Key Discoveries Made in Metal Ion Metabolism in Mitochondria

The findings could have implications in future treatment of iron deficiency anemia, as well as Parkinson’s disease and Alzheimer’s disease.

Although scientists usually think of mitochondria as the cell’s power plant, this organelle is also the cell’s foundry where metals like iron and manganese undergo many of their metabolic transitions, says Michael D. Garrick, PhD, professor of biochemistry, an author on the study published online Jan. 9.

Previously, no pathway for their entry into mitochondria was known. Since it was obvious that iron and manganese did have to get inside, some investigators believed that they entered freely.

“We were skeptical of this concept because iron entry into cells and transit across them must be carefully regulated because iron is potentially so dangerous,” Garrick says. “Then we found the divalent metal transporter 1 (DMT1) on the outer mitochondrial membrane so we investigated to see if it played a role in import.”

Working with colleagues from Witten/Herdecke University in Germany and the U.S. Environmental Protection Agency (EPA), Jacobs School of Medicine and Biomedical Sciences researchers published data indicating that uptake of iron and manganese ions reflects DMT1 levels, showing that the two metals rely on DMT1 to cross the outer mitochondrial membrane.

The same data also suggest that another, yet to be identified route is also responsible for some iron entry.

“That’s exciting too because we have discovered something unknown to work out as well as something that is known (DMT1),” Garrick says.

Other Jacobs School authors are:

• Laura M. Garrick, PhD, research associate professor of biochemistry
• Lin Zhao, senior research support specialist in the Department of Biochemistry

Too much or too little iron in the body and brain is implicated in several diseases.

Iron deficiency is the most common disease in the world, but is often easily treated by giving people more iron in their diet.

“There is, however, a modest subset that do not respond well to being given more iron through diet,” Garrick notes. “And among them, there are some who don’t respond well to injectable iron. We are certainly improving the understanding for that group.”

Garrick notes there is also a disease known as hereditary hemochromatosis, where the body absorbs too much iron from foods and whose symptoms usually do not show up in men until their 30s or 40s and in women until they are postmenopausal.

“It is a very interesting difference,” he says. “Menstruation is the reason why women take longer to show the disease. Every month they lose iron, so it tends to keep them from overloading.”

Males are often treated by phlebotomy after they are first diagnosed. Females are too, but treatment usually starts later.

Chelation treatments, which use chemicals to help remove metals, can also be used to treat hemochromatosis and other types of iron overload. The thought is they may also be beneficial in treating Parkinson’s disease.

In 2008, the Garricks and Zhao were co-authors on a study that pointed the way toward treating Parkinson’s disease by using DMT1 as a molecular target for developing therapeutic interventions.

That paper — published in the Proceedings of the National Academy of Sciences — showed that in the parts of the brain that were affected by Parkinson’s disease, the transporter DMT1 was elevated compared to normal controls.

“And we found if we chemically induced Parkinson’s disease in rats and mice that had a genetic deficiency in DMT1, that those animals had considerable resistance to induction of the animal models,” Michael Garrick says.

That paper has been cited frequently, but recognition in terms of how to apply it to Parkinson’s disease has been limited because many scientists believe the degeneration starts in the mitochondria, Garrick notes.

“We were kind of stuck because at that time knowledge of how iron got into the mitochondria was limited,” he says. “Now we are very excited to find that DMT1 is part of the reason why iron can get into the mitochondria because it now connects to our work in 2008.”

“We now see a more complete picture because it may come back to the idea that handling iron in particular regions of the brain — even at the mitochondrial level — is dependent on DMT1.”

Clinical trials are currently underway in Australia, using the same kind of chelation approach to treat Alzheimer’s disease.

Garrick’s most recent research collaboration resulted from a bit of synchronicity.

He was working with Jerome A. Roth, PhD, professor emeritus of pharmacology and toxicology, who was investigating the idea that manganese uptake could be an indicator for the protein called parkin.

When this protein gene is mutated, people are at higher risk for Parkinson’s disease.

“So Dr. Roth and I worked together and found that parkin, which is involved in making proteins in the mitochondria turn over, did target a form of DMT1, so I’m thinking that DMT1 somehow gets to the mitochondria.”

At that same time, Andrew Ghio, MD, of the EPA contacted Garrick, noting he had been isolating mitochondria and was finding DMT1 to be a very persistent contaminant.

Garrick was also contacted by Frank Thévenod, MD, PhD, who was working with Natascha Wolff, PhD, at Witten/Herdecke University and had found some mitochondrial proteins that might be associated with DMT1.

“That was strange because DMT1 was not supposed to be in the mitochondria. It was supposed to be in the plasma membrane and in vesicles inside the cell called endosomes,” he says.

“I made the introductions so we could all work together because we all had come to the same idea and same point of interest at the same time,” Garrick adds.

The researchers began sharing their results and methods and published several papers that proved DMT1 was associated with mitochondria.

“Some scientists thought we were just seeing contamination of mitochondria with endosomes,” Garrick says. “But, the physiological pathway for metals with respect to endosomes is getting out, not getting in. Our data showed control of metals getting in, not getting out.”

“The reason we think this new paper is so important is that we’ve shown not only is the transporter there, we’ve shown it is working in the right way there,” he adds. “Now that we’ve shown function, we have connected stories and bridges for issues in terms of diseases like Parkinson’s.”

The Garricks were among three groups that first discovered DMT1 by studying a mutant rat known as the Belgrade rat and showing that it played an important role in iron entry into cells, plus iron exit from the endosome on its route toward the mitochondria.

“We’ve come back to a place where it turns out that DMT1 is probably going to be very important,” Michael Garrick says.

“We’ve been working on it for 20 years. We were there at the beginning and have been there ever since.”