Parkin-mediated mitochondrial quality control and cardiovascular disease

It is well established that smoking increases the risk of developing cardiovascular disease but the underlying cause of this increased susceptibility is unclear. In the heart, mitochondria are responsible for providing the beating muscle cells in the heart with energy. However, mitochondria are known to be targets for environmental pollutants, including tobacco smoke. In fact, exposure to cigarette smoke can directly impair mitochondrial function as well as their removal from the cell. This can lead to accumulation of damaged and potentially harmful mitochondria in the cell. Normally, damaged mitochondria are removed by vesicles called autophagosomes in a process known as mitochondrial autophagy or mitophagy. A protein called Parkin plays an important role in labeling dysfunctional mitochondria for degradation. However, the events and identity of proteins that direct the events downstream of Parkin are still unclear. Recent data indicate that the mitochondrial protein Fis1 plays a role in mediating removal of mitochondria downstream of Parkin. We have also discovered that Parkin can localize to the nucleus where it activates clearance of impaired mitochondria in the cytosol. This raises the important question of how Parkin regulates mitochondrial clearance in the cytosol from the nucleus. In this proposal, we will identify how nuclear Parkin activates mitochondrial degradation in the heart. Moreover, we will investigate how Fis1 regulates mitophagy at the mitochondria downstream of Parkin activation. These studies will provide important new insights into the mechanisms regulating clearance of damaged mitochondria in the heart.