Autophagy during cardiac stress: joys and frustrations of autophagy

Abstract

The study of autophagy has been transformed by the cloning of most genes in the pathway and the introduction of GFP-LC3 as a reporter to allow visual assessment of autophagy. The field of cardiac biology is not alone in attempting to understand the implications of autophagy. The purpose of this review is to address some of the controversies and conundrums associated with the evolving studies of autophagy in the heart. Autophagy is a cellular process involving a complex orchestration of regulatory gene products as well as machinery for assembly, selective targeting, and degradation of autophagosomes and their contents. Our understanding of the role of autophagy in human disease is rapidly evolving as investigators examine the process in different tissues and different pathophysiological contexts. In the field of heart disease, autophagy has been examined in the settings of ischemia and reperfusion, preconditioning, cardiac hypertrophy, and heart failure. This review addresses the role of autophagy in cardioprotection, the balance of catabolism and anabolism, the concept of mitochondrial quality control, and the implications of impaired autophagic flux or frustrated autophagy.

Figure 1

Fates of autophagosomes and lysosomes. The phagophore forms and engulfs a target, typically a damaged organelle or protein aggregate. Under normal circumstances, the autophagosome fuses with a lysosome, which degrades the autophagosome’s inner membrane and contents (a). As digestion proceeds, the amino acids and other hydrolyzed components are exported to the cytosol (a′). Amino acid export may support glutathione biosynthesis and sulfhydryl repair by enzymes associated with the autophagolysosome membrane. Lysosomes that are unable to fuse with autophagosomes may become leaky (b). In the setting of frustrated autophagy, in which lysosomal fusion is prevented, autophagosomes may accumulate and eventually fuse with the plasma membrane (c). Autophagosome contents may be ejected from the cell as exosomes (c′).