analysis into the human copper transporter in the mitochondria’s inner membrane, a project that aligns perfectly with the institute’s continued emphasis on translational “bench-to-bedside” medicine.

“We’re really heavily focused on making the discoveries to get to translational steps,” Cobine says. “This first grant set the building blocks to really get towards translational medicine.”

In other words, to start saving lives.

One of Cobine’s long-term research goals is to explore the possibility of tweaking SLC25A3 with a targeted drug treatment to render it more or less receptive to copper depending on a patient’s particular needs.

“There is a chance you can have a trackable target, this protein (SLC25A3), and to take a drug to turn this protein on and off,” Cobine says. “And I can change your response to excess or deficiency of copper, absolutely.”

Is the discovery’s translational potential enough to call it a breakthrough?

“Yeah, you can call it a breakthrough,” Cobine says. “I don't think anyone will call us on that. It’s a breakthrough because we spent a long time with the transporters and we know how (copper) gets in (the mitochondria), therefore we start to ask questions about what happens when it doesn't get in, and that's a breakthrough. It's an important result that we were super excited about, that reviewers at NIH were excited about.”

Cobine says his research also appealed to the NIH due to it being essentially “nutritional science at a cellular level.”

“All the copper we get comes from our diet,” Cobine says. “We take up small amounts every day from lots of different sources. Seafood can have really high levels.”

Cobine says copper is especially abundant in shellfish, stuff like lobster, crab, even shrimp on the barbie.

There’s also a good bit of copper in coffee.

In chicken? Not so much.

“OK,” Cobine says, “maybe that’s why I don’t eat Chick-fil-A.”