P21‐Activated Kinase 1 is Necessary for Autophagy and Mitophagy in Cardiomyocytes

Abstract

P21‐Activated Kinase 1 (PAK1) is a serine‐threonine kinase that regulates multiple signal transduction pathways in cardiomyocytes. Despite the large body of evidence indicating a key role for PAK1 in cardiac protective signalling, the mechanisms underlying the cardioprotective effects of PAK1 remain elusive. Autophagy is a cellular process in which unwanted organelles and proteins are degraded and recycled to maintain cellular homeostasis. Mitophagy is a form of selective autophagy that eliminates damaged mitochondria from the cell via the lysosome system to control mitochondrial quality. Autophagy and mitophagy are essential for cell survival in response to starvation, but may become detrimental under other conditions. How autophagy and mitophagy are regulated for adaptation in different contexts is under intense investigation. In this study, we explored whether PAK1 regulates autophagy and mitophagy in cardiomyocytes. PAK1 was knocked down by using siRNA in H9c2 cardiac myoblasts and then the expression levels of the autophagosome marker LC3‐II were analysed by Western blot. Interestingly, downregulation of PAK1 reduced LC3‐II levels in the total cell lysates, which was not significantly increased by the lysosomal protease inhibitors pepstatin A (pepA) and E64d, suggesting that autophagy flux is reduced by downregulation of PAK1. Similarly, PAK1 knockdown reduced LC3‐II expression levels in mitochondria either in the presence or absence of pepA and E64d, indicating limited mitochondrial degradation or mitophagy in the absence of PAK1. These results were reproduced in mouse hearts lacking PAK1. Together, our results suggest that PAK1 is essential to maintain the activities of autophagy and mitophagy in cardiomyocytes in vitro and in vivo. Current studies in our lab are investigating the functional significance of autophagy and mitophagy in PAK1‐induced myocardial protection.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.