Autophagy in Health and Disease

Autophagy is a conserved homeostatic mechanism used by many cells and organisms to eliminate unwanted and dysfunctional proteins and organelles. It is also used to recycle cellular components and molecules to generate energy during starvation. The Boudina lab has extensively studied this pathway in the context of diabetic cardiomyopathy and diet-induced obesity. One of our ongoing projects is investigating the role of liver autophagy in the maintenance of blood glucose levels during fasting. Using conditional knockout of the autophagy machinery (Atg3 and Atg16L), we examine the mechanisms linking autophagy and glucose release from the liver. The goal is to manipulate liver autophagy to regulate blood glucose levels in the setting of type 2 diabetes.

Along this line of research, we recently identified the autophagy adaptor protein p62 or sequestosome 1 as a key player in redox homeostasis in the heart. The absence of p62 in the heart results in Nrf2 degradation, increased ROS, and age-associated cardiac dysfunction. Similarly, we found that p62 deficiency in the heart reduced HIF-1a stabilization and exacerbated cardiac dysfunction during hypoxia. We seek to understand how p62 stabilizes Nrf2 and HIF-1a in the heart, as this information could be used to develop p62 mimetics for the treatment of ischemic heart disease.