Hossein Ardehali, MD, PhD, professor of Medicine in the Division of Cardiology and of Pharmacology, leads a lab committed to investigating the role of mitochondria and cellular metabolism in cardiovascular disease. As director of the Center for Molecular Cardiology at the Feinberg Cardiovascular Research Institute (FCVRI), he also supports overall research efforts in molecular cardiology throughout the medical school.
Ardhali earned his MD/PhD from Vanderbilt University School of Medicine and completed a residency and fellowship at Johns Hopkins Hospital, before joining Northwestern in 2005. He is a member of the Robert H. Lurie Comprehensive Cancer Center of Northwestern University.
What are your research interests?
The major focus of our research is on cellular and mitochondrial iron homeostasis and the role of mRNA-binding proteins in diabetes and cardiovascular disease. Iron is an essential molecule for cellular physiology; however, excess iron (especially in the mitochondria) can lead to cell damage, due to excess oxidative stress. Thus, iron levels are tightly regulated inside the cell. Our group has identified the mechanism of iron export out of the mitochondria and novel regulators of cellular iron.
Additionally, we have shown that mitochondrial iron accumulation is detrimental in cardiovascular disease, and that a reduction in mitochondrial iron protects against multiple forms of cardiomyopathy, including chemotoxicity and ischemic damage.
For the second project, we are focusing on the tandem zinc-finger mRNA-binding family of proteins. Our studies have demonstrated that a member of this family, tristetraprolin (TTP), regulates hepatic response to insulin. Our data demonstrate that TTP is involved in late effects of insulin (i.e., six to eight hours after insulin release) in the liver and regulates lipid uptake into the liver to prevent excessive lipid accumulation. We also have evidence that TTP regulates glucose and branched-chain amino acid metabolism.
What is the ultimate goal of your research?
As a physician-scientist, it is my ultimate goal to translate our findings into clinical practice. We are currently conducting studies to use specific iron chelators that can reduce mitochondrial iron as a treatment for heart failure and ischemic heart disease. This requires generation of novel iron chelators that can penetrate the mitochondria, which we are currently working on. We are also hoping that by targeting TTP, we can fine-tune some of the effects of insulin in the liver, which may lead to novel treatments for diabetes.
How did you become interested in this area of research?
When I was a cardiology fellow at Johns Hopkins, I was working on a mitochondrial potassium channel. One member of the protein complex I was working on belonged to a family of proteins that have been shown to regulate mitochondrial iron. I told my mentor that I believed that this protein regulates mitochondrial iron, and I asked him if I could continue to characterize this protein as an independent investigator. He agreed with the plan, and the more I worked on iron, the more questions arose and the more exciting the field became to our group.
For the project on the mRNA-binding proteins, I owe it to one of my former students in the Medical Scientist Training Program (MSTP), Marina Bayeva, MD, PhD. While looking for alternative pathways that regulate cellular iron, she discovered that TTP gets activated in response to low iron and drives iron conservation within the cell. Through our conversations with investigators who work on the yeast-homolog of these proteins, we then became interested in how these proteins mediate their effects on metabolism and mitochondrial function.
Where have you recently published papers?
I ask my lab members to shoot for high-impact journals and to publish in journals that are targeted to the general audience (i.e., not just cardiology journals).
Our recent papers have been published in Cell Metabolism, Nature Communications, Journal of Clinical Investigation, EMBO Molecular Medicine, and Proceedings of the National Academy of Sciences.
What do you enjoy about teaching/mentoring young scientists in the lab?
I am very fortunate to have the opportunity to work with a group of extremely bright students, postdoctoral fellows and technicians in the lab. When they join the lab, I try my best to guide them and teach them how to do science.
When I am confident that they are ready to become independent, I let them do the things they enjoy doing, and this is the stage that I start learning tremendously from them. Generally, most people in my lab get to that stage about one and a half to two years after starting in the lab.
What is most gratifying to me is when they become successful and make important scientific discoveries on their own. This tells me I have prepared them for their own independent careers.
How does your research advance medical science and knowledge?
Biomedical research is the driving force in advancing our understanding of human health and disease. The impact of biomedical research is not limited to its reduction of the burden of human disease; it also plays a significant role in the U.S. economy, the training of future physicians and scientists, and the creation of new technologies and jobs.
Thus, at a time when there are discussions about reducing biomedical research funds, it’s important that we talk to our elected officials and emphasize to them that biomedical research is a critical component of American healthcare and the economy.