Abstract P052: Parkin Deficiency Results in Disarray of the Mitochondrial Network and Increased Susceptibility to Myocardial Infarction

Abstract

Parkin is an E3 ubiquitin ligase that was recently discovered to be involved in mitochondrial turnover via autophagy. Although Parkin has been characterized in the setting of neurodegenerative diseases, it is expressed in many other tissues including the heart. In this study, we have investigated the functional role of Parkin in the myocardium using global Parkin knockout (PKO) mice. We found that PKO mice have no overt cardiac phenotypes under normal conditions. Echocardiography showed normal left ventricular fractional shortening (38.82 3.55% for PKO vs. 39.89 1.19% for WT) and ejection fraction (68.53 4.21% for PKO vs. 71.27 1.60% for WT) at 12 weeks of age. Cardiac mitochondria isolated from PKO mice had normal respiratory rates and displayed normal coupling. Additionally, Parkin deficient mitochondria were as susceptible to mitochondrial permeability transition pore (mPTP) opening as WT mitochondria. However, mitochondria from PKO mice had higher baseline absorbance values than WT mitochondria (0.66 0.02 for PKO vs. 0.59 0.02 for WT), suggesting a smaller morphology. Ultrastructural analysis by transmission electron microscopy (TEM) confirmed a disorganized mitochondrial network with the presence of clusters of small mitochondria at 12 weeks of age in PKO hearts. At 6 months, PKO mice displayed a decline in cardiac function, and TEM revealed the presence of degenerating mitochondria. Although PKO mice have normal cardiac function at 12-weeks, they were very susceptible to stress. The PKO mice developed more severe dilated cardiomyopathies with reduced survival rates compared to WT in response to myocardial infarction. These data demonstrate that Parkin is involved in the maintenance of the mitochondrial network in the myocardium, and that Parkin deficiency exacerbates stress-induced heart failure. Given the role of Parkin in mitochondrial turnover, Parkin deficiency may result in a gradual decline of mitochondrial quality, the effects of which may surface under conditions of acute stress.