Abstract 13717: Alternative Autophagy is the Predominant Form of Autophagy in the Heart during Energy Starvation
Autophagy is a bulk degradation process in which cytosolic proteins and organelles are sequestered into double membrane vesicles, termed autophagosomes, and degraded in lysosomes. Although autophagy is generally adaptive, excessive autophagy may induce myocardial damage. A complete understanding of the signaling mechanism involved would allow us to control autophagy during stress and achieve better cardiomyocyte (CM) survival. Recent evidence suggests that, besides conventional autophagy (CA), which utilizes ER as the membrane source for autophagosome formation, alternative autophagy (AA), which utilizes a distinct source, namely, the trans-Golgi membrane, exists. Importantly, the function of AA in the heart remains to be elucidated. We have shown that CA was selectively inhibited in atg7-KO CMs, whereas AA was inhibited in ulk1-KO CMs. Here, atg7-KO and ulk1-KO mice were used to study AA and CA, respectively. In atg7-KO mice, left ventricular (LV) function was decreased at baseline (LVEF, WT 77±5%, atg7-KO 50±6%, p<0.05), but not by starvation. In contrast, in ulk1-KO mice, LV function was adversely affected only after starvation (WT 76±5%, ulk1-KO 43±6%, p<0.05). AA is Rab9-dependent and more strongly activated during starvation than CA, as evaluated by quantitation of autophagosomes per cell by electron microscopy (AA 18.3±1.1, CA 9.8±1.6, p<0.05). Rab9 activated by starvation is recruited to Ulk1, but not Ulk2, in the AA pathway, and phosphorylation of Ulk1 Ser555 by AMP-activated protein kinase is essential for this recruitment. Suppression of CA induced marked accumulation of p62 in CMs at baseline, whereas that of AA markedly inhibited starvation-induced increases in mitophagy, and this was accompanied by accumulation of damaged mitochondria and decreases in mitochondrial membrane potential, suggesting that the maintenance of mitochondrial function during starvation critically depends upon AA. These results suggest that CA plays an important role in maintaining baseline LV function and degrading p62, whereas AA is the predominant form of autophagy during energy starvation, acting to maintain LV and mitochondrial function. Selective modulation of AA might be a novel strategy for preventing stress-induced myocardial injury.
- © 2012 by American Heart Association, Inc.