Subcellular Regulation of Autophagic Flux in Cardiomyocytes and the Heart

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DESCRIPTION (provided by applicant): Autophagy is the process whereby cytoplasmic components, including organelles, are engulfed by a double membrane structure and targeted for destruction by fusion with a lysosome. This physiological process occurs as part of normal housekeeping, as a way to recycle proteins and as a response to injury. It can be used as a mechanism to induce cell death when apoptosis is blocked but more interestingly, also prevents apoptosis through an unknown mechanism. Autophagy plays an important role in the heart in response to myocardial ischemia and reperfusion, hypertrophy and heart failure. We hypothesize that autophagy is a selective rather than nonspecific process and that damaged mitochondria may be the preferred target for autophagy in one circumstance while endoplasmic reticulum, contractile elements or aggresomes may be selective targets in other settings. We propose to test this by using reporters of autophagic uptake that are restricted to a single subcellular compartment. We will investigate specific physiologic stimuli that may upregulate autophagy and use these reporters to determine which conditions induce selective targeting of individual compartments. Since relatively little is known about the differences in the autophagic processes leading to cell death compared to promoting cell survival, we will investigate autophagic stimuli and the roles of selective autophagic removal of compartments in determining cell death. These proposed activities will 1) provide much needed tools to study the autophagy pathway 2) determine the selective capacity of autophagy in removing damaged cellular components under conditons such as ischemia/reperfusion, starvation and organelle damage and 3) demonstrate the relationship between these processes and cardiomyocyte survival. Autophagy, the process by which cells recycle damaged organelles and cytoplasmic components, plays an integral role in cardioprotection following myocardial infarction and may alter the development of heart failure by promoting cell survival. It is important to thoroughly understand the role of autophagy in the heart and the complex molecular pathways that regulate this process as it may lead to the development of novel therapeutic agents for treatment of coronary artery disease and heart failure.