UC San Diego

The lysosomal degradation of misfolded proteins and dysfunctional organelles by the process of autophagy is critical for the maintenance of heart function. Parkin is an E3 ubiquitin ligase that participates in the removal of dysfunctional mitochondria via mitochondrial autophagy (mitophagy). Mutations in the PARK2 gene encoding Parkin are linked to juvenile recessive forms of Parkinson's disease. As a result, Parkin has mainly been studied in the context of neurodegenerative disease. However, Parkin is highly expressed in the heart, an organ that is rich in mitochondria and therefore susceptible to cell death caused by mitochondrial dysfunction. The functional role of Parkin in the heart remains largely unexplored. While characterizing the cardiac phenotype of Parkin knockout (Parkin-/-) mice, I found that Parkin was not essential for the normal turnover of mitochondria in the heart. Instead, I determined that Parkin was a critical component in the response to acute cardiac stress such as a myocardial infarction (MI). I found that Parkin supported the adaption to MI stress by enabling mitophagy in the infarction border zone for the clearance of dysfunctional mitochondria. Further, I determined that the mechanism of Parkin function in the heart was dependent on the activity of the mitochondrial fission protein Drp1, but did not depend on the mitochondrial kinase PINK1. Lastly, I investigated the role of Parkin in response to chronic pathophysiological stresses that cause cardiac hypertrophy. Parkin-/- mice had impairments in both physiological hypertrophy in response to exercise and pathological hypertrophy in response to transverse aortic constriction. In contrast, cardiac-specific Parkin transgenic mice (Parkin-TG) had a normal hypertrophic response to pressure overload, but rapidly developed heart failure. Thus, I conclude that Parkin is crucial for the development of cardiac hypertrophy in response to chronic stress in addition to its role in adaptation to acute stress. Parkin may be a viable therapeutic target to promote autophagic clearance of dysfunctional mitochondria, but excessive Parkin may be detrimental and can result in a predisposition to heart failure in response to chronic stress